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Franklin CE, Achtyes E, Altinay M, Bailey K, Bhati MT, Carr BR, Conroy SK, Husain MM, Khurshid KA, Lencz T, McDonald WM, Mickey BJ, Murrough J, Nestor S, Nickl-Jockschat T, Nikayin S, Reeves K, Reti IM, Selek S, Sanacora G, Trapp NT, Viswanath B, Wright JH, Sullivan P, Zandi PP, Potash JB. The genetics of severe depression. Mol Psychiatry 2025; 30:1117-1126. [PMID: 39406997 DOI: 10.1038/s41380-024-02731-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 08/21/2024] [Accepted: 08/27/2024] [Indexed: 02/20/2025]
Abstract
Genome-wide association studies (GWASs) of major depressive disorder (MDD) have recently achieved extremely large sample sizes and yielded substantial numbers of genome-wide significant loci. Because of the approach to ascertainment and assessment in many of these studies, some of these loci appear to be associated with dysphoria rather than with MDD, potentially decreasing the clinical relevance of the findings. An alternative approach to MDD GWAS is to focus on the most severe forms of MDD, with the hope that this will enrich for loci of larger effect, rendering their identification plausible, and providing potentially more clinically actionable findings. Here we review the genetics of severe depression by using clinical markers of severity including: age of onset, recurrence, degree of impairment, and treatment with ECT. There is evidence for increased family-based and Single Nucleotide Polymorphism (SNP)-based estimates of heritability in recurrent and early-onset illness as well as severe functional impariment. GWAS have been performed looking at severe forms of MDD and a few genome-wide loci have been identified. Several whole exome sequencing studies have also been performed, identifying associated rare variants. Although these findings have not yet been rigorously replicated, the elevated heritability seen in severe MDD phenotypes suggests the value of pursuing additional genome-wide interrogation of samples from this population. The challenge now is generating a cohort of adequate size with consistent phenotyping that will allow for careful and robust classifications and distinctions to be made. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ics consortium.
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Affiliation(s)
- Clio E Franklin
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Eric Achtyes
- Department of Psychiatry, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
| | - Murat Altinay
- Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, OH, USA
| | - Kala Bailey
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Mahendra T Bhati
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Brent R Carr
- Department of Psychiatry, University of Florida Health, Gainsville, FL, USA
| | - Susan K Conroy
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Mustafa M Husain
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Khurshid A Khurshid
- Department of Psychiatry, University of Massachusetts Memorial Health, Worchester, MA, USA
| | - Todd Lencz
- Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Glen Oaks, NY, USA
| | - William M McDonald
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Brian J Mickey
- Department of Psychiatry, Huntsman Mental Health Institute, University of Utah Health School of Medicine, Salt Lake City, UT, USA
| | - James Murrough
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- VISN 2 Mental Illness Research, Education, and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA
| | - Sean Nestor
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Thomas Nickl-Jockschat
- Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany
- German Center for Mental Health (DZPG), partner site Halle-Jena-Magdeburg, Magdeburg, Germany
- Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Halle-Jena-Magdeburg, Magdeburg, Germany
| | - Sina Nikayin
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Kevin Reeves
- Department of Psychiatry and Behavioral Health, Ohio State University College of Medicine, Columbus, OH, USA
| | - Irving M Reti
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Salih Selek
- Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Care Center at Houston, Houston, TX, USA
| | - Gerard Sanacora
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Nicholas T Trapp
- Department of Psychiatry, Carver College of Medicine, and Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
| | - Biju Viswanath
- Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Jesse H Wright
- Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY, USA
| | - Patrick Sullivan
- Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Peter P Zandi
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - James B Potash
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Liu C, Gershon ES. Endophenotype 2.0: updated definitions and criteria for endophenotypes of psychiatric disorders, incorporating new technologies and findings. Transl Psychiatry 2024; 14:502. [PMID: 39719446 PMCID: PMC11668880 DOI: 10.1038/s41398-024-03195-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 11/28/2024] [Accepted: 12/05/2024] [Indexed: 12/26/2024] Open
Abstract
Recent genetic studies have linked numerous loci to psychiatric disorders. However, the biological pathways that connect these genetic associations to psychiatric disorders' specific pathophysiological processes are largely unclear. Endophenotypes, first defined over five decades ago, are heritable traits, independent of disease state that are associated with a disease, encompassing a broad range of neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, and neuropsychological characteristics. Considering the advancements in genetics and genomics over recent decades, we propose a revised definition of endophenotypes as 'genetically influenced phenotypes linked to disease or treatment characteristics and their related events.' We also updated endophenotype criteria to include (1) reliable measurement, (2) association with the disease or its related events, and (3) genetic mediation. 'Genetic mediation' is introduced to differentiate between causality and pleiotropic effects and allows non-linear relationships. Furthermore, this updated Endophenotype 2.0 framework expands to encompass genetically regulated responses to disease-related factors, including environmental risks, illness progression, treatment responses, and resilience phenotypes, which may be state-dependent. This broadened definition paves the way for developing new endophenotypes crucial for genetic analyses in psychiatric disorders. Integrating genetics, genomics, and diverse endophenotypes into multi-dimensional mechanistic models is vital for advancing our understanding of psychiatric disorders. Crucially, elucidating the biological underpinnings of endophenotypes will enhance our grasp of psychiatric genetics, thereby improving disease risk prediction and treatment approaches.
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Affiliation(s)
- Chunyu Liu
- Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.
- School of Life Sciences, Central South University, Changsha, China.
| | - Elliot S Gershon
- Departments of Psychiatry and Human Genetics, The University of Chicago, Chicago, IL, USA.
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Kawikova I, Hakenova K, Lebedeva M, Kleteckova L, Jakob L, Spicka V, Wen L, Spaniel F, Vales K. Perinatal Hypoxia and Immune System Activation in Schizophrenia Pathogenesis: Critical Considerations During COVID-19 Pandemic. Physiol Res 2024; 73:S615-S639. [PMID: 39589306 PMCID: PMC11627263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 10/01/2024] [Indexed: 11/27/2024] Open
Abstract
Schizophrenia, a severe psychiatric, neurodevelopmental disorder affecting about 0.29-1 % of the global population, is characterized by hallucinations, delusions, cognitive impairments, disorganized thoughts and speech, leading to significant social withdrawal and emotional blunting. During the 1980s, considerations about diseases that result from complex interactions of genetic background and environmental factors started to appear. One of the critical times of vulnerability is the perinatal period. Concerning schizophrenia, obstetric complications that are associated with hypoxia of the fetus or neonate were identified as a risk. Also, maternal infections during pregnancy were linked to schizophrenia by epidemiological, serologic and genetic studies. Research efforts then led to the development of experimental models testing the impact of perinatal hypoxia or maternal immune activation on neurodevelopmental disorders. These perinatal factors are usually studied separately, but given that the models are now validated, it is feasible to investigate both factors together. Inclusion of additional factors, such as metabolic disturbances or chronic stress, may need to be considered also. Understanding the interplay of perinatal factors in schizophrenia's etiology is crucial for developing targeted prevention and therapeutic strategies.
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Affiliation(s)
- I Kawikova
- Department of Medicine, Yale University, New Haven, CT, USA,
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Rosete C, Ciernia AV. The Two Faces of HDAC3: Neuroinflammation in Disease and Neuroprotection in Recovery. Epigenomics 2024; 16:1373-1388. [PMID: 39513228 PMCID: PMC11728336 DOI: 10.1080/17501911.2024.2419357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 10/17/2024] [Indexed: 11/15/2024] Open
Abstract
Histone deacetylase 3 (HDAC3) is a critical regulator of gene expression, influencing a variety of cellular processes in the central nervous system. As such, dysfunction of this enzyme may serve as a key driver in the pathophysiology of various neuropsychiatric disorders and neurodegenerative diseases. HDAC3 plays a crucial role in regulating neuroinflammation, and is now widely recognized as a major contributor to neurological conditions, as well as in promoting neuroprotective recovery following brain injury, hemorrhage and stroke. Emerging evidence suggests that pharmacological inhibition of HDAC3 can mitigate behavioral and neuroimmune deficits in various brain diseases and disorders, offering a promising therapeutic strategy. Understanding HDAC3 in the healthy brain lays the necessary foundation to define and resolve its dysfunction in a disease state. This review explores the mechanisms of HDAC3 in various cell types and its involvement in disease pathology, emphasizing the potential of HDAC3 inhibition to address neuroimmune, gene expression and behavioral deficits in a range of neurodegenerative and neuropsychiatric conditions.
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Affiliation(s)
- Cal Rosete
- Djavad Mowafaghian Centre for Brain Health, Vancouver, V6T 1Z3, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, V6T 2A1, Canada
| | - Annie Vogel Ciernia
- Djavad Mowafaghian Centre for Brain Health, Vancouver, V6T 1Z3, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, V6T 2A1, Canada
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Greve AN, Hemager N, Mortensen EL, Gantriis DL, Burton BK, Ellersgaard D, Plessen KJ, Thorup AAE, Jepsen JRM, Nordentoft M, Mors O, Simonsen A. Comparing cognition in parents with schizophrenia or bipolar disorder and their 7-year-old offspring. Psychiatry Res 2024; 340:116112. [PMID: 39121759 DOI: 10.1016/j.psychres.2024.116112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 06/15/2024] [Accepted: 07/27/2024] [Indexed: 08/12/2024]
Abstract
Individuals with schizophrenia (SZ) or bipolar disorder (BP) display cognitive impairments, while their first-degree relatives perform at an intermediate level between the patient groups and controls. However, the environmental impact of having an ill relative likely varies with the type of kinship and some studies suggest that offspring may be particularly disadvantaged. The present study aimed to investigate the relationship between parent and child cognition in parents with SZ or BD and their 7-year-old offspring. A population-based cohort of 522 children (parental SZ, n = 202; parental BP, n = 120; controls, n = 200) and their parents underwent the same assessment battery covering a wide range of cognitive functions. We used Bayesian statistics to model performance. We found that performance on non-verbal tests was better in offspring than parents with SZ or BP, using the controls as reference. However, for verbal tests, there was little to no evidence for this pattern or even some evidence for the opposite in the BP group: relatively better performance in parents than offspring. The findings suggest that the offspring of parents with SZ or BP may be particularly disadvantaged in verbal abilities. Future studies will show whether this pattern persists throughout development.
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Affiliation(s)
- Aja Neergaard Greve
- Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus N, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark.
| | - Nicoline Hemager
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark; Copenhagen Research Center for Mental Health- CORE, Mental Health Center Copenhagen, Copenhagen University Hospital, Mental Health Services Capital Region, Denmark; Child and Adolescent Mental Health Centre, Mental Health Services Capital Region, Research Unit, Copenhagen University Hospital, Copenhagen, Denmark
| | - Erik Lykke Mortensen
- Department of Public Health and Center for Healthy Aging, University of Copenhagen, Denmark
| | - Ditte Lou Gantriis
- Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus N, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark
| | - Birgitte Klee Burton
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark; Child and Adolescent Mental Health Centre, Mental Health Services Capital Region, Research Unit, Copenhagen University Hospital, Copenhagen, Denmark
| | - Ditte Ellersgaard
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark; Copenhagen Research Center for Mental Health- CORE, Mental Health Center Copenhagen, Copenhagen University Hospital, Mental Health Services Capital Region, Denmark
| | - Kerstin J Plessen
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark; Child and Adolescent Mental Health Centre, Mental Health Services Capital Region, Research Unit, Copenhagen University Hospital, Copenhagen, Denmark; Division of Child and Adolescent Psychiatry, Department of Psychiatry, University Hospital Lausanne, Switzerland
| | - Anne A E Thorup
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark; Child and Adolescent Mental Health Centre, Mental Health Services Capital Region, Research Unit, Copenhagen University Hospital, Copenhagen, Denmark; University of Copenhagen, Institute for Clinical Medicine, Faculty of Health, Denmark
| | - Jens Richardt Møllegaard Jepsen
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark; Copenhagen Research Center for Mental Health- CORE, Mental Health Center Copenhagen, Copenhagen University Hospital, Mental Health Services Capital Region, Denmark; Child and Adolescent Mental Health Centre, Mental Health Services Capital Region, Research Unit, Copenhagen University Hospital, Copenhagen, Denmark; Centre for Neuropsychiatric Schizophrenia Research & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Copenhagen University Hospital, Psychiatric Hospital Centre Glostrup, Denmark
| | - Merete Nordentoft
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark; Copenhagen Research Center for Mental Health- CORE, Mental Health Center Copenhagen, Copenhagen University Hospital, Mental Health Services Capital Region, Denmark; University of Copenhagen, Institute for Clinical Medicine, Faculty of Health, Denmark
| | - Ole Mors
- Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus N, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark
| | - Arndis Simonsen
- Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus N, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark
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6
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Auvergne A, Traut N, Henches L, Troubat L, Frouin A, Boetto C, Kazem S, Julienne H, Toro R, Aschard H. Multitrait Analysis to Decipher the Intertwined Genetic Architecture of Neuroanatomical Phenotypes and Psychiatric Disorders. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2024:S2451-9022(24)00266-0. [PMID: 39260564 DOI: 10.1016/j.bpsc.2024.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/28/2024] [Accepted: 08/12/2024] [Indexed: 09/13/2024]
Abstract
BACKGROUND There is increasing evidence of shared genetic factors between psychiatric disorders and brain magnetic resonance imaging (MRI) phenotypes. However, deciphering the joint genetic architecture of these outcomes has proven to be challenging, and new approaches are needed to infer the genetic structures that may underlie those phenotypes. Multivariate analyses are a meaningful approach to reveal links between MRI phenotypes and psychiatric disorders missed by univariate approaches. METHODS First, we conducted univariate and multivariate genome-wide association studies for 9 MRI-derived brain volume phenotypes in 20,000 UK Biobank participants. Next, we performed various complementary enrichment analyses to assess whether and how univariate and multitrait approaches could distinguish disorder-associated and non-disorder-associated variants from 6 psychiatric disorders: bipolar disorder, attention-deficit/hyperactivity disorder, autism, schizophrenia, obsessive-compulsive disorder, and major depressive disorder. Finally, we conducted a clustering analysis of top associated variants based on their MRI multitrait association using an optimized k-medoids approach. RESULTS A univariate MRI genome-wide association study revealed only negligible genetic correlations with psychiatric disorders, while a multitrait genome-wide association study identified multiple new associations and showed significant enrichment for variants related to both attention-deficit/hyperactivity disorder and schizophrenia. Clustering analyses also detected 2 clusters that showed not only enrichment for association with attention-deficit/hyperactivity disorder and schizophrenia but also a consistent direction of effects. Functional annotation analyses of those clusters pointed to multiple potential mechanisms, suggesting in particular a role of neurotrophin pathways in both MRI phenotypes and schizophrenia. CONCLUSIONS Our results show that multitrait association signature can be used to infer genetically driven latent MRI variables associated with psychiatric disorders, thereby opening paths for future biomarker development.
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Affiliation(s)
- Antoine Auvergne
- Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France.
| | - Nicolas Traut
- Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France
| | - Léo Henches
- Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France
| | - Lucie Troubat
- Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France
| | - Arthur Frouin
- Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France
| | - Christophe Boetto
- Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France
| | - Sayeh Kazem
- Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France
| | - Hanna Julienne
- Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France
| | - Roberto Toro
- Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France
| | - Hugues Aschard
- Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
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Sullivan PF, Yao S, Hjerling-Leffler J. Schizophrenia genomics: genetic complexity and functional insights. Nat Rev Neurosci 2024; 25:611-624. [PMID: 39030273 DOI: 10.1038/s41583-024-00837-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2024] [Indexed: 07/21/2024]
Abstract
Determining the causes of schizophrenia has been a notoriously intractable problem, resistant to a multitude of investigative approaches over centuries. In recent decades, genomic studies have delivered hundreds of robust findings that implicate nearly 300 common genetic variants (via genome-wide association studies) and more than 20 rare variants (via whole-exome sequencing and copy number variant studies) as risk factors for schizophrenia. In parallel, functional genomic and neurobiological studies have provided exceptionally detailed information about the cellular composition of the brain and its interconnections in neurotypical individuals and, increasingly, in those with schizophrenia. Taken together, these results suggest unexpected complexity in the mechanisms that drive schizophrenia, pointing to the involvement of ensembles of genes (polygenicity) rather than single-gene causation. In this Review, we describe what we now know about the genetics of schizophrenia and consider the neurobiological implications of this information.
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Affiliation(s)
- Patrick F Sullivan
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
| | - Shuyang Yao
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jens Hjerling-Leffler
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
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8
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Meijsen J, Hu K, Krebs MD, Athanasiadis G, Washbrook S, Zetterberg R, Avelar E Silva RN, Shorter JR, Gådin JR, Bergstedt J, Howard DM, Ye W, Lu Y, Valdimarsdóttir UA, Ingason A, Helenius D, Plana-Ripoll O, McGrath JJ, Micali N, Andreassen OA, Werge TM, Fang F, Buil A. Quantifying the relative importance of genetics and environment on the comorbidity between mental and cardiometabolic disorders using 17 million Scandinavians. Nat Commun 2024; 15:5064. [PMID: 38871766 PMCID: PMC11176385 DOI: 10.1038/s41467-024-49507-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 06/07/2024] [Indexed: 06/15/2024] Open
Abstract
Mental disorders are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders. Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and near-complete genealogies of Denmark and Sweden (n = 17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six mental disorders and 15 cardiometabolic disorders. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with cardiometabolic disorders, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with cardiometabolic disorders was mainly or fully driven by environmental factors. In this work we provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.
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Affiliation(s)
- Joeri Meijsen
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark.
| | - Kejia Hu
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Morten D Krebs
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark
| | - Georgios Athanasiadis
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark
- Department of Evolutionary Biology, Ecology and Environmental Sciences, University of Barcelona, Barcelona, Spain
| | - Sarah Washbrook
- Center for Eating and feeding Disorders research, Psychiatric Centre Ballerup, Mental Health Services in the Capital Region of Denmark, Copenhagen, Denmark
| | - Richard Zetterberg
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark
| | - Raquel Nogueira Avelar E Silva
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark
| | - John R Shorter
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Jesper R Gådin
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark
| | - Jacob Bergstedt
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - David M Howard
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Yi Lu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Unnur A Valdimarsdóttir
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Andrés Ingason
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark
| | - Dorte Helenius
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark
| | - Oleguer Plana-Ripoll
- Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
| | - John J McGrath
- Queensland Centre for Mental Health Research, Brisbane, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia
- National Centre for Register-based Research, Aarhus University, Aarhus, Denmark
| | - Nadia Micali
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark
- Center for Eating and feeding Disorders research, Psychiatric Centre Ballerup, Mental Health Services in the Capital Region of Denmark, Copenhagen, Denmark
- Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Ole A Andreassen
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- KG Jebsen Centre for Neurodevelopmental disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Thomas M Werge
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Fang Fang
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Alfonso Buil
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen University Hospital, Roskilde, Denmark.
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9
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Meijsen J, Hu K, Krebs MD, Athanasiadis G, Washbrook S, Zetterberg R, e Silva RNA, Shorter JR, Gådin JR, Bergstedt J, Howard DM, Ye W, Lu Y, Valdimarsdóttir UA, Ingason A, Mikkelsen DH, Plana-Ripoll O, McGrath JJ, Micali N, Andreassen OA, Werge TM, Fang F, Buil A. Quantifying the Relative Importance of Genetics and Environment on the Comorbidity between Mental- and Cardiometabolic Disorders: A Comprehensive Analysis of National Register Data from 17 million Scandinavians. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.02.29.24303530. [PMID: 38464139 PMCID: PMC10925466 DOI: 10.1101/2024.02.29.24303530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Mental disorders (MDs) are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders (CMDs). Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and complete genealogies of Denmark and Sweden (n=17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six MDs and 14 CMDs. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with CMDs, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with CMDs was mainly or fully driven by environmental factors. These findings provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.
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Affiliation(s)
- Joeri Meijsen
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
| | - Kejia Hu
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Morten Dybdahl Krebs
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
| | - Georgios Athanasiadis
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
- Department of Evolutionary Biology, Ecology and Environmental Sciences, University of Barcelona, Barcelona, Spain
| | - Sarah Washbrook
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
| | - Richard Zetterberg
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
| | - Raquel Nogueira Avelar e Silva
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
| | - John R. Shorter
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
- Department of Science and Environment, Roskilde University, Denmark
| | - Jesper R. Gådin
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
| | - Jacob Bergstedt
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - David M. Howard
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Weimin Ye
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | | | - Yi Lu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Unnur A. Valdimarsdóttir
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Andrés Ingason
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
- Lundbeck Foundation GeoGenetics Centre, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark
| | - Dorte Helenius Mikkelsen
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
| | - Oleguer Plana-Ripoll
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
| | - John J. McGrath
- Queensland Centre for Mental Health Research, Brisbane, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia
- National Centre for Register-based Research, Aarhus University, Aarhus, Denmark
| | - Nadia Micali
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- Center for Eating and feeding Disorders research, Psychiatric Centre Ballerup, Mental Health Services in the Capital Region of Denmark, Copenhagen, Denmark
- Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Ole A. Andreassen
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- KG Jebsen Centre for Neurodevelopmental disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Thomas M. Werge
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
- Lundbeck Foundation GeoGenetics Centre, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark
| | - Fang Fang
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Alfonso Buil
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
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10
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Waszczuk MA, Jonas KG, Bornovalova M, Breen G, Bulik CM, Docherty AR, Eley TC, Hettema JM, Kotov R, Krueger RF, Lencz T, Li JJ, Vassos E, Waldman ID. Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies. Mol Psychiatry 2023; 28:4943-4953. [PMID: 37402851 PMCID: PMC10764644 DOI: 10.1038/s41380-023-02142-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/17/2023] [Accepted: 06/16/2023] [Indexed: 07/06/2023]
Abstract
Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical 'splitting' and 'lumping' approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come.
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Affiliation(s)
- Monika A Waszczuk
- Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
| | - Katherine G Jonas
- Department of Psychiatry, Stony Brook University School of Medicine, Stony Brook, NY, USA
| | | | - Gerome Breen
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- UK National Institute for Health and Care Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS Trust, London, UK
| | - Cynthia M Bulik
- Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Anna R Docherty
- Huntsman Mental Health Institute, Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Thalia C Eley
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- UK National Institute for Health and Care Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS Trust, London, UK
| | - John M Hettema
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
- Department of Psychiatry, Texas A&M Health Sciences Center, Bryan, TX, USA
| | - Roman Kotov
- Department of Psychiatry, Stony Brook University School of Medicine, Stony Brook, NY, USA
| | - Robert F Krueger
- Psychology Department, University of Minnesota, Minneapolis, MN, USA
| | - Todd Lencz
- Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, NY, USA
- Institute for Behavioral Science, The Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - James J Li
- Department of Psychology, University of Wisconsin, Madison, WI, USA
- Waisman Center, University of Wisconsin, Madison, WI, USA
| | - Evangelos Vassos
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- UK National Institute for Health and Care Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS Trust, London, UK
| | - Irwin D Waldman
- Department of Psychology, Emory University, Atlanta, GA, USA
- Center for Computational and Quantitative Genetics, Emory University, Atlanta, GA, USA
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11
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Wu Y, Goleva SB, Breidenbach LB, Kim M, MacGregor S, Gandal MJ, Davis LK, Wray NR. 150 risk variants for diverticular disease of intestine prioritize cell types and enable polygenic prediction of disease susceptibility. CELL GENOMICS 2023; 3:100326. [PMID: 37492107 PMCID: PMC10363821 DOI: 10.1016/j.xgen.2023.100326] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 03/11/2023] [Accepted: 04/20/2023] [Indexed: 07/27/2023]
Abstract
We conducted a genome-wide association study (GWAS) analysis of diverticular disease (DivD) of intestine within 724,372 individuals and identified 150 independent genome-wide significant DNA variants. Integration of the GWAS results with human gut single-cell RNA sequencing data implicated gut myocyte, mesothelial and stromal cells, and enteric neurons and glia in DivD development. Ninety-five genes were prioritized based on multiple lines of evidence, including SLC9A3, a drug target gene of tenapanor used for the treatment of the constipation subtype of irritable bowel syndrome. A DivD polygenic score (PGS) enables effective risk prediction (area under the curve [AUC], 0.688; 95% confidence interval [CI], 0.645-0.732) and the top 20% PGS was associated with ∼3.6-fold increased DivD risk relative to the remaining population. Our statistical and bioinformatic analyses suggest that the mechanism of DivD is through colon structure, gut motility, gastrointestinal mucus, and ionic homeostasis. Our analyses reinforce the link between gastrointestinal disorders and the enteric nervous system through genetics.
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Affiliation(s)
- Yeda Wu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
- QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
| | - Slavina B. Goleva
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Lindsay B. Breidenbach
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Minsoo Kim
- Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Stuart MacGregor
- QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
| | - Michael J. Gandal
- Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Lea K. Davis
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Psychiatry and Behavioural Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Departments of Medicine and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University, 511-A Light Hall, 2215 Garland Avenue, Nashville, TN 37232, USA
| | - Naomi R. Wray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
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12
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Gao X, Yao L, Li F, Yang C, Zhu F, Gong Q, Lui S. The cortical hypogyrification pattern in antipsychotic-naive first-episode schizophrenia. Cereb Cortex 2023; 33:7619-7626. [PMID: 36916957 DOI: 10.1093/cercor/bhad065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/12/2023] [Accepted: 02/13/2023] [Indexed: 03/15/2023] Open
Abstract
Schizophrenia is thought to be a neurodevelopmental disease with high genetic heritability, and evidence from neuroimaging studies has consistently shown widespread cortical local gyrification index (LGI) alterations; however, genes accounting for LGI alterations in schizophrenia remain unknown. The present study examined the LGI alterations in first-episode antipsychotic-naive schizophrenia compared with controls (235 patients and 214 controls); transcription-neuroimaging association analysis was used to evaluate the relationship between LGI deficits and specific risk genes. The expression profiles of 232 schizophrenia risk genes were extracted from six donated normal brains from the Allen Human Brain Atlas database. The correlation between LGI alterations and clinical symptoms was also tested. We found lower LGI values involved in frontotemporal regions and limbic systems. Nonparametric correlation analysis showed that 83 risk genes correlated with the hypogyrification pattern in schizophrenia. These identified risk genes were functionally enriched for the development of the central nervous system. The LGI in the left superior temporal gyrus was negatively associated with Positive and Negative Syndrome Scale negative symptoms. In summary, the present study provides a set of risk genes possibly related to the hypogyrification pattern in antipsychotic-naive first-episode schizophrenia, which could help to unveil the neurobiological underpinnings of cortical impairments in early-stage schizophrenia.
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Affiliation(s)
- Xin Gao
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Li Yao
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Fei Li
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Chengmin Yang
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Fei Zhu
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Qiyong Gong
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Su Lui
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
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13
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Weiser M, Frenkel O, Fenchel D, Tzur D, Sandin S, Janecka M, Levi L, Davidson M, Laor L, Fruchter E, Reichenberg A. Familial clustering of psychiatric disorders and low IQ. Psychol Med 2023; 53:2878-2884. [PMID: 34911593 DOI: 10.1017/s0033291721004852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Although the ICD and DSM differentiate between different psychiatric disorders, these often share symptoms, risk factors, and treatments. This was a population-based, case-control, sibling study examining familial clustering of all psychiatric disorders and low IQ, using data from the Israel Draft-Board Registry on all Jewish adolescents assessed between 1998 and 2014. METHODS We identified all cases with autism spectrum disorder (ASD, N = 2128), severe intellectual disability (ID, N = 9572), attention-deficit hyperactive disorder (ADHD) (N = 3272), psychotic (N = 7902), mood (N = 9704), anxiety (N = 10 606), personality (N = 24 816), or substance/alcohol abuse (N = 791) disorders, and low IQ (⩾2 SDs below the population mean, N = 31 186). Non-CNS control disorders were adolescents with Type-1 diabetes (N = 2427), hernia (N = 29 558) or hematological malignancies (N = 931). Each case was matched with 10 age-matched controls selected at random from the Draft-Board Registry, with replacement, and for each case and matched controls, we ascertained all full siblings. The main outcome measure was the relative recurrence risk (RRR) of the sibling of a case having the same (within-disorder RRR) or a different (across-disorder RRR) disorder. RESULTS Within-disorder RRRs were increased for all diagnostic categories, ranging from 11.53 [95% confidence interval (CI): 9.23-14.40] for ASD to 2.93 (95% CI: 2.80-3.07) for personality disorders. The median across-disorder RRR between any pair of psychiatric disorders was 2.16 (95% CI: 1.45-2.43); the median RRR between low IQ and any psychiatric disorder was 1.37 (95% CI: 0.93-1.98). There was no consistent increase in across-disorder RRRs between the non-CNS disorders and psychiatric disorders and/or low IQ. CONCLUSION These large population-based study findings suggest shared etiologies among most psychiatric disorders, and low IQ.
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Affiliation(s)
- Mark Weiser
- Department of Psychiatry, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Or Frenkel
- Department of Psychiatry, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
| | - Daphna Fenchel
- Department of Psychiatry, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
| | - Dorit Tzur
- Medical Corps, Israel Defense Force, Israel
| | - Sven Sandin
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Magdalena Janecka
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Linda Levi
- Department of Psychiatry, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
| | | | | | - Eyal Fruchter
- Medical Corps, Israel Defense Force, Israel
- Department of Psychiatry, Rambam Medical Center, Haifa, Israel
- Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Abraham Reichenberg
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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14
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Nakamura T, Takata A. The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research. Mol Psychiatry 2023; 28:1868-1889. [PMID: 36878965 PMCID: PMC10575785 DOI: 10.1038/s41380-023-02005-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 02/15/2023] [Accepted: 02/15/2023] [Indexed: 03/08/2023]
Abstract
Despite enormous efforts employing various approaches, the molecular pathology in the schizophrenia brain remains elusive. On the other hand, the knowledge of the association between the disease risk and changes in the DNA sequences, in other words, our understanding of the genetic pathology of schizophrenia, has dramatically improved over the past two decades. As the consequence, now we can explain more than 20% of the liability to schizophrenia by considering all analyzable common genetic variants including those with weak or no statistically significant association. Also, a large-scale exome sequencing study identified single genes whose rare mutations substantially increase the risk for schizophrenia, of which six genes (SETD1A, CUL1, XPO7, GRIA3, GRIN2A, and RB1CC1) showed odds ratios larger than ten. Based on these findings together with the preceding discovery of copy number variants (CNVs) with similarly large effect sizes, multiple disease models with high etiological validity have been generated and analyzed. Studies of the brains of these models, as well as transcriptomic and epigenomic analyses of patient postmortem tissues, have provided new insights into the molecular pathology of schizophrenia. In this review, we overview the current knowledge acquired from these studies, their limitations, and directions for future research that may redefine schizophrenia based on biological alterations in the responsible organ rather than operationalized criteria.
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Affiliation(s)
- Takumi Nakamura
- Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Atsushi Takata
- Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
- Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
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15
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Andreassen AK, Lambek R, Hemager N, Knudsen CB, Veddum L, Carlsen AH, Bundgaard AF, Søndergaard A, Brandt JM, Gregersen M, Krantz MF, Burton BK, Jepsen JRM, Thorup AAE, Nordentoft M, Mors O, Bliksted VF, Greve A. Working memory heterogeneity from age 7 to 11 in children at familial high risk of schizophrenia or bipolar disorder- The Danish High Risk and Resilience Study. J Affect Disord 2023; 332:318-326. [PMID: 37059192 DOI: 10.1016/j.jad.2023.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 03/30/2023] [Accepted: 04/07/2023] [Indexed: 04/16/2023]
Abstract
BACKGROUND Despite the genetic overlap between bipolar disorder and schizophrenia, working memory impairments are mainly found in children of parents with schizophrenia. However, working memory impairments are characterized by substantial heterogeneity, and it is unknown how this heterogeneity develops over time. We used a data-driven approach to assess working memory heterogeneity and longitudinal stability in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP). METHODS Based on the performances on four working memory tasks by 319 children (FHR-SZ, N = 202, FHR-BP, N = 118) measured at age 7 and 11, latent profile transition analysis was used to test for the presence of subgroups, and the stability of subgroup membership over time. Population-based controls (VIA 7, N = 200, VIA 11, N = 173) were included as a reference group. The working memory subgroups were compared based on caregiver- and teacher ratings of everyday working memory function, and dimensional psychopathology. RESULTS A model with three subgroups characterized by different levels of working memory function (an impaired subgroup, a mixed subgroup, and an above average subgroup) best fitted the data. The impaired subgroup had the highest ratings of everyday working memory impairments and psychopathology. Overall, 98 % (N = 314) stayed in the same subgroup from age 7 to 11. CONCLUSION Persistent working memory impairments are present in a subset of children at FHR-SZ and FHR-BP throughout middle childhood. Attention should be given to these children, as working memory impairments influence daily life, and may serve as a vulnerability marker of transition to severe mental illness.
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Affiliation(s)
- Anna Krogh Andreassen
- Psychosis Research Unit, Aarhus University Hospital Psychiatry, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, Aarhus University, Denmark.
| | - Rikke Lambek
- Department of Psychology and Behavioral Sciences, Aarhus University, Denmark
| | - Nicoline Hemager
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; CORE - Copenhagen Research Centre for Mental Health, Mental Health Services in the Capital Region of Denmark, Mental Health Centre Copenhagen, Denmark; Child and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Denmark
| | - Christina Bruun Knudsen
- Psychosis Research Unit, Aarhus University Hospital Psychiatry, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, Aarhus University, Denmark
| | - Lotte Veddum
- Psychosis Research Unit, Aarhus University Hospital Psychiatry, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, Aarhus University, Denmark
| | - Anders Helles Carlsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, Aarhus University, Denmark; Research Unit, Research Unit, Aarhus University Hospital Psychiatry, Denmark
| | | | - Anne Søndergaard
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; CORE - Copenhagen Research Centre for Mental Health, Mental Health Services in the Capital Region of Denmark, Mental Health Centre Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Julie Marie Brandt
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; CORE - Copenhagen Research Centre for Mental Health, Mental Health Services in the Capital Region of Denmark, Mental Health Centre Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Maja Gregersen
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; CORE - Copenhagen Research Centre for Mental Health, Mental Health Services in the Capital Region of Denmark, Mental Health Centre Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette Falkenberg Krantz
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; CORE - Copenhagen Research Centre for Mental Health, Mental Health Services in the Capital Region of Denmark, Mental Health Centre Copenhagen, Denmark; Child and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Denmark
| | - Birgitte Klee Burton
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Child and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Denmark
| | - Jens Richardt Møllegaard Jepsen
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; CORE - Copenhagen Research Centre for Mental Health, Mental Health Services in the Capital Region of Denmark, Mental Health Centre Copenhagen, Denmark; Child and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Denmark; Center for Clinical Interventions and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Center Glostrup, Copenhagen University Hospital - Metal Health Services CPH, Denmark
| | - Anne Amalie Elgaard Thorup
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Child and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Denmark
| | - Merete Nordentoft
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; CORE - Copenhagen Research Centre for Mental Health, Mental Health Services in the Capital Region of Denmark, Mental Health Centre Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ole Mors
- Psychosis Research Unit, Aarhus University Hospital Psychiatry, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark
| | - Vibeke Fuglsang Bliksted
- Psychosis Research Unit, Aarhus University Hospital Psychiatry, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, Aarhus University, Denmark
| | - Aja Greve
- Psychosis Research Unit, Aarhus University Hospital Psychiatry, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark
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Li Z, Sun X, He J, Kong D, Wang J, Wang L. Identification of a Hypoxia-Related Signature as Candidate Detector for Schizophrenia Based on Genome-Wide Gene Expression. Hum Hered 2023; 88:18-28. [PMID: 36913932 PMCID: PMC10124753 DOI: 10.1159/000529902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 02/15/2023] [Indexed: 03/15/2023] Open
Abstract
INTRODUCTION Schizophrenia (SCZ), a severe neuropsychiatric disorder with high genetic susceptibility, has high rates of misdiagnosis due to the unavoidably subjective factors and heterogeneous clinical presentations. Hypoxia has been identified as an importantly risk factor that participates in the development of SCZ. Therefore, development of a hypoxia-related biomarker for SCZ diagnosis is promising. Therefore, we dedicated to develop a biomarker that could contribute to distinguishing healthy controls and SCZ patients. METHODS GSE17612, GSE21935, and GSE53987 datasets, consisting of 97 control samples and 99 SCZ samples, were involved in our study. The hypoxia score was calculated based on the single-sample gene-set enrichment analysis using the hypoxia-related differentially expressed genes to quantify the expression levels of these genes for each SCZ patient. Patients in high-score groups were defined if their hypoxia score was in the upper half of all hypoxia scores and patients in low-score groups if their hypoxia score was in the lower half. GSEA was applied to detect the functional pathway of these differently expressed genes. CIBERSORT algorithm was utilized to evaluate the tumor-infiltrating immune cells of SCZ patients. RESULTS In this study, we developed and validated a biomarker consisting of 12 hypoxia-related genes that could distinguish healthy controls and SCZ patients robustly. We found that the metabolism reprogramming might be activated in the patient with high hypoxia score. Finally, CIBERSORT analysis illustrated that lower composition of naive B cells and higher composition of memory B cells might be observed in low-score groups of SCZ patients. CONCLUSION These findings revealed that the hypoxia-related signature was acceptable as a detector for SCZ, providing further insight into effective diagnosis and treatment strategies for SCZ.
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Affiliation(s)
- Zhitao Li
- Department of Psychiatry and Psychological Clinic, Affiliated Quanzhou First Hospital, Fujian Medical University, Quanzhou, China
| | - Xinyu Sun
- Department of Psychiatry and Psychological Clinic, Affiliated Quanzhou First Hospital, Fujian Medical University, Quanzhou, China
| | - Jia He
- Department of Psychiatry and Psychological Clinic, Affiliated Quanzhou First Hospital, Fujian Medical University, Quanzhou, China
| | - Dongyan Kong
- Department of Psychiatry and Psychological Clinic, Affiliated Quanzhou First Hospital, Fujian Medical University, Quanzhou, China
| | - Jinyi Wang
- Department of Psychiatry, Quanzhou Third Hospital, Quanzhou, China
| | - Lili Wang
- Department of Psychiatry, Quanzhou Third Hospital, Quanzhou, China
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Dattani S, Sham PC, Jermy BS, Coleman JRI, Howard DM, Lewis CM. Common and rare variant associations with latent traits underlying depression, bipolar disorder, and schizophrenia. Transl Psychiatry 2023; 13:46. [PMID: 36746926 PMCID: PMC9902570 DOI: 10.1038/s41398-023-02324-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 01/07/2023] [Accepted: 01/18/2023] [Indexed: 02/08/2023] Open
Abstract
Genetic studies in psychiatry have primarily focused on the effects of common genetic variants, but few have investigated the role of rare genetic variants, particularly for major depression. In order to explore the role of rare variants in the gap between estimates of single nucleotide polymorphism (SNP) heritability and twin study heritability, we examined the contribution of common and rare genetic variants to latent traits underlying psychiatric disorders using high-quality imputed genotype data from the UK Biobank. Using a pre-registered analysis, we used items from the UK Biobank Mental Health Questionnaire relevant to three psychiatric disorders: major depression (N = 134,463), bipolar disorder (N = 117,376) and schizophrenia (N = 130,013) and identified a general hierarchical factor for each that described participants' responses. We calculated participants' scores on these latent traits and conducted single-variant genetic association testing (MAF > 0.05%), gene-based burden testing and pathway association testing associations with these latent traits. We tested for enrichment of rare variants (MAF 0.05-1%) in genes that had been previously identified by common variant genome-wide association studies, and genes previously associated with Mendelian disorders having relevant symptoms. We found moderate genetic correlations between the latent traits in our study and case-control phenotypes in previous genome-wide association studies, and identified one common genetic variant (rs72657988, minor allele frequency = 8.23%, p = 1.01 × 10-9) associated with the general factor of schizophrenia, but no other single variants, genes or pathways passed significance thresholds in this analysis, and we did not find enrichment in previously identified genes.
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Affiliation(s)
- Saloni Dattani
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
- Department of Psychiatry, Li Ka Shing (LKS) Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.
| | - Pak C Sham
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- NIHR Maudsley Biomedical Research Centre, South London and Maudsley NHS Trust, London, UK
- Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China
- Centre for PanorOmic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Bradley S Jermy
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- NIHR Maudsley Biomedical Research Centre, South London and Maudsley NHS Trust, London, UK
| | - Jonathan R I Coleman
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- NIHR Maudsley Biomedical Research Centre, South London and Maudsley NHS Trust, London, UK
| | - David M Howard
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
| | - Cathryn M Lewis
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, UK
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18
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Veleva I, Stoychev K, Stoimenova-Popova M, Stoyanov L, Mineva-Dimitrova E, Angelov I. Toxoplasma gondii seropositivity and cognitive function in adults with schizophrenia. Schizophr Res Cogn 2022; 30:100269. [PMID: 36065435 PMCID: PMC9440062 DOI: 10.1016/j.scog.2022.100269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/22/2022] [Accepted: 08/22/2022] [Indexed: 11/29/2022]
Abstract
Introduction and methods Based on the limited research focusing on the severity of cognitive deterioration in schizophrenia with preceding toxoplasmosis, we sampled 89 demographically matched paranoid schizophrenia patients (mean age 38.97 years) with (n = 42) and without (n = 47) seroprevalence of IgG type anti T. gondii antibodies as marker of past infection. They underwent examination of verbal memory (10 words Luria test), logical memory and visual memory (BVRT), processing speed (TMT-A/DSST) and executive functions (TMT-B/verbal fluency). We compared the results of both groups, taking into account the normative values for the Bulgarian population where available. We also compared the two groups in terms of clinical severity as evidenced by positive, negative and disorganization sub-scores of the PANSS. Results While both groups were expectedly under the population norms for verbal and logical memory, seropositive patients showed significantly bigger impairment in verbal memory (Luria Smax = 72.85 vs 78.51; p = 0.029), psychomotor speed (TMT-A 50.98 s vs 44.64 s; p = 0.017), semantic verbal fluency (27.12 vs 30.02; p = 0.011) and literal verbal fluency (17.17 vs 18.78; p = 0.014) compared to the seronegative ones. In addition to that, they gave less correct answers on the BVRT (2.98 vs 4.09; p = 0.006) while making markedly more errors (13.95 vs 10.21; p = 0.002). Despite not reaching statistical significance, past toxoplasmosis was associated with higher score on the PANSS disorganization sub-scale (16.50 points vs 14.72 points) and with lower educational attainment. Conclusion Our results suggest a more profound neuropathological insult(s) resulting in greater cognitive impairment in schizophrenia cases that are exposed to T. gondii infection.
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Affiliation(s)
- Ivanka Veleva
- Department of Psychiatry and Medical Psychology, Medical University Pleven, Bulgaria
| | - Kaloyan Stoychev
- Department of Psychiatry and Medical Psychology, Medical University Pleven, Bulgaria
| | | | - Lyudmil Stoyanov
- Department of Infectious Diseases, Epidemiology, Parasitology and Tropical Medicine, Medical University Pleven, Bulgaria
| | | | - Ivelin Angelov
- Department of Infectious Diseases, Epidemiology, Parasitology and Tropical Medicine, Medical University Pleven, Bulgaria
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19
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Sigström R, Kowalec K, Jonsson L, Clements CC, Karlsson R, Nordenskjöld A, Pålsson E, Sullivan PF, Landén M. Association Between Polygenic Risk Scores and Outcome of ECT. Am J Psychiatry 2022; 179:844-852. [PMID: 36069021 PMCID: PMC10113810 DOI: 10.1176/appi.ajp.22010045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Identifying biomarkers associated with response to electroconvulsive therapy (ECT) may aid clinical decisions. The authors examined whether greater polygenic liabilities for major depressive disorder, bipolar disorder, and schizophrenia are associated with improvement following ECT for a major depressive episode. METHODS Between 2013 and 2017, patients who had at least one treatment series recorded in the Swedish National Quality Register for ECT were invited to provide a blood sample for genotyping. The present study included 2,320 participants (median age, 51 years; 62.8% women) who had received an ECT series for a major depressive episode (77.1% unipolar depression), who had a registered treatment outcome, and whose polygenic risk scores (PRSs) could be calculated. Ordinal logistic regression was used to estimate the effect of PRS on Clinical Global Impressions improvement scale (CGI-I) score after each ECT series. RESULTS Greater PRS for major depressive disorder was significantly associated with less improvement on the CGI-I (odds ratio per standard deviation, 0.89, 95% CI=0.82, 0.96; R2=0.004), and greater PRS for bipolar disorder was associated with greater improvement on the CGI-I (odds ratio per standard deviation, 1.14, 95% CI=1.05, 1.23; R2=0.005) after ECT. PRS for schizophrenia was not associated with improvement. In an overlapping sample (N=1,207) with data on response and remission derived from the self-rated version of the Montgomery-Åsberg Depression Rating Scale, results were similar except that schizophrenia PRS was also associated with remission. CONCLUSIONS Improvement after ECT is associated with polygenic liability for major depressive disorder and bipolar disorder, providing evidence of a genetic component for ECT clinical response. These liabilities may be considered along with clinical predictors in future prediction models of ECT outcomes.
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Affiliation(s)
- Robert Sigström
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (Sigström, Jonsson, Pålsson, Landén); Department of Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden (Sigström); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Kowalec, Clements, Karlsson, Sullivan, Landén); College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden (Nordenskjöld); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan)
| | - Kaarina Kowalec
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (Sigström, Jonsson, Pålsson, Landén); Department of Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden (Sigström); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Kowalec, Clements, Karlsson, Sullivan, Landén); College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden (Nordenskjöld); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan)
| | - Lina Jonsson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (Sigström, Jonsson, Pålsson, Landén); Department of Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden (Sigström); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Kowalec, Clements, Karlsson, Sullivan, Landén); College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden (Nordenskjöld); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan)
| | - Caitlin C Clements
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (Sigström, Jonsson, Pålsson, Landén); Department of Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden (Sigström); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Kowalec, Clements, Karlsson, Sullivan, Landén); College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden (Nordenskjöld); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan)
| | - Robert Karlsson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (Sigström, Jonsson, Pålsson, Landén); Department of Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden (Sigström); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Kowalec, Clements, Karlsson, Sullivan, Landén); College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden (Nordenskjöld); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan)
| | - Axel Nordenskjöld
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (Sigström, Jonsson, Pålsson, Landén); Department of Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden (Sigström); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Kowalec, Clements, Karlsson, Sullivan, Landén); College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden (Nordenskjöld); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan)
| | - Erik Pålsson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (Sigström, Jonsson, Pålsson, Landén); Department of Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden (Sigström); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Kowalec, Clements, Karlsson, Sullivan, Landén); College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden (Nordenskjöld); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan)
| | - Patrick F Sullivan
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (Sigström, Jonsson, Pålsson, Landén); Department of Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden (Sigström); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Kowalec, Clements, Karlsson, Sullivan, Landén); College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden (Nordenskjöld); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan)
| | - Mikael Landén
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (Sigström, Jonsson, Pålsson, Landén); Department of Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden (Sigström); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Kowalec, Clements, Karlsson, Sullivan, Landén); College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden (Nordenskjöld); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan)
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20
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Zacher Kjeldsen MM, Bricca A, Liu X, Frokjaer VG, Madsen KB, Munk-Olsen T. Family History of Psychiatric Disorders as a Risk Factor for Maternal Postpartum Depression: A Systematic Review and Meta-analysis. JAMA Psychiatry 2022; 79:1004-1013. [PMID: 35976654 PMCID: PMC9386615 DOI: 10.1001/jamapsychiatry.2022.2400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/28/2022] [Indexed: 11/14/2022]
Abstract
Importance Current evidence on the association between family history of psychiatric disorders and postpartum depression is inconsistent; family studies have identified familial risk of postpartum depression, whereas systematic reviews and umbrella reviews, compiling all risk factors for postpartum depression, often have not. Objective To investigate the association between family history of psychiatric disorders and risk of developing postpartum depression within 12 months post partum. Data Sources Literature searches were conducted in PubMed, Embase, and PsycINFO in September 2021 and updated in March 2022, accompanied by citation and reference search. Study Selection Studies eligible for inclusion comprised peer-reviewed cohort and case-control studies reporting an odds ratio (OR) or sufficient data to calculate one for the association between family history of any psychiatric disorder and postpartum depression. Study selection was made by 2 independent reviewers: title and abstract screening followed by full-text screening. Data Extraction and Synthesis Reporting was performed using the MOOSE checklist. Two reviewers independently extracted predefined information and assessed included studies for risk of bias using the Newcastle-Ottawa Scale. Data were pooled in a meta-analysis using a random-effects model. Heterogeneity was investigated with meta-regression, subgroup, and sensitivity analyses. Publication bias was investigated using a funnel plot, and GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to evaluate the overall certainty of the findings. Main Outcomes and Measures The primary outcome was the pooled association between family history of psychiatric disorders and postpartum depression. Results A total of 26 studies were included, containing information on 100 877 women. Meta-analysis showed an increased OR of developing postpartum depression when mothers had a family history of psychiatric disorders (OR, 2.08; 95% CI, 1.67-2.59; I2 = 57.14%) corresponding to a risk ratio of 1.79 (95% CI, 1.52-2.09), assuming a 15% postpartum depression prevalence in the general population. Subgroup, sensitivity, and meta-regression analyses were in line with the primary analysis. The overall certainty of evidence was deemed as moderate according to GRADE. Conclusions and Relevance In this study, there was moderate certainty of evidence for an almost 2-fold higher risk of developing postpartum depression among mothers who have a family history of any psychiatric disorder compared with mothers without.
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Affiliation(s)
- Mette-Marie Zacher Kjeldsen
- National Centre for Register-based Research, Aarhus University, Aarhus, Denmark
- Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Alessio Bricca
- Research Unit for Musculoskeletal Function and Physiotherapy, Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
- The Research Unit PROgrez, Department of Physiotherapy and Occupational Therapy, Næstved-Slagelse-Ringsted Hospitals, Slagelse, Denmark
| | - Xiaoqin Liu
- National Centre for Register-based Research, Aarhus University, Aarhus, Denmark
| | - Vibe G. Frokjaer
- Neurobiology Research Unit, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark
- Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Trine Munk-Olsen
- National Centre for Register-based Research, Aarhus University, Aarhus, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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21
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The dubious precision and utility of heritability estimates. Behav Brain Sci 2022; 45:e164. [PMID: 36098431 DOI: 10.1017/s0140525x21001527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Uchiyama et al. question heritability estimates in a convincing manner. We offer additional arguments to further bolster their claims, highlighting methodological issues in heritability coefficients' derivation, their misuse in various contexts, and their potential contributions to exacerbating common erroneous intuitions that have been shown to lead to deleterious social phenomena. We conclude that science should move away from using them.
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22
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Dattani S, Howard DM, Lewis CM, Sham PC. Clarifying the causes of consistent and inconsistent findings in genetics. Genet Epidemiol 2022; 46:372-389. [PMID: 35652173 PMCID: PMC9544854 DOI: 10.1002/gepi.22459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/12/2022] [Accepted: 04/22/2022] [Indexed: 11/29/2022]
Abstract
As research in genetics has advanced, some findings have been unexpected or shown to be inconsistent between studies or datasets. The reasons these inconsistencies arise are complex. Results from genetic studies can be affected by various factors including statistical power, linkage disequilibrium, quality control, confounding and selection bias, as well as real differences from interactions and effect modifiers, which may be informative about the mechanisms of traits and disease. Statistical artefacts can manifest as differences between results but they can also conceal underlying differences, which implies that their critical examination is important for understanding the underpinnings of traits. In this review, we examine these factors and outline how they can be identified and conceptualised with structural causal models. We explain the consequences they have on genetic estimates, such as genetic associations, polygenic scores, family‐ and genome‐wide heritability, and describe methods to address them to aid in the estimation of true effects of genetic variation. Clarifying these factors can help researchers anticipate when results are likely to diverge and aid researchers' understanding of causal relationships between genes and complex traits.
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Affiliation(s)
- Saloni Dattani
- Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.,Department of Psychiatry, Li Ka Shing (LKS) Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - David M Howard
- Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.,Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK
| | - Cathryn M Lewis
- Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.,Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Pak C Sham
- Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, and Centre for Panoromic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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23
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Lei W, Xiao Q, Wang C, Gao W, Xiao Y, Dai Y, Lu G, Su L, Zhong Y. Cell-type-specific genes associated with cortical structural abnormalities in pediatric bipolar disorder. PSYCHORADIOLOGY 2022; 2:56-65. [PMID: 38665968 PMCID: PMC11044809 DOI: 10.1093/psyrad/kkac009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 08/06/2022] [Accepted: 08/19/2022] [Indexed: 04/28/2024]
Abstract
Background Pediatric bipolar disorder (PBD) has been proven to be related to abnormal brain structural connectivity, but how the abnormalities in PBD correlate with gene expression is debated. Objective This study aims at identification of cell-type-specific gene modules based on cortical structural differences in PBD. Methods Morphometric similarity networks (MSN) were computed as a marker of interareal cortical connectivity based on MRI data from 102 participants (59 patients and 43 controls). Partial least squares (PLS) regression was used to calculate MSN differences related to transcriptomic data in AHBA. The biological processes and cortical cell types associated with this gene expression profile were determined by gene enrichment tools. Results MSN analysis results demonstrated differences of cortical structure between individuals diagnosed with PBD and healthy control participants. MSN differences were spatially correlated with the PBD-related weighted genes. The weighted genes were enriched for "trans-synaptic signaling" and "regulation of ion transport", and showed significant specific expression in excitatory and inhibitory neurons. Conclusions This study identified the genes that contributed to structural network aberrations in PBD. It was found that transcriptional changes of excitatory and inhibitory neurons might be associated with abnormal brain structural connectivity in PBD.
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Affiliation(s)
- Wenkun Lei
- School of Psychology, Nanjing Normal University, Nanjing, Jiangsu 210097, China
- Nanjing Normal University, Jiangsu Key Laboratory of Mental Health and Cognitive Science, Nanjing, Jiangsu 210097, China
| | - Qian Xiao
- The Mental Health Centre of Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Chun Wang
- The Department of Psychiatry, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Weijia Gao
- The Children's Hospital affiliated to the Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Yiwen Xiao
- School of Psychology, Nanjing Normal University, Nanjing, Jiangsu 210097, China
- Nanjing Normal University, Jiangsu Key Laboratory of Mental Health and Cognitive Science, Nanjing, Jiangsu 210097, China
| | - Yingliang Dai
- School of Psychology, Nanjing Normal University, Nanjing, Jiangsu 210097, China
- Nanjing Normal University, Jiangsu Key Laboratory of Mental Health and Cognitive Science, Nanjing, Jiangsu 210097, China
| | - Guangming Lu
- The Department of Medical Imaging, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Linyan Su
- The Second Xiangya Hospital of Central South University, Changsha, Hunan 410008, China
| | - Yuan Zhong
- School of Psychology, Nanjing Normal University, Nanjing, Jiangsu 210097, China
- Nanjing Normal University, Jiangsu Key Laboratory of Mental Health and Cognitive Science, Nanjing, Jiangsu 210097, China
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24
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Song J, Yao S, Kowalec K, Lu Y, Sariaslan A, Szatkiewicz JP, Larsson H, Lichtenstein P, Hultman CM, Sullivan PF. The impact of educational attainment, intelligence and intellectual disability on schizophrenia: a Swedish population-based register and genetic study. Mol Psychiatry 2022; 27:2439-2447. [PMID: 35379910 PMCID: PMC9135619 DOI: 10.1038/s41380-022-01500-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 02/14/2022] [Accepted: 02/22/2022] [Indexed: 01/16/2023]
Abstract
Schizophrenia (SCZ) is highly heterogenous and no subtypes characterizing treatment response or longitudinal course well. Cognitive impairment is a core clinical feature of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive traits is complex, with limited studies of comprehensive epidemiological and genomic evidence. To examine the relation between SCZ and three cognitive traits, educational attainment (EDU), premorbid cognitive ability, and intellectual disability (ID), we used two Swedish samples: a national cohort (14,230 SCZ cases and 3,816,264 controls) and a subsample with comprehensive genetic data (4992 cases and 6009 controls). Population-based analyses confirmed worse cognition as a risk factor for SCZ, and the pedigree and SNP-based genetic correlations were comparable. In the genotyped cases, those with high EDU and premorbid cognitive ability tended to have higher polygenetic risk scores (PRS) of EDU and intelligence and fewer rare exonic variants. Finally, by applying an empirical clustering method, we dissected SCZ cases into four replicable subgroups characterized by EDU and ID. In particular, the subgroup with higher EDU in the national cohort had fewer adverse outcomes including long hospitalization and death. In the genotyped subsample, this subgroup had higher PRS of EDU and no excess of rare genetic burdens than controls. In conclusion, we found extensive evidence of a robust relation between cognitive traits and SCZ, underscoring the importance of cognition in dissecting the heterogeneity of SCZ.
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Affiliation(s)
- Jie Song
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Shuyang Yao
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Kaarina Kowalec
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- College of Pharmacy, University of Manitoba, Winnipeg, MB, Canada
| | - Yi Lu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Amir Sariaslan
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
| | - Jin P Szatkiewicz
- Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA
| | - Henrik Larsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- School of Medical Sciences, Örebo University, Örebo, Sweden
| | - Paul Lichtenstein
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Christina M Hultman
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Icahn School of Medicine, Department of Psychiatry, Mt Sinai Hospital, New York, NY, USA
| | - Patrick F Sullivan
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
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25
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Kuhns L, Kroon E, Colyer-Patel K, Cousijn J. Associations between cannabis use, cannabis use disorder, and mood disorders: longitudinal, genetic, and neurocognitive evidence. Psychopharmacology (Berl) 2022; 239:1231-1249. [PMID: 34741634 PMCID: PMC9520129 DOI: 10.1007/s00213-021-06001-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 10/11/2021] [Indexed: 12/16/2022]
Abstract
RATIONALE Cannabis use among people with mood disorders increased in recent years. While comorbidity between cannabis use, cannabis use disorder (CUD), and mood disorders is high, the underlying mechanisms remain unclear. OBJECTIVES We aimed to evaluate (1) the epidemiological evidence for an association between cannabis use, CUD, and mood disorders; (2) prospective longitudinal, genetic, and neurocognitive evidence of underlying mechanisms; and (3) prognosis and treatment options for individuals with CUD and mood disorders. METHODS Narrative review of existing literature is identified through PubMed searches, reviews, and meta-analyses. Evidence was reviewed separately for depression, bipolar disorder, and suicide. RESULTS Current evidence is limited and mixed but suggestive of a bidirectional relationship between cannabis use, CUD, and the onset of depression. The evidence more consistently points to cannabis use preceding onset of bipolar disorder. Shared neurocognitive mechanisms and underlying genetic and environmental risk factors appear to explain part of the association. However, cannabis use itself may also influence the development of mood disorders, while others may initiate cannabis use to self-medicate symptoms. Comorbid cannabis use and CUD are associated with worse prognosis for depression and bipolar disorder including increased suicidal behaviors. Evidence for targeted treatments is limited. CONCLUSIONS The current evidence base is limited by the lack of well-controlled prospective longitudinal studies and clinical studies including comorbid individuals. Future studies in humans examining the causal pathways and potential mechanisms of the association between cannabis use, CUD, and mood disorder comorbidity are crucial for optimizing harm reduction and treatment strategies.
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Affiliation(s)
- Lauren Kuhns
- Department of Psychology, Neuroscience of Addiction (NofA, University of Amsterdam, Amsterdam, the Netherlands.
- The Amsterdam Brain and Cognition Center (ABC), University of Amsterdam, Amsterdam, the Netherlands.
| | - Emese Kroon
- Department of Psychology, Neuroscience of Addiction (NofA, University of Amsterdam, Amsterdam, the Netherlands
- The Amsterdam Brain and Cognition Center (ABC), University of Amsterdam, Amsterdam, the Netherlands
| | - Karis Colyer-Patel
- Department of Psychology, Neuroscience of Addiction (NofA, University of Amsterdam, Amsterdam, the Netherlands
| | - Janna Cousijn
- Department of Psychology, Neuroscience of Addiction (NofA, University of Amsterdam, Amsterdam, the Netherlands
- The Amsterdam Brain and Cognition Center (ABC), University of Amsterdam, Amsterdam, the Netherlands
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26
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Kamran M, Bibi F, ur. Rehman A, Morris DW. Major Depressive Disorder: Existing Hypotheses about Pathophysiological Mechanisms and New Genetic Findings. Genes (Basel) 2022; 13:646. [PMID: 35456452 PMCID: PMC9025468 DOI: 10.3390/genes13040646] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/16/2022] [Accepted: 03/23/2022] [Indexed: 01/08/2023] Open
Abstract
Major depressive disorder (MDD) is a common mental disorder generally characterized by symptoms associated with mood, pleasure and effectiveness in daily life activities. MDD is ranked as a major contributor to worldwide disability. The complex pathogenesis of MDD is not yet understood, and this is a major cause of failure to develop new therapies and MDD recurrence. Here we summarize the literature on existing hypotheses about the pathophysiological mechanisms of MDD. We describe the different approaches undertaken to understand the molecular mechanism of MDD using genetic data. Hundreds of loci have now been identified by large genome-wide association studies (GWAS). We describe these studies and how they have provided information on the biological processes, cell types, tissues and druggable targets that are enriched for MDD risk genes. We detail our understanding of the genetic correlations and causal relationships between MDD and many psychiatric and non-psychiatric disorders and traits. We highlight the challenges associated with genetic studies, including the complexity of MDD genetics in diverse populations and the need for a study of rare variants and new studies of gene-environment interactions.
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Affiliation(s)
- Muhammad Kamran
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (M.K.); (A.u.R.)
- Centre for Neuroimaging, Cognition and Genomics (NICOG), Discipline of Biochemistry, National University of Ireland Galway, H91 CF50 Galway, Ireland
| | - Farhana Bibi
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan;
| | - Asim. ur. Rehman
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (M.K.); (A.u.R.)
| | - Derek W. Morris
- Centre for Neuroimaging, Cognition and Genomics (NICOG), Discipline of Biochemistry, National University of Ireland Galway, H91 CF50 Galway, Ireland
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27
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Barbu MC, Huider F, Campbell A, Amador C, Adams MJ, Lynall ME, Howard DM, Walker RM, Morris SW, Van Dongen J, Porteous DJ, Evans KL, Bullmore E, Willemsen G, Boomsma DI, Whalley HC, McIntosh AM. Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system. Mol Psychiatry 2022; 27:1647-1657. [PMID: 34880450 PMCID: PMC9095457 DOI: 10.1038/s41380-021-01412-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 10/11/2021] [Accepted: 11/26/2021] [Indexed: 12/28/2022]
Abstract
Antidepressants are an effective treatment for major depressive disorder (MDD), although individual response is unpredictable and highly variable. Whilst the mode of action of antidepressants is incompletely understood, many medications are associated with changes in DNA methylation in genes that are plausibly linked to their mechanisms. Studies of DNA methylation may therefore reveal the biological processes underpinning the efficacy and side effects of antidepressants. We performed a methylome-wide association study (MWAS) of self-reported antidepressant use accounting for lifestyle factors and MDD in Generation Scotland (GS:SFHS, N = 6428, EPIC array) and the Netherlands Twin Register (NTR, N = 2449, 450 K array) and ran a meta-analysis of antidepressant use across these two cohorts. We found ten CpG sites significantly associated with self-reported antidepressant use in GS:SFHS, with the top CpG located within a gene previously associated with mental health disorders, ATP6V1B2 (β = -0.055, pcorrected = 0.005). Other top loci were annotated to genes including CASP10, TMBIM1, MAPKAPK3, and HEBP2, which have previously been implicated in the innate immune response. Next, using penalised regression, we trained a methylation-based score of self-reported antidepressant use in a subset of 3799 GS:SFHS individuals that predicted antidepressant use in a second subset of GS:SFHS (N = 3360, β = 0.377, p = 3.12 × 10-11, R2 = 2.12%). In an MWAS analysis of prescribed selective serotonin reuptake inhibitors, we showed convergent findings with those based on self-report. In NTR, we did not find any CpGs significantly associated with antidepressant use. The meta-analysis identified the two CpGs of the ten above that were common to the two arrays used as being significantly associated with antidepressant use, although the effect was in the opposite direction for one of them. Antidepressants were associated with epigenetic alterations in loci previously associated with mental health disorders and the innate immune system. These changes predicted self-reported antidepressant use in a subset of GS:SFHS and identified processes that may be relevant to our mechanistic understanding of clinically relevant antidepressant drug actions and side effects.
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Affiliation(s)
- Miruna C Barbu
- Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
| | - Floris Huider
- Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Archie Campbell
- Centre for Genomic and Experimental Medicine, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Carmen Amador
- MRC Human Genetics Unit, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Mark J Adams
- Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
| | | | - David M Howard
- Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Rosie M Walker
- Centre for Genomic and Experimental Medicine, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Stewart W Morris
- Centre for Genomic and Experimental Medicine, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Jenny Van Dongen
- Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - David J Porteous
- Centre for Genomic and Experimental Medicine, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Kathryn L Evans
- Centre for Genomic and Experimental Medicine, The Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Edward Bullmore
- Department of Psychiatry, University of Cambridge, Cambridge, UK
| | - Gonneke Willemsen
- Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Dorret I Boomsma
- Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Heather C Whalley
- Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
| | - Andrew M McIntosh
- Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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28
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McPherson P, Sall S, Santos A, Thompson W, Dwyer DS. Catalytic Reaction Model of Suicide. Front Psychiatry 2022; 13:817224. [PMID: 35356712 PMCID: PMC8959568 DOI: 10.3389/fpsyt.2022.817224] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/07/2022] [Indexed: 12/20/2022] Open
Abstract
Suicide is a devastating outcome of unresolved issues that affect mental health, general wellbeing and socioeconomic stress. The biology of suicidal behavior is still poorly understood, although progress has been made. Suicidal behavior runs in families and genetic studies have provided initial glimpses into potential genes that contribute to suicide risk. Here, we attempt to unify the biology and behavioral dimensions into a model that can guide research in this area. The proposed model envisions suicidal behavior as a catalytic reaction that may result in suicide depending on the conditions, analogously to enzyme catalysis of chemical reactions. A wide array of substrates or reactants, such as hopelessness, depression, debilitating illnesses and diminished motivation can mobilize suicidal thoughts and behaviors (STBs), which can then catalyze the final step/act of suicide. Here, we focus on three biological substrates in particular: threat assessment, motivation to engage in life and impulsivity. Genetic risk factors can affect each of these processes and tilt the balance toward suicidal behavior when existential crises (real or perceived) emerge such as loss of a loved one, sudden changes in social status or serious health issues. Although suicide is a uniquely human behavior, many of the fundamental biological processes are evolutionarily conserved. Insights from animal models may help to shape our understanding of suicidal behavior in man. By examining counterparts of the major biological processes in other organisms, new ideas about the role of genetic risk factors may emerge along with possible therapeutic interventions or preventive measures.
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Affiliation(s)
- Pamela McPherson
- Department of Psychiatry and Behavioral Medicine, Shreveport, LA, United States
| | - Saveen Sall
- Department of Psychiatry and Behavioral Medicine, Shreveport, LA, United States
| | - Aurianna Santos
- Department of Psychiatry and Behavioral Medicine, Shreveport, LA, United States
| | - Willie Thompson
- Department of Psychiatry and Behavioral Medicine, Shreveport, LA, United States
| | - Donard S Dwyer
- Department of Psychiatry and Behavioral Medicine, Shreveport, LA, United States.,Department of Pharmacology, Toxicology and Neuroscience, LSU Health Shreveport, Shreveport, LA, United States
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29
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Kendler KS. The beginnings of biometrical psychiatric genetics: Studies of the insane diathesis 1905-1909. Am J Med Genet B Neuropsychiatr Genet 2022; 189:6-15. [PMID: 34997802 DOI: 10.1002/ajmg.b.32885] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 11/09/2022]
Abstract
The year 1900 saw not only the rediscovery of Mendel's hybridization studies but also the publication by Karl Pearson of his newly developed tetrachoric correlation which he used to study the parent-offspring resemblance for the "insane diathesis" in 1905. This was followed by more detailed reports by two of his students/associates: Heron in 1907 and Goring in 1909. Both calculated the tetrachoric correlation for insanity in parent-offspring and Heron for sib-sib pairs. Estimates ranged from approximately +0.30 to +0.60. These papers were statistically sophisticated but demonstrated minimal interest in the phenotype being studied. They are of historical interest because they laid the groundwork for biometrical psychiatric genetics which emerged as a major research paradigm in latter third of the 20th century. In a biting critique of Heron's paper by a young Ernst Rüdin, we see the beginnings of a long-running argument in psychiatric genetics about the relative value of detailed phenotyping versus novel statistical methods and of Mendelian versus Biometrical methods. While much interest has focused on the eugenic orientation of German psychiatric genetics in the early 20th century, these early British biometrical geneticists, like the majority of geneticists of that day, were also ardent advocates of the eugenic application of their research results.
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Affiliation(s)
- Kenneth S Kendler
- Virginia Institute of Psychiatric and Behavioral Genetics, and Department of Psychiatry, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA
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30
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Gene-Environment Interactions in Schizophrenia: A Literature Review. Genes (Basel) 2021; 12:genes12121850. [PMID: 34946799 PMCID: PMC8702084 DOI: 10.3390/genes12121850] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
Schizophrenia is a devastating mental illness with a strong genetic component that is the subject of extensive research. Despite the high heritability, it is well recognized that non-genetic factors such as certain infections, cannabis use, psychosocial stress, childhood adversity, urban environment, and immigrant status also play a role. Whenever genetic and non-genetic factors co-exist, interaction between the two is likely. This means that certain exposures would only be of consequence given a specific genetic makeup. Here, we provide a brief review of studies reporting evidence of such interactions, exploring genes and variants that moderate the effect of the environment to increase risk of developing psychosis. Discovering these interactions is crucial to our understanding of the pathogenesis of complex disorders. It can help in identifying individuals at high risk, in developing individualized treatments and prevention plans, and can influence clinical management.
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31
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Sannes AC, Christensen JO, Nielsen MB, Gjerstad J. The association between abusive supervision and anxiety in female employees is stronger in carriers of the CRHR1 TAT haplotype. CURRENT RESEARCH IN BEHAVIORAL SCIENCES 2021. [DOI: 10.1016/j.crbeha.2021.100021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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32
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Hime GR, Stonehouse SLA, Pang TY. Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man. World J Psychiatry 2021; 11:711-735. [PMID: 34733638 PMCID: PMC8546770 DOI: 10.5498/wjp.v11.i10.711] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/19/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Mental illness remains the greatest chronic health burden globally with few in-roads having been made despite significant advances in genomic knowledge in recent decades. The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations, and that has to be supported by a continuous growth in knowledge. The majority of neuropsychiatric symptoms reflect complex gene-environment interactions, with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms. It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stress-related behavioural phenotypes in both paternal and maternal lineages, providing further supporting evidence for heritability in humans. However, unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions. While rodents will remain the dominant model system for preclinical studies (especially for addressing complex behavioural phenotypes), there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models. Here, we will discuss the utility and advantages of two alternative model organisms-Caenorhabditis elegans and Drosophila melanogaster-and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.
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Affiliation(s)
- Gary R Hime
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, VIC, Australia
| | - Sophie LA Stonehouse
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville 3052, VIC, Australia
| | - Terence Y Pang
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, VIC, Australia
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville 3052, VIC, Australia
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33
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Kendall KM, Van Assche E, Andlauer TFM, Choi KW, Luykx JJ, Schulte EC, Lu Y. The genetic basis of major depression. Psychol Med 2021; 51:2217-2230. [PMID: 33682643 DOI: 10.1017/s0033291721000441] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene-environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.
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Affiliation(s)
- K M Kendall
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - E Van Assche
- Department of Psychiatry, University of Muenster, Muenster, Germany
| | - T F M Andlauer
- Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - K W Choi
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA02114, USA
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA02114, USA
- Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA02115, USA
| | - J J Luykx
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Outpatient Second Opinion Clinic, GGNet Mental Health, Warnsveld, The Netherlands
| | - E C Schulte
- Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
| | - Y Lu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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34
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Sewell MDE, Jiménez-Sánchez L, Shen X, Edmondson-Stait AJ, Green C, Adams MJ, Rifai OM, McIntosh AM, Lyall DM, Whalley HC, Lawrie SM. Associations between major psychiatric disorder polygenic risk scores and blood-based markers in UK biobank. Brain Behav Immun 2021; 97:32-41. [PMID: 34107350 DOI: 10.1016/j.bbi.2021.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/16/2021] [Accepted: 06/04/2021] [Indexed: 01/08/2023] Open
Abstract
Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors, and are associated with peripheral abnormalities. The relationships between such genetic architectures and blood-based markers are, however, unclear. We investigated relationships between polygenic risk scores (PRS) for these disorders and peripheral markers in the UK Biobank cohort. We calculated polygenic risk scores for n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) UK Biobank cohort subjects. We then examined associations between disorder PRS and 58 inflammatory/immune, hematological, bone, cardiovascular, hormone, liver, renal and diabetes-associated blood markers using two generalized linear regression models: 'minimally adjusted' controlling for variables such as age and sex, and 'fully adjusted' including additional lifestyle covariates: BMI, alcohol and smoking status, and medication intake. There were 38/58 MDD PRS, 32/58 SCZ PRS, and 20/58 BD PRS-blood marker associations detected for our minimally adjusted model. Of these, 13/38 (MDD PRS), 14/32 (SCZ PRS), and 10/20 (BD PRS) associations remained significant after controlling for lifestyle factors. Many were disorder-specific, with 8/13 unique MDD PRS associations identified. Several disorder-specific associations for MDD and SCZ were immune-related, with mostly positive and negative associations identified for MDD and SCZ PRS respectively. This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk. The results also implicate inflammatory dysfunction in MDD and SCZ, albeit with differences in patterns between the two conditions, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.
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Affiliation(s)
- Michael D E Sewell
- Translational Neuroscience PhD Programme, Centre for Clinical Brain Sciences, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.
| | - Lorena Jiménez-Sánchez
- Translational Neuroscience PhD Programme, Centre for Clinical Brain Sciences, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK
| | - Xueyi Shen
- Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK
| | - Amelia J Edmondson-Stait
- Translational Neuroscience PhD Programme, Centre for Clinical Brain Sciences, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK
| | - Claire Green
- Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK
| | - Mark J Adams
- Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
| | - Olivia M Rifai
- Translational Neuroscience PhD Programme, Centre for Clinical Brain Sciences, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK
| | - Andrew M McIntosh
- Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
| | - Donald M Lyall
- Institute of Health & Wellbeing, University of Glasgow, Glasgow G12 8RZ, UK
| | - Heather C Whalley
- Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK
| | - Stephen M Lawrie
- Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK
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Major Depressive Disorder and Lifestyle: Correlated Genetic Effects in Extended Twin Pedigrees. Genes (Basel) 2021; 12:genes12101509. [PMID: 34680904 PMCID: PMC8535260 DOI: 10.3390/genes12101509] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/21/2021] [Accepted: 09/22/2021] [Indexed: 12/27/2022] Open
Abstract
In recent years, evidence has accumulated with regard to the ubiquity of pleiotropy across the genome, and shared genetic etiology is thought to play a large role in the widespread comorbidity among psychiatric disorders and risk factors. Recent methods investigate pleiotropy by estimating genetic correlation from genome-wide association summary statistics. More comprehensive estimates can be derived from the known relatedness between genetic relatives. Analysis of extended twin pedigree data allows for the estimation of genetic correlation for additive and non-additive genetic effects, as well as a shared household effect. Here we conduct a series of bivariate genetic analyses in extended twin pedigree data on lifetime major depressive disorder (MDD) and three indicators of lifestyle, namely smoking behavior, physical inactivity, and obesity, decomposing phenotypic variance and covariance into genetic and environmental components. We analyze lifetime MDD and lifestyle data in a large multigenerational dataset of 19,496 individuals by variance component analysis in the ‘Mendel’ software. We find genetic correlations for MDD and smoking behavior (rG = 0.249), physical inactivity (rG = 0.161), body-mass index (rG = 0.081), and obesity (rG = 0.155), which were primarily driven by additive genetic effects. These outcomes provide evidence in favor of a shared genetic etiology between MDD and the lifestyle factors.
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Sall S, Thompson W, Santos A, Dwyer DS. Analysis of Major Depression Risk Genes Reveals Evolutionary Conservation, Shared Phenotypes, and Extensive Genetic Interactions. Front Psychiatry 2021; 12:698029. [PMID: 34335334 PMCID: PMC8319724 DOI: 10.3389/fpsyt.2021.698029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/21/2021] [Indexed: 12/29/2022] Open
Abstract
Major depressive disorder (MDD) affects around 15% of the population at some stage in their lifetime. It can be gravely disabling and it is associated with increased risk of suicide. Genetics play an important role; however, there are additional environmental contributions to the pathogenesis. A number of possible risk genes that increase liability for developing symptoms of MDD have been identified in genome-wide association studies (GWAS). The goal of this study was to characterize the MDD risk genes with respect to the degree of evolutionary conservation in simpler model organisms such as Caenorhabditis elegans and zebrafish, the phenotypes associated with variation in these genes and the extent of network connectivity. The MDD risk genes showed higher conservation in C. elegans and zebrafish than genome-to-genome comparisons. In addition, there were recurring themes among the phenotypes associated with variation of these risk genes in C. elegans. The phenotype analysis revealed enrichment for essential genes with pleiotropic effects. Moreover, the MDD risk genes participated in more interactions with each other than did randomly-selected genes from similar-sized gene sets. Syntenic blocks of risk genes with common functional activities were also identified. By characterizing evolutionarily-conserved counterparts to the MDD risk genes, we have gained new insights into pathogenetic processes relevant to the emergence of depressive symptoms in man.
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Affiliation(s)
- Saveen Sall
- Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Willie Thompson
- Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Aurianna Santos
- Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Donard S. Dwyer
- Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Shreveport, Shreveport, LA, United States
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Cazes J, Dimick MK, Kennedy KG, Fiksenbaum L, Zai CC, Patel R, Islam AH, Tampakeras M, Freeman N, Kennedy JL, MacIntosh BJ, Goldstein BI. Structural neuroimaging phenotypes of a novel multi-gene risk score in youth bipolar disorder. J Affect Disord 2021; 289:135-143. [PMID: 33979723 DOI: 10.1016/j.jad.2021.04.040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/19/2021] [Accepted: 04/21/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD. METHODS MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions. RESULTS MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; β=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC. LIMITATIONS Cross-sectional design, modest sample size. CONCLUSIONS There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.
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Affiliation(s)
| | - Mikaela K Dimick
- University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Kody G Kennedy
- University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Lisa Fiksenbaum
- Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Clement C Zai
- Neurogenetics Section and Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Harvard T.H. Chan School of Public Health, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA
| | - Ronak Patel
- University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Alvi H Islam
- University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Maria Tampakeras
- Neurogenetics Section and Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Natalie Freeman
- Neurogenetics Section and Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - James L Kennedy
- University of Toronto, Toronto, ON, Canada; Neurogenetics Section and Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Bradley J MacIntosh
- Hurvitz Brain Sciences, Sunnybrook Research Institute, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Benjamin I Goldstein
- University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
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Lisoway AJ, Chen CC, Zai CC, Tiwari AK, Kennedy JL. Toward personalized medicine in schizophrenia: Genetics and epigenetics of antipsychotic treatment. Schizophr Res 2021; 232:112-124. [PMID: 34049235 DOI: 10.1016/j.schres.2021.05.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/30/2021] [Accepted: 05/02/2021] [Indexed: 12/21/2022]
Abstract
Schizophrenia is a complex psychiatric disorder where genetic, epigenetic, and environmental factors play a role in disease onset, course of illness, and treatment outcome. Pharmaco(epi)genetic research presents an important opportunity to improve patient care through prediction of medication side effects and response. In this narrative review, we discuss the current state of research and important progress of both genetic and epigenetic factors involved in antipsychotic response, over the past five years. The review is largely focused on the following frequently prescribed antipsychotics: olanzapine, risperidone, aripiprazole, and clozapine. Several consistent pharmacogenetic findings have emerged, in particular pharmacokinetic genes (primarily cytochrome P450 enzymes) and pharmacodynamic genes involving dopamine, serotonin, and glutamate neurotransmission. In addition to studies analysing DNA sequence variants, there are also several pharmacoepigenetic studies of antipsychotic response that have focused on the measurement of DNA methylation. Although pharmacoepigenetics is still in its infancy, consideration of both genetic and epigenetic factors contributing to antipsychotic response and side effects no doubt will be increasingly important in personalized medicine. We provide recommendations for next steps in research and clinical evaluation.
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Affiliation(s)
- Amanda J Lisoway
- Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Canada
| | - Cheng C Chen
- Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Canada
| | - Clement C Zai
- Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada; Department of Psychiatry, University of Toronto, Canada
| | - Arun K Tiwari
- Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Canada
| | - James L Kennedy
- Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Canada; Department of Psychiatry, University of Toronto, Canada.
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39
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Greve AN, Uher R, Als TD, Jepsen JRM, Mortensen EL, Gantriis DL, Ohland J, Burton BK, Ellersgaard D, Christiani CJ, Spang KS, Hemager N, Plessen KJ, Thorup AAE, Bliksted V, Nordentoft M, Mors O. A Nationwide Cohort Study of Nonrandom Mating in Schizophrenia and Bipolar Disorder. Schizophr Bull 2021; 47:1342-1350. [PMID: 33772315 PMCID: PMC8379547 DOI: 10.1093/schbul/sbab021] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Nonrandom mating in parents with schizophrenia or bipolar disorder increases the population-level genetic variance among the offspring generation and creates familial (risk) environments likely to be shaped by specific conditions. The objective of this study was to investigate the occurrence of mental disorder and levels of cognitive and social functioning in individuals who have children by partners with schizophrenia or bipolar disorder compared to controls. The Danish High Risk and Resilience Study VIA 7 is a population-based cohort study conducted in Denmark between 2013 and 2016. This study focus on parents diagnosed with schizophrenia (n = 150) or bipolar disorder (n = 100) and control parents (n = 182), as well as their partners without schizophrenia or bipolar disorder (n = 440). We used linear mixed-effect models, and main outcomes were mental disorders, intelligence, processing speed, verbal working memory, and social functioning. We found that parents having children by a partner with schizophrenia or bipolar disorder more often fulfilled the criteria for a mental disorder and had poorer social functioning compared to parents having children by a partner without schizophrenia or bipolar disorder. Furthermore, parents having children by a partner with schizophrenia performed poorer on processing speed compared to parents in the control group. The presence of nonrandom mating found in this study has implications for our understanding of familial transmission of these disorders and our findings should be considered in future investigations of potential risk factors for children with a parent with schizophrenia or bipolar disorder.
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Affiliation(s)
- Aja Neergaard Greve
- Psychosis Research Unit, Aarhus University Hospital—Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus N, Denmark,The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,To whom correspondence should be addressed; tel: +45 6179 7035, e-mail:
| | - Rudolf Uher
- Department of Psychiatry, Dalhousie University, 5909 Veterans’ Memorial Lane, Halifax, NS, Canada
| | - Thomas Damm Als
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, 8000 Aarhus C, Denmark
| | - Jens Richardt Møllegaard Jepsen
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Centre for Neuropsychiatric Schizophrenia Research and Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, Copenhagen University Hospital, Ndr. Ringvej 29–67, 2600 Glostrup, Denmark,Copenhagen Research Centre for Mental Health (CORE), Mental Health Centre Copenhagen, Copenhagen University Hospital, Kildegaardsvej 28, Building 15, 4th, 2900 Hellerup, Denmark,Child and Adolescent Mental Health Centre, Copenhagen University Hospital, Gentofte Hospitalsvej nr 3A, 2900 Hellerup, Denmark
| | - Erik Lykke Mortensen
- Department of Public Health and Center for Healthy Aging, University of Copenhagen, Oester Farimagsgade 5, 1014 Copenhagen K, Denmark
| | - Ditte Lou Gantriis
- Psychosis Research Unit, Aarhus University Hospital—Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus N, Denmark,The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark
| | - Jessica Ohland
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Copenhagen Research Centre for Mental Health (CORE), Mental Health Centre Copenhagen, Copenhagen University Hospital, Kildegaardsvej 28, Building 15, 4th, 2900 Hellerup, Denmark
| | - Birgitte Klee Burton
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Child and Adolescent Mental Health Centre, Copenhagen University Hospital, Gentofte Hospitalsvej nr 3A, 2900 Hellerup, Denmark
| | - Ditte Ellersgaard
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Copenhagen Research Centre for Mental Health (CORE), Mental Health Centre Copenhagen, Copenhagen University Hospital, Kildegaardsvej 28, Building 15, 4th, 2900 Hellerup, Denmark
| | - Camilla Jerlang Christiani
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Copenhagen Research Centre for Mental Health (CORE), Mental Health Centre Copenhagen, Copenhagen University Hospital, Kildegaardsvej 28, Building 15, 4th, 2900 Hellerup, Denmark
| | - Katrine S Spang
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Child and Adolescent Mental Health Centre, Copenhagen University Hospital, Gentofte Hospitalsvej nr 3A, 2900 Hellerup, Denmark
| | - Nicoline Hemager
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Copenhagen Research Centre for Mental Health (CORE), Mental Health Centre Copenhagen, Copenhagen University Hospital, Kildegaardsvej 28, Building 15, 4th, 2900 Hellerup, Denmark,Child and Adolescent Mental Health Centre, Copenhagen University Hospital, Gentofte Hospitalsvej nr 3A, 2900 Hellerup, Denmark
| | - Kerstin J Plessen
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Child and Adolescent Mental Health Centre, Copenhagen University Hospital, Gentofte Hospitalsvej nr 3A, 2900 Hellerup, Denmark,Division of Child and Adolescent Psychiatry, Department of Psychiatry, University Hospital Lausanne, Switzerland
| | - Anne A E Thorup
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Child and Adolescent Mental Health Centre, Copenhagen University Hospital, Gentofte Hospitalsvej nr 3A, 2900 Hellerup, Denmark
| | - Vibeke Bliksted
- Psychosis Research Unit, Aarhus University Hospital—Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus N, Denmark,The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Department of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark
| | - Merete Nordentoft
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark,Copenhagen Research Centre for Mental Health (CORE), Mental Health Centre Copenhagen, Copenhagen University Hospital, Kildegaardsvej 28, Building 15, 4th, 2900 Hellerup, Denmark
| | - Ole Mors
- Psychosis Research Unit, Aarhus University Hospital—Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus N, Denmark,The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark
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40
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Fürtjes AE, Coleman JRI, Tyrrell J, Lewis CM, Hagenaars SP. Associations and limited shared genetic aetiology between bipolar disorder and cardiometabolic traits in the UK Biobank. Psychol Med 2021; 52:1-10. [PMID: 33766158 PMCID: PMC9811277 DOI: 10.1017/s0033291721000945] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 02/23/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND People with bipolar disorder (BPD) are more likely to die prematurely, which is partly attributed to comorbid cardiometabolic traits. Previous studies report cardiometabolic abnormalities in BPD, but their shared aetiology remains poorly understood. This study examined the phenotypic associations and shared genetic aetiology between BPD and various cardiometabolic traits. METHODS In a subset of the UK Biobank sample (N = 61 508) we investigated phenotypic associations between BPD (ncases = 4186) and cardiometabolic traits, represented by biomarkers, anthropometric traits and cardiometabolic diseases. To determine shared genetic aetiology in European ancestry, polygenic risk scores (PRS) and genetic correlations were calculated between BPD and cardiometabolic traits. RESULTS Several traits were significantly associated with increased risk for BPD, namely low total cholesterol, low high-density lipoprotein cholesterol, high triglycerides, high glycated haemoglobin, low systolic blood pressure, high body mass index, high waist-to-hip ratio; and stroke, coronary artery disease and type 2 diabetes diagnosis. BPD was associated with higher polygenic risk for triglycerides, waist-to-hip ratio, coronary artery disease and type 2 diabetes. Shared genetic aetiology persisted for coronary artery disease, when correcting PRS associations for cardiometabolic base phenotypes. Associations were not replicated using genetic correlations. CONCLUSIONS This large study identified increased phenotypic cardiometabolic abnormalities in BPD participants. It is found that the comorbidity of coronary artery disease may be based on shared genetic aetiology. These results motivate hypothesis-driven research to consider individual cardiometabolic traits rather than a composite metabolic syndrome when attempting to disentangle driving mechanisms of cardiometabolic abnormalities in BPD.
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Affiliation(s)
- Anna E. Fürtjes
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Jonathan R. I. Coleman
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- National Institute for Health Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Trust, London, UK
| | - Jess Tyrrell
- Genetics of Complex Traits, The College of Medicine and Health, University of Exeter, The RILD Building, RD&E Hospital, Exeter, EX2 5DW, UK
| | - Cathryn M. Lewis
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Saskia P. Hagenaars
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
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41
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Circadian depression: A mood disorder phenotype. Neurosci Biobehav Rev 2021; 126:79-101. [PMID: 33689801 DOI: 10.1016/j.neubiorev.2021.02.045] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 02/18/2021] [Accepted: 02/28/2021] [Indexed: 12/15/2022]
Abstract
Major mood syndromes are among the most common and disabling mental disorders. However, a lack of clear delineation of their underlying pathophysiological mechanisms is a major barrier to prevention and optimised treatments. Dysfunction of the 24-h circadian system is a candidate mechanism that has genetic, behavioural, and neurobiological links to mood syndromes. Here, we outline evidence for a new clinical phenotype, which we have called 'circadian depression'. We propose that key clinical characteristics of circadian depression include disrupted 24-h sleep-wake cycles, reduced motor activity, low subjective energy, and weight gain. The illness course includes early age-of-onset, phenomena suggestive of bipolarity (defined by bidirectional associations between objective motor and subjective energy/mood states), poor response to conventional antidepressant medications, and concurrent cardiometabolic and inflammatory disturbances. Identifying this phenotype could be clinically valuable, as circadian-targeted strategies show promise for reducing depressive symptoms and stabilising illness course. Further investigation of underlying circadian disturbances in mood syndromes is needed to evaluate the clinical utility of this phenotype and guide the optimal use of circadian-targeted interventions.
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42
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Wilson S, Elkins IJ, Malone SM, Iacono WG, McGue M. Associations Between Common Forms of Psychopathology and Fecundity: Evidence From a Prospective, Longitudinal Twin Study. Clin Psychol Sci 2021; 9:197-209. [PMID: 34012724 PMCID: PMC8127725 DOI: 10.1177/2167702620957321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
We examined associations between common psychiatric disorders and fecundity in a population-based cohort of 1252 twins prospectively assessed from adolescence into adulthood. Major depressive, anxiety, and alcohol use disorders were associated with lower likelihood of having children and having fewer children. Survival analyses yielded similar results accounting for timing/recurrence. Although both early- and adult-onset psychiatric disorders were associated with decreased fecundity, early-onset major depressive, anxiety (among boys), and alcohol use disorders (among girls) were associated with greater likelihood of having a child during adolescence. Among twin pairs discordant for psychiatric disorders, twins affected by anxiety and alcohol use, but not major depressive, disorders were less likely to have children than unaffected co-twins. However, unaffected twins with an affected co-twin were no more likely to have children than twins from unaffected twin pairs, inconsistent with the balancing selection hypothesis that increased fecundity in unaffected relatives accounts for persistence of psychiatric disorders.
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43
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Wu Y, Murray GK, Byrne EM, Sidorenko J, Visscher PM, Wray NR. GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression. Nat Commun 2021; 12:1146. [PMID: 33608531 PMCID: PMC7895976 DOI: 10.1038/s41467-021-21280-7] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 01/06/2021] [Indexed: 01/31/2023] Open
Abstract
Genetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here, genome-wide association study (GWAS) analyses based on 456,327 UK Biobank (UKB) individuals identify 8 independent and significant loci for PUD at, or near, genes MUC1, MUC6, FUT2, PSCA, ABO, CDX2, GAST and CCKBR. There are previously established roles in susceptibility to Helicobacter pylori infection, response to counteract infection-related damage, gastric acid secretion or gastrointestinal motility for these genes. Only two associations have been previously reported for duodenal ulcer, here replicated trans-ancestrally. The results highlight the role of host genetic susceptibility to infection. Post-GWAS analyses for PUD, GORD, IBS and IBD add insights into relationships between these gastrointestinal diseases and their relationships with depression, a commonly comorbid disorder.
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Affiliation(s)
- Yeda Wu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
| | - Graham K Murray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Department of Psychiatry, University of Cambridge, Cambridge, UK
- Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
- Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Enda M Byrne
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Julia Sidorenko
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Peter M Visscher
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Naomi R Wray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
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44
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Wu W, Howard D, Sibille E, French L. Differential and spatial expression meta-analysis of genes identified in genome-wide association studies of depression. Transl Psychiatry 2021; 11:8. [PMID: 33414381 PMCID: PMC7791035 DOI: 10.1038/s41398-020-01127-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 11/11/2020] [Accepted: 11/27/2020] [Indexed: 01/29/2023] Open
Abstract
Major depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide and affects individuals of all ages. It causes significant psychosocial impairments and is a major cause of disability. A recent consortium study identified 102 genetic variants and 269 genes associated with depression. To provide targets for future depression research, we prioritized these recently identified genes using expression data. We examined the differential expression of these genes in three studies that profiled gene expression of MDD cases and controls across multiple brain regions. In addition, we integrated anatomical expression information to determine which brain regions and transcriptomic cell types highly express the candidate genes. We highlight 12 of the 269 genes with the most consistent differential expression: MANEA, UBE2M, CKB, ITPR3, SPRY2, SAMD5, TMEM106B, ZC3H7B, LST1, ASXL3, ZNF184 and HSPA1A. The majority of these top genes were found to have sex-specific differential expression. We place greater emphasis on ZNF184 as it is the top gene in a more conservative analysis of the 269. Specifically, the differential expression of ZNF184 was strongest in subcortical regions in males and females. Anatomically, our results suggest the importance of the dorsal lateral geniculate nucleus, cholinergic, monoaminergic and enteric neurons. These findings provide a guide for targeted experiments to advance our understanding of the genetic underpinnings of depression.
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Affiliation(s)
- Wennie Wu
- Institute for Medical Science, University of Toronto, Toronto, Canada
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
- Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Derek Howard
- Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Etienne Sibille
- Institute for Medical Science, University of Toronto, Toronto, Canada
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
- Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
| | - Leon French
- Institute for Medical Science, University of Toronto, Toronto, Canada.
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada.
- Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada.
- Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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45
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Baselmans BML, Yengo L, van Rheenen W, Wray NR. Risk in Relatives, Heritability, SNP-Based Heritability, and Genetic Correlations in Psychiatric Disorders: A Review. Biol Psychiatry 2021; 89:11-19. [PMID: 32736793 DOI: 10.1016/j.biopsych.2020.05.034] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/14/2020] [Accepted: 05/27/2020] [Indexed: 12/19/2022]
Abstract
The genetic contribution to psychiatric disorders is observed through the increased rates of disorders in the relatives of those diagnosed with disorders. These increased rates are observed to be nonspecific; for example, children of those with schizophrenia have increased rates of schizophrenia but also a broad range of other psychiatric diagnoses. While many factors contribute to risk, epidemiological evidence suggests that the genetic contribution carries the highest risk burden. The patterns of inheritance are consistent with a polygenic architecture of many contributing risk loci. The genetic studies of the past decade have provided empirical evidence identifying thousands of DNA variants associated with psychiatric disorders. Here, we describe how these latest results are consistent with observations from epidemiology. We provide an R tool (CHARRGe) to calculate genetic parameters from epidemiological parameters and vice versa. We discuss how the single nucleotide polymorphism-based estimates of heritability and genetic correlation relate to those estimated from family records.
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Affiliation(s)
- Bart M L Baselmans
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Loïc Yengo
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Wouter van Rheenen
- Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands
| | - Naomi R Wray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
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46
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Bigdeli TB, Fanous AH, Li Y, Rajeevan N, Sayward F, Genovese G, Gupta R, Radhakrishnan K, Malhotra AK, Sun N, Lu Q, Hu Y, Li B, Chen Q, Mane S, Miller P, Cheung KH, Gur RE, Greenwood TA, Braff DL, Achtyes ED, Buckley PF, Escamilla MA, Lehrer D, Malaspina DP, McCarroll SA, Rapaport MH, Vawter MP, Pato MT, Pato CN, Zhao H, Kosten TR, Brophy M, Pyarajan S, Shi Y, O’Leary TJ, Gleason T, Przygodzki R, Muralidhar S, Gaziano JM, Huang GD, Concato J, Siever LJ, Aslan M, Harvey PD. Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans. Schizophr Bull 2020; 47:517-529. [PMID: 33169155 PMCID: PMC7965063 DOI: 10.1093/schbul/sbaa133] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. METHODS We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. RESULTS Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. CONCLUSIONS We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.
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Affiliation(s)
- Tim B Bigdeli
- VA New York Harbor Healthcare System, Brooklyn, NY,Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY
| | - Ayman H Fanous
- VA New York Harbor Healthcare System, Brooklyn, NY,Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY
| | - Yuli Li
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Nallakkandi Rajeevan
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Frederick Sayward
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Giulio Genovese
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA,Department of Genetics, Harvard Medical School, Boston, MA
| | - Rishab Gupta
- Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY
| | - Krishnan Radhakrishnan
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,College of Medicine, University of Kentucky, Lexington, KY
| | - Anil K Malhotra
- Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY,Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY,Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, NY
| | - Ning Sun
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Qiongshi Lu
- Department of Medicine, Yale School of Medicine, New Haven, CT,Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, WI
| | - Yiming Hu
- Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Boyang Li
- Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Quan Chen
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Shrikant Mane
- Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Perry Miller
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Kei-Hoi Cheung
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Raquel E Gur
- Departments of Psychiatry and Child & Adolescent Psychiatry and Lifespan Brain Institute, University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia, Philadelphia, PA
| | | | - David L Braff
- Department of Psychiatry, University of California, La Jolla, San Diego, CA,VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA
| | | | - Eric D Achtyes
- Cherry Health and Michigan State University College of Human Medicine, Grand Rapids, MI
| | - Peter F Buckley
- School of Medicine, Virginia Commonwealth University, Richmond, VA
| | - Michael A Escamilla
- Department of Psychiatry, School of Medicine, University of Texas Rio Grande Valley, Harlingen, TX
| | - Douglas Lehrer
- Department of Psychiatry, Wright State University, Dayton, OH
| | - Dolores P Malaspina
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Steven A McCarroll
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA,Department of Genetics, Harvard Medical School, Boston, MA
| | - Mark H Rapaport
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA
| | - Marquis P Vawter
- Department of Psychiatry and Human Behavior, University of California, Irvine, CA
| | - Michele T Pato
- Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY
| | - Carlos N Pato
- Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY
| | | | - Hongyu Zhao
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Thomas R Kosten
- Departments of Psychiatry, Neuroscience, Pharmacology, and Immunology and Rheumatology, Baylor College of Medicine, Houston, TX
| | - Mary Brophy
- Massachusetts Area Veterans Epidemiology, Research, and Information Center (MAVERIC), Jamaica Plain, MA,Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA
| | - Saiju Pyarajan
- Massachusetts Area Veterans Epidemiology, Research, and Information Center (MAVERIC), Jamaica Plain, MA
| | - Yunling Shi
- Massachusetts Area Veterans Epidemiology, Research, and Information Center (MAVERIC), Jamaica Plain, MA
| | - Timothy J O’Leary
- Office of Research and Development, Veterans Health Administration, Washington, DC
| | - Theresa Gleason
- Office of Research and Development, Veterans Health Administration, Washington, DC
| | - Ronald Przygodzki
- Office of Research and Development, Veterans Health Administration, Washington, DC
| | - Sumitra Muralidhar
- Office of Research and Development, Veterans Health Administration, Washington, DC
| | - J Michael Gaziano
- Massachusetts Area Veterans Epidemiology, Research, and Information Center (MAVERIC), Jamaica Plain, MA,Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | | | - Grant D Huang
- Office of Research and Development, Veterans Health Administration, Washington, DC
| | - John Concato
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Larry J Siever
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY,University of Miami Miller School of Medicine, James J. Peters Veterans Affairs Medical Center, Bronx, NY
| | - Mihaela Aslan
- Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT,Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Philip D Harvey
- Research Service Bruce W. Carter VA Medical Center, Miami, FL,Department of Psychiatry, University of Miami Miller School of Medicine, Miami, FL,To whom correspondence should be addressed; Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 1450 Miami, FL 33136, USA; tel: (305)-243-4094, fax: (305)-243-1619, e-mail:
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47
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Kim AR, Sin JE. Genetic and environmental contributions to psychopathological symptoms in adulthood: Clarifying the role of individual and parental risk factors. Asian J Psychiatr 2020; 53:102195. [PMID: 32563947 DOI: 10.1016/j.ajp.2020.102195] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 04/27/2020] [Accepted: 06/02/2020] [Indexed: 10/24/2022]
Abstract
Psychopathology-related suicide attempts and deaths are increasing, and the research focus remains on mental disorder in childhood and adolescence. We examined the genetic and environmental contributions to internalizing, externalizing, and general psychopathological distress to clarify the role of individual/parental risk factors for suicide in young adults. Data from 1206 young adults were obtained from a publicly available dataset from the Human Connectome Project. Heritability estimates were analyzed by twin modelling using OpenMx and data from a subsample of 402 monozygotic and dizygotic twins. The estimated prevalence of psychopathological symptoms ranged from 9 to 16%. The heritability of internalizing, externalizing, and general psychopathological distress reached significance, with estimates ranging from 22 to 46%. Shared (common) environments contributed to aggressive behavior (30 %). Determining factors for psychopathological distress (internalizing, externalizing, general) were evaluated using logistic regression analysis. Household income (<$50,000), childhood conduct problems, and maternal drug or alcohol problems were common risk factors of internalizing, externalizing, and general psychopathological distress. Marijuana dependence and maternal anxiety were additional risk factors of externalizing distress. The presence of alcohol and maternal drug or alcohol problems was linked to general psychopathological distress. The results highlight risk factors associated with psychopathological symptoms that should be considered in the early detection of high-risk groups and implementation of family-based interventions. Providing continuous care and/or follow-up in at-risk children and young adults may improve mental health and well-being.
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Affiliation(s)
- Ah Rim Kim
- Department of Nursing, Far East University, 76-32 Daehak-gil, Gamgok-myeon, Eumseong-gun, Chungbuk, 27601, Republic of Korea.
| | - Jae Eun Sin
- Division of Cancer Control & Policy, National Cancer Control Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea.
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48
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Chen SW, Kuo CF, Huang YT, Lin WT, Chien-Chia Wu V, Chou AH, Lin PJ, Chang SH, Chu PH. Association of Family History With Incidence and Outcomes of Aortic Dissection. J Am Coll Cardiol 2020; 76:1181-1192. [DOI: 10.1016/j.jacc.2020.07.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 06/30/2020] [Accepted: 07/07/2020] [Indexed: 01/23/2023]
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49
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Muntané G, Farré X, Bosch E, Martorell L, Navarro A, Vilella E. The shared genetic architecture of schizophrenia, bipolar disorder and lifespan. Hum Genet 2020; 140:441-455. [PMID: 32772156 DOI: 10.1007/s00439-020-02213-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 07/27/2020] [Indexed: 12/11/2022]
Abstract
Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap-pleiotropy-between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder.
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Affiliation(s)
- Gerard Muntané
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Hospital Universitari Institut Pere Mata, IISPV Universitat Rovira i Virgili, Reus, Spain. .,Departament de Ciències Experimentals i de la Salut, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
| | - Xavier Farré
- Departament de Ciències Experimentals i de la Salut, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain
| | - Elena Bosch
- Departament de Ciències Experimentals i de la Salut, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain
| | - Lourdes Martorell
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Hospital Universitari Institut Pere Mata, IISPV Universitat Rovira i Virgili, Reus, Spain
| | - Arcadi Navarro
- Departament de Ciències Experimentals i de la Salut, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats, ICREA, Barcelona, Spain.,Barcelonaβeta Brain Research Center, Fundació Pasqual Maragall, Barcelona, Spain
| | - Elisabet Vilella
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Hospital Universitari Institut Pere Mata, IISPV Universitat Rovira i Virgili, Reus, Spain
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50
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Abstract
Abstract
A long-established hypothesis is that schizophrenia has a strong genetic component. In the early 1990s, the first genetic variant that substantially increases risk for psychosis was identified. Since this initial reporting of deletions in the chromosomal region 22q11.2, nearly two decades passed until substantial insights into schizophrenia’s genetic architecture were gained. Schizophrenia is a polygenic disorder and genetic risk is conferred by both common and rare alleles distributed across the genome. A small number of rare, deleterious copy number variants (CNVs) are associated with moderate to substantial increases in individual risk to schizophrenia. These deletions and duplications are also associated with a range of neurodevelopmental disorders. The diagnostic investigation of CNVs in patients with schizophrenia is likely to represent one of the first examples of genetic testing in clinical psychiatry. The prerequisites for this are currently being defined.
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Affiliation(s)
- Franziska Degenhardt
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy , LVR Klinikum Essen, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
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