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Borkhataria CH, Sharma S, Vaja P, Tank C, Mori D, Patel K, Kyada A. Quality management, ethical considerations, and emerging challenges in genomics and biobanking: A comprehensive review. Clin Chim Acta 2025; 569:120161. [PMID: 39864572 DOI: 10.1016/j.cca.2025.120161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/29/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 01/28/2025]
Abstract
The integration of genomics into personalized medicine has the potential to transform healthcare by customizing treatments according to individual genetic profiles. This paper examines the diverse applications of genomics, including the identification of disease susceptibility, improvement of diagnostic methods, optimization of drug therapies, and monitoring of treatment responses. It also explores the expanding global market for genetic testing and the increasing implementation of whole-genome sequencing in clinical practice, with a focus on pilot programs that are advancing comprehensive genomic analysis. Despite challenges such as high costs, data interpretation complexities, and ethical concerns, significant efforts are being made to address these issues. Additionally, the creation of biobanks as vital resources for preserving high-quality biosamples and supporting research highlights the critical need for infrastructure development in genomics. By fostering interdisciplinary collaboration and establishing robust ethical and regulatory frameworks, personalized medicine can ensure equitable access to tailored therapies and enhance health outcomes for everyone. This abstract provides an overview of the transformative potential of genomics and personalized medicine in ushering in a new era of precision healthcare.
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Affiliation(s)
| | - Shweta Sharma
- B K Mody Government Pharmacy College Rajkot Gujarat India
| | - Payal Vaja
- School of Pharmacy, Dr. Subhash University Junagadh Gujarat India
| | | | - Dhaval Mori
- B K Mody Government Pharmacy College Rajkot Gujarat India
| | | | - Ashishkumar Kyada
- Department of Pharmaceutical Sciences, Marwadi University Rajkot Gujarat India
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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] [Academic Contribution 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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Lu K, Zhou Z, Huang Z, Bu C, Gong H, Jiang L, Zhang D, Fang Q, Zhang XY, Song Y. Unveiling the genetic networks: Exploring the dynamic interaction of photosynthetic phenotypes in woody plants across varied light gradients. PLANT PHYSIOLOGY AND BIOCHEMISTRY : PPB 2025; 221:109616. [PMID: 39933425 DOI: 10.1016/j.plaphy.2025.109616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 10/13/2024] [Revised: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 02/13/2025]
Abstract
Understanding the mechanisms by which genes control and regulate complex quantitative traits during periods of fluctuating resources remains a challenging and uncertain task in photosynthesis studies. Most studies have focused on the structure of photosynthesis, the photosynthetic response under stress, or the genetic mechanisms involved in photosynthetic effects and neglected the interactive genetic mechanism that governs various traits through significant quantitative trait loci (QTLs). In this study, we have developed a differential dynamic system that enables the identification of QTLs based on the photosynthetic phenotypic and genotypic data under varying levels of light intensity gradients. The framework not only allows for the assessment of the direct effects of QTLs on phenotypes but also captures how they influence interactions among phenotypes as light intensities change. We have analyzed the genetic effects and genetic variance, visualized the genetic network associated with photosynthesis interactions, and validated the effectiveness and stability of the DDS framework. Pivotal pleiotropic QTLs were identified individually to uncover the process and pattern of interaction. Through functional annotation, we made an intriguing discovery that seemingly unimportant QTLs can still have significant genetic effects on phenotypic changes through their regulation with other QTLs. This finding emphasizes the significance of considering the interactive genetic architecture when seeking to understand the genetic interaction mechanism of photosynthesis in natural populations of woody plants. Moreover, our research provides a novel framework that can be extended to explore the interactive genetic architecture among organisms, contributing to a deeper understanding of stress resistance mechanisms in woody plants.
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Affiliation(s)
- Kaiyan Lu
- College of Science, Beijing Forestry University, No. 35, Qinghua East Road, 100083, Beijing, PR China
| | - Ziyang Zhou
- College of Science, Beijing Forestry University, No. 35, Qinghua East Road, 100083, Beijing, PR China
| | - Ziyuan Huang
- Department of Emergency Medicine, University of Massachusetts Chan Medical School, 368 Plantation St, 01605-2324, Worcester, MA, USA
| | - Chenhao Bu
- College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, 100083, Beijing, PR China
| | - Huiying Gong
- College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, 100083, Beijing, PR China
| | - Libo Jiang
- School of Life Sciences and Medicines, Shandong University of Technology, No. 266, Xincun West Road, Shandong Province, 255049, Zibo, PR China
| | - Deqiang Zhang
- College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, 100083, Beijing, PR China
| | - Qing Fang
- Faculty of Science, Yamagata University, Yamagata, 990, Japan
| | - Xiao-Yu Zhang
- College of Science, Beijing Forestry University, No. 35, Qinghua East Road, 100083, Beijing, PR China.
| | - Yuepeng Song
- College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, 100083, Beijing, PR China.
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Barton AR, Santander CG, Skoglund P, Moltke I, Reich D, Mathieson I. Insufficient evidence for natural selection associated with the Black Death. Nature 2025; 638:E19-E22. [PMID: 39972236 DOI: 10.1038/s41586-024-08496-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/13/2023] [Accepted: 12/05/2024] [Indexed: 02/21/2025]
Affiliation(s)
- Alison R Barton
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Cindy G Santander
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Pontus Skoglund
- Ancient Genomics Laboratory, The Francis Crick Institute, London, UK
| | - Ida Moltke
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - David Reich
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA
| | - Iain Mathieson
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Hong Y, Wang Y, Shu W. Deciphering the genetic underpinnings of neuroticism: A Mendelian randomization study of druggable gene targets. J Affect Disord 2025; 370:147-158. [PMID: 39491682 DOI: 10.1016/j.jad.2024.11.002] [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] [Academic Contribution Register] [Received: 08/31/2024] [Revised: 10/26/2024] [Accepted: 11/01/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Neuroticism, known for its association with a greater risk of psychiatric conditions such as depression and anxiety, is a critical focus of research. METHODS Cis-expression quantitative trait loci (eQTLs) from 31,684 whole blood samples provided by the eQTLGen Consortium, alongside data from a large neuroticism cohort, were analyzed to identify genes causally linked to neuroticism. To further explore the influence of gene expression changes on neuroticism, colocalization analysis was conducted. Identified drug targets were assessed for potential side effects using a phenome-wide association study (PheWAS). Additionally, we utilized multiple databases to explore the interactions between drugs and genes for drug prediction and assess the current medications for drug repurposing. RESULTS The analysis involved a total of 4473 druggable genes, with two-sample Mendelian randomization (MR) identifying 186 genes that are causally linked to neuroticism. Colocalization analysis highlighted 11 genes (TLR4, MMRN1, EP300, BRAF, ORM1, ACVR1B, LRRC17, NOS2, ADAMTS6, GPX1, and VCL) with a posterior probability of colocalization (PPH4) >0.8. PheWAS revealed that drugs targeting BRAF, LRRC17, ADAMTS6, and GPX1 were also associated with other traits. Notably, six of these genes (TLR4, MMRN1, BRAF, ACVR1B, NOS2, and GPX1) are already being explored for drug development in psychiatric and other diseases. CONCLUSION This study pinpointed six genes as promising therapeutic targets for neuroticism. The repurposing and development of drugs targeting these genes hold potential for managing neuroticism and associated psychiatric disorders.
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Affiliation(s)
- Yanggang Hong
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
| | - Yi Wang
- The First School of Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Wanyi Shu
- School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
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Buonaiuto S, Marsico F, Mohammed A, Chinthala LK, Amos-Abanyie EK, Prins P, Mozhui K, Rooney RJ, Williams RW, Davis RL, Finkel TH, Brown CW, Colonna V. The Biorepository and Integrative Genomics resource for inclusive genomics: insights from a diverse pediatric and admixed cohort. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.03.25319944. [PMID: 39802793 PMCID: PMC11722445 DOI: 10.1101/2025.01.03.25319944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Indexed: 02/22/2025]
Abstract
The Biorepository and Integrative Genomics (BIG) Initiative in Tennessee has developed a pioneering resource to address gaps in genomic research by linking genomic, phenotypic, and environmental data from a diverse Mid-South population, including underrepresented groups. We analyzed 13,152 genomes from BIG and found significant genetic diversity, with 50% of participants inferred to have non-European or several types of admixed ancestry. Ancestry within the BIG cohort is stratified, with distinct geographic and demographic patterns, as African ancestry is more common in urban areas, while European ancestry is more common in suburban regions. We observe ancestry-specific rates of novel genetic variants, which are enriched for functional or clinical relevance. Disease prevalence analysis linked ancestry and environmental factors, showing higher odds ratios for asthma and obesity in minority groups, particularly in the urban area. Finally, we observe discrepancies between self-reported race and genetic ancestry, with related individuals self-identifying in differing racial categories. These findings underscore the limitations of race as a biomedical variable. BIG has proven to be an effective model for community-centered precision medicine. We integrated genomics education, and fostered great trust among the contributing communities. Future goals include cohort expansion, and enhanced genomic analysis, to ensure equitable healthcare outcomes.
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Affiliation(s)
| | | | | | | | | | | | - Pjotr Prins
- Dept of Genetics, Genomics and Informatics, UTHSC, USA
| | - Kyobeni Mozhui
- Dept of Genetics, Genomics and Informatics, UTHSC, USA
- Department of Preventive Medicine, Division of Preventive Medicine, UTHSC, USA
| | | | - Robert W Williams
- Department of Preventive Medicine, Division of Preventive Medicine, UTHSC, USA
| | | | - Terri H Finkel
- Dept of Pediatrics, Division of Rheumatology, UTHSC, USA
- Dept of Pediatrics, Division of Genetics, UTHSC, USA
| | - Chester W Brown
- Dept of Genetics, Genomics and Informatics, UTHSC, USA
- Dept of Pediatrics, Division of Genetics, UTHSC, USA
| | - Vincenza Colonna
- Dept of Genetics, Genomics and Informatics, UTHSC, USA
- Dept of Pediatrics, Division of Rheumatology, UTHSC, USA
- Institute of Genetics and Biophysics, National Research Council, Naples, 80111, Italy
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Liu N, Guan M, Ma B, Chu H, Tian G, Zhang Y, Li C, Zheng W, Wang X. Unraveling genetic mysteries: A comprehensive review of GWAS and DNA insights in animal and plant pathosystems. Int J Biol Macromol 2025; 285:138216. [PMID: 39631605 DOI: 10.1016/j.ijbiomac.2024.138216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/19/2024] [Revised: 11/13/2024] [Accepted: 11/28/2024] [Indexed: 12/07/2024]
Abstract
DNA serves as the carrier of genetic information, with sequence variations playing a pivotal role in defining hereditary traits. Genome-Wide Association Studies (GWAS) facilitate the investigation of the links between genetic variations and phenotypes, significantly influencing biological research, particularly in animal and plant pathology. By identifying genetic markers associated with specific traits or diseases, GWAS enhances our understanding of host-pathogen interactions and improves disease-resistant breeding strategies. It has been vital in revealing the genetic basis of disease resistance, pinpointing key genes and DNA loci, which enrich genetic resources for breeding programs and deepen our knowledge of disease resistance mechanisms at the DNA level. Additionally, GWAS contributes to pathogen population genetics, facilitating a thorough exploration of pathogen virulence. Integrating GWAS with marker-assisted selection enhances breeding efficiency and precision in selecting for disease-resistant traits. While previous research has largely focused on host genetics, the genetic variation of pathogens is equally significant. Notably, reports integrating animal and plant pathosystems are still lacking. Given the importance of these systems, this review summarizes key advancements in this field, addresses current challenges, and proposes future directions, thereby offering a vital reference for ongoing research.
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Affiliation(s)
- Na Liu
- Collaborative Innovation Center of Henan Grain Crops/State Key Laboratory of Wheat and Maize Crop Science, College of Life Sciences, Henan Agricultural University, 450046 Zhengzhou, China
| | - Mengxin Guan
- Collaborative Innovation Center of Henan Grain Crops/State Key Laboratory of Wheat and Maize Crop Science, College of Life Sciences, Henan Agricultural University, 450046 Zhengzhou, China
| | - Baozhan Ma
- Collaborative Innovation Center of Henan Grain Crops/State Key Laboratory of Wheat and Maize Crop Science, College of Life Sciences, Henan Agricultural University, 450046 Zhengzhou, China
| | - Hao Chu
- Collaborative Innovation Center of Henan Grain Crops/State Key Laboratory of Wheat and Maize Crop Science, College of Life Sciences, Henan Agricultural University, 450046 Zhengzhou, China
| | - Guangxiang Tian
- Collaborative Innovation Center of Henan Grain Crops/State Key Laboratory of Wheat and Maize Crop Science, College of Life Sciences, Henan Agricultural University, 450046 Zhengzhou, China
| | - Yanyan Zhang
- Collaborative Innovation Center of Henan Grain Crops/State Key Laboratory of Wheat and Maize Crop Science, College of Life Sciences, Henan Agricultural University, 450046 Zhengzhou, China
| | - Chuang Li
- Collaborative Innovation Center of Henan Grain Crops/State Key Laboratory of Wheat and Maize Crop Science, College of Life Sciences, Henan Agricultural University, 450046 Zhengzhou, China; Center of Crop Genome Engineering, College of Agronomy, Henan Agricultural University, 450046 Zhengzhou, China.
| | - Wenming Zheng
- Collaborative Innovation Center of Henan Grain Crops/State Key Laboratory of Wheat and Maize Crop Science, College of Life Sciences, Henan Agricultural University, 450046 Zhengzhou, China.
| | - Xu Wang
- Collaborative Innovation Center of Henan Grain Crops/State Key Laboratory of Wheat and Maize Crop Science, College of Life Sciences, Henan Agricultural University, 450046 Zhengzhou, China.
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Fathoni A, Boonkum W, Chankitisakul V, Buaban S, Duangjinda M. Integrating Genomic Selection and a Genome-Wide Association Study to Improve Days Open in Thai Dairy Holstein Cattle: A Comprehensive Genetic Analysis. Animals (Basel) 2024; 15:43. [PMID: 39794985 PMCID: PMC11718913 DOI: 10.3390/ani15010043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/25/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Days open (DO) is a critical economic and reproductive trait that is commonly employed in genetic selection. Making improvements using conventional genetic techniques is exceedingly challenging. Therefore, new techniques are required to improve the accuracy of genetic selection using genomic data. This study examined the genetic approaches of traditional AIREML and single-step genomic AIREML (ssGAIREML) to assess genetic parameters and the accuracy of estimated breeding values while also investigating SNP regions associated with DO and identifying candidate genes through a genome-wide association study (GWAS). The dataset included 59415 DO records from 36368 Thai-Holstein crossbred cows and 882 genotyped animals. The cows were classified according to their Holstein genetic proportion (breed group, BG) as follows: BG1 (>93.7% Holstein genetics), BG2 (87.5% to 93.6% Holstein genetics), and BG3 (<87.5% Holstein genetics). AIREML was utilized to estimate genetic parameters and variance components. The results of this study reveal that the average DO values for BG1, BG2, and BG3 were 97.64, 97.25, and 96.23 days, respectively. The heritability values were estimated to be 0.02 and 0.03 for the traditional AIREML and ssGAIREML approaches, respectively. Depending on the dataset, the ssGAIREML method produced more accurate estimated breeding values than the traditional AIREML method, ranging from 40.5 to 45.6%. The highest values were found in the top 20% of the dam dataset. For the GWAS, we found 12 potential candidate genes (DYRK1A, CALCR, MIR489, MIR653, SLC36A1, GNA14, GNAQ, TRNAC-GCA, XYLB, ACVR2B, SLC22A14, and EXOC2) that are believed to have a significant influence on days open. In summary, the ssGAIREML method has the potential to enhance the accuracy and heritability of reproductive values compared to those obtained using conventional AIREML. Consequently, it is a viable alternative for transitioning from conventional methodologies to the ssGAIREML method in the breeding program for dairy cattle in Thailand. Moreover, the 12 identified potential candidate genes can be utilized in future studies to select markers for days open in regard to dairy cattle.
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Affiliation(s)
- Akhmad Fathoni
- Department of Animal Science, Faculty of Agriculture, Khon Kaen University, Khon Kaen 40002, Thailand; (A.F.); (W.B.); (V.C.)
- Department of Animal Breeding and Reproduction, Faculty of Animal Science, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Wuttigrai Boonkum
- Department of Animal Science, Faculty of Agriculture, Khon Kaen University, Khon Kaen 40002, Thailand; (A.F.); (W.B.); (V.C.)
- Network Center for Animal Breeding and Omics Research, Faculty of Agriculture, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Vibuntita Chankitisakul
- Department of Animal Science, Faculty of Agriculture, Khon Kaen University, Khon Kaen 40002, Thailand; (A.F.); (W.B.); (V.C.)
- Network Center for Animal Breeding and Omics Research, Faculty of Agriculture, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sayan Buaban
- Department of Livestock Development, Bureau of Animal Husbandry and Genetic Improvement, Pathum Thani 12000, Thailand;
| | - Monchai Duangjinda
- Department of Animal Science, Faculty of Agriculture, Khon Kaen University, Khon Kaen 40002, Thailand; (A.F.); (W.B.); (V.C.)
- Network Center for Animal Breeding and Omics Research, Faculty of Agriculture, Khon Kaen University, Khon Kaen 40002, Thailand
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Salenius K, Väljä N, Thusberg S, Iris F, Ladd-Acosta C, Roos C, Nykter M, Fasano A, Autio R, Lin J. Exploring autism spectrum disorder and co-occurring trait associations to elucidate multivariate genetic mechanisms and insights. BMC Psychiatry 2024; 24:934. [PMID: 39696186 DOI: 10.1186/s12888-024-06392-w] [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] [Academic Contribution Register] [Received: 08/01/2024] [Accepted: 12/08/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a partially heritable neurodevelopmental trait, and people with ASD may also have other co-occurring trait such as ADHD, anxiety disorders, depression, mental health issues, learning difficulty, physical health traits and communication challenges. The concomitant development of ASD and other neurological traits is assumed to result from a complex interplay between genetics and the environment. However, only a limited number of studies have performed multivariate genome-wide association studies (GWAS) for ASD. METHODS We conducted to-date the largest multivariate GWAS on ASD and 8 ASD co-occurring traits (ADHD, ADHD childhood, anxiety stress (ASDR), bipolar (BIP), disruptive behaviour (DBD), educational attainment (EA), major depression, and schizophrenia (SCZ)) using summary statistics from leading studies. Multivariate associations and central traits were further identified. Subsequently, colocalization and Mendelian randomization (MR) analysis were performed on the associations identified with the central traits containing ASD. To further validate our findings, pathway and quantified trait loci (QTL) resources as well as independent datasets consisting of 112 (45 probands) whole genome sequence data from the GEMMA project were utilized. RESULTS Multivariate GWAS resulted in 637 significant associations (p < 5e-8), among which 322 are reported for the first time for any trait. 37 SNPs were identified to contain ASD and one or more traits in their central trait set, including variants mapped to known SFARI ASD genes MAPT, CADPS and NEGR1 as well as novel ASD genes KANSL1, NSF and NTM, associated with immune response, synaptic transmission, and neurite growth respectively. Mendelian randomization analyses found that genetic liability for ADHD childhood, ASRD and DBT has causal effects on the risk of ASD while genetic liability for ASD has causal effects on the risk of ADHD, ADHD childhood, BIP, WA, MDD and SCZ. Frequency differences of SNPs found in NTM and CADPS genes, respectively associated with neurite growth and neural/endocrine calcium regulation, were found between GEMMA ASD probands and controls. Pathway, QTL and cell type enrichment implicated microbiome, enteric inflammation, and central nervous system enrichments. CONCLUSIONS Our study, combining multivariate GWAS with systematic decomposition, identified novel genetic associations related to ASD and ASD co-occurring driver traits. Statistical tests were applied to discern evidence for shared and interpretable liability between ASD and co-occurring traits. These findings expand upon the current understanding of the complex genetics regulating ASD and reveal insights of neuronal brain disruptions potentially driving development and manifestation.
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Affiliation(s)
- Karoliina Salenius
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland
| | - Niina Väljä
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland
| | - Sini Thusberg
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland
| | | | - Christine Ladd-Acosta
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
| | | | - Matti Nykter
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland
- Foundation for the Finnish Cancer Institute, Helsinki, Finland
| | - Alessio Fasano
- European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
- Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, USA
| | - Reija Autio
- Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Jake Lin
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
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Xiao R, Dong L, Xie B, Liu B. A Mendelian randomization study: physical activities and chronic kidney disease. Ren Fail 2024; 46:2295011. [PMID: 38178379 PMCID: PMC10773648 DOI: 10.1080/0886022x.2023.2295011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/28/2023] [Accepted: 12/08/2023] [Indexed: 01/06/2024] Open
Abstract
Increasing evidence has shown that physical activity is related to a lower risk of chronic kidney disease (CKD), thus indicating a potential target for prevention. However, the causality is not clear; specifically, physical activity may protect against CKD, and CKD may lead to a reduction in physical activity. Our study examined the potential bidirectional relationship between physical activity and CKD by using a genetically informed method. Genome-wide association studies from the UK Biobank baseline data were used for physical activity phenotypes and included 460,376 participants. For kidney function (estimated Glomerular Filtration Rate (eGFR) and CKD, with eGFR < 60 mL/min/1.73 m2), CKDGen Consortium data were used, which included 480,698 CKD participants of European ancestry. Mendelian randomization (MR) analysis was used to determine the causal relationship between physical activities and kidney function. Two-sample MR genetically predicted that heavy DIY (do it yourself) (e.g., weeding, lawn mowing, carpentry, and digging) decreased the risk of CKD (odds ratio [OR] = 0.287, 95% CI = 0.117-0.705, p = 0.0065) and improved the level of eGFR (β = 0.036, 95% CI = 0.005-0.067, p = 0.021). The bidirectional MR showed no reverse causality. It is worth noting that other physical activities, such as walking for pleasure, strenuous sports, light DIY (e.g., pruning and watering the lawn), and other exercises (e.g., swimming, cycling, keeping fit, and bowling), were not significantly correlated with CKD and eGFR. This study used genetic data to provide reliable and robust causal evidence that heavy physical activity (e.g., weeding, lawn mowing, carpentry, and digging) can protect kidney function and further lower the risk of CKD.
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Affiliation(s)
- Rui Xiao
- Department of General Practice, Yongchuan Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Li Dong
- Department of Nephrology and Rheumatology, Yongchuan Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Bo Xie
- Department of General Practice, Yongchuan Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Beizhong Liu
- Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing, China
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11
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Fisher DN, Bechsgaard J, Bilde T. Exploring changes in social spider DNA methylation profiles in all cytosine contexts following infection. Heredity (Edinb) 2024; 133:410-417. [PMID: 39266675 PMCID: PMC11589119 DOI: 10.1038/s41437-024-00724-y] [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] [Academic Contribution Register] [Received: 05/13/2024] [Revised: 08/27/2024] [Accepted: 08/27/2024] [Indexed: 09/14/2024] Open
Abstract
Living at high density and with low genetic diversity are factors that should both increase the susceptibility of organisms to disease. Therefore, group living organisms, especially those that are inbred, should be especially vulnerable to infection and therefore have particular strategies to cope with infection. Phenotypic plasticity, underpinned by epigenetic changes, could allow group living organisms to rapidly respond to infection challenges. To explore the potential role of epigenetic modifications in the immune response to a group-living species with low genetic diversity, we compared the genome-wide DNA methylation profiles of five colonies of social spiders (Stegodyphus dumicola) in their natural habitat in Namibia at the point just before they succumbed to infection to a point at least six months previously where they were presumably healthier. We found increases in genome- and chromosome-wide methylation levels in the CpG, CHG, and CHH contexts, although the genome-wide changes were not clearly different from zero. These changes were most prominent in the CHG context, especially at a narrow region of chromosome 13, hinting at an as-of-yet unsuspected role of this DNA methylation context in phenotypic plasticity. However, there were few clear patterns of differential methylation at the base level, and genes with a known immune function in spiders had mean methylation changes close to zero. Our results suggest that DNA methylation may change with infection at large genomic scales, but that this type of epigenetic change is not necessarily integral to the immune response of social spiders.
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Affiliation(s)
- David N Fisher
- School of Biological Sciences, University of Aberdeen, King's College, Aberdeen, UK.
| | - Jesper Bechsgaard
- Department of Biology, Section for Genetic Ecology and Evolution, Centre for Ecological Genetics, Aarhus University, Aarhus, Denmark
| | - Trine Bilde
- Department of Biology, Section for Genetic Ecology and Evolution, Centre for Ecological Genetics, Aarhus University, Aarhus, Denmark
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12
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Lee HW, Lee BH, Shekhtman T, Park YM, Kelsoe JR. Relationship between Polygenic Risk Score and the Hypnotics in Bipolar I Disorder. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE : THE OFFICIAL SCIENTIFIC JOURNAL OF THE KOREAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY 2024; 22:585-593. [PMID: 39420606 PMCID: PMC11494434 DOI: 10.9758/cpn.23.1152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 12/11/2023] [Revised: 02/02/2024] [Accepted: 02/04/2024] [Indexed: 10/19/2024]
Abstract
Objective Bipolar disorder (BD) is marked by significant change in mood and energy levels with sleep disturbance a common feature, resulting in diminished quality of life and impaired daily functioning. This study assessed the association between BD-polygenic risk scores (PRS) and hypnotics in bipolar I disorder (BD-I) patients. Methods Large-sample data were collected from the genome-wide association study of a multicenter Bipolar Genomic Study, and 1,394 BD-I patients with available medication information were divided into two groups depending on whether they used hypnotics or not. The Diagnostic Interview for Genetic Studies (DIGS) score was used to assess the clinical manifestations and function of the participants and the association between the use of hypnotics and genetic risk was analyzed. Results Of the 1,394 total participants, 556 (40%) patients received hypnotics, mostly benzodiazepines, administered singly or in combination with other sleeping agents such as, Z-drugs, melatonin-related drugs, and trazodone. The DIGS score was significantly higher for negative categories in the group prescribed hypnotics as was the BD-PRS score, according to the four p value thresholds (p = 0.3, 0.2, 0.1, and 0.05). Logistic regression analysis confirmed a statistically significant association between the BD-PRS and hypnotic use. Conclusion Our results suggest an association between hypnotic use and genetic susceptibility to BD. Sleep disturbances in participants were based on the prescription status of hypnotics supporting the hypothesis that sleep disturbances may be associated with genetic aspects of BD-I. Further genetic studies on genetic overlaps between BD and specific phenotypes or medication responses are required.
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Affiliation(s)
- Hyeon Woo Lee
- Department of Psychiatry, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Bun-Hee Lee
- Maum and Maum Psychiatric Clinic, Seoul, Korea
| | - Tatyana Shekhtman
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Young-Min Park
- Department of Psychiatry, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - John R. Kelsoe
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
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13
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Akcesme B, Islam N, Lekic D, Cutuk R, Basovic N. Analysis of Alzheimer's disease associated deleterious non-synonymous single nucleotide polymorphisms and their impacts on protein structure and function by performing in-silico methods. Neurogenetics 2024; 26:8. [PMID: 39589570 DOI: 10.1007/s10048-024-00786-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/08/2024] [Accepted: 10/17/2024] [Indexed: 11/27/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder that is presented with a progressive loss of memory, a decline in cognitive abilities and multiple changes in behavior. Its pathogenicity has been linked to genetic factors in approximately 60-80% of the cases specifically APOE gene family and as well as other gene families. This study utilized advanced computational biology methods to analyze AD-associated nsSNPs extracted from the NHGRI-EBI GWAS Catalog. Ensembl Variant Effect Predictor (VEP) is used to annotate the variants associated with AD. Annotated missense variants were subjected to PolyPhen-2, SNPs&Go, PredictSNP servers which were used to predict pathogenicity of selected missense variants by protein sequence information. DynaMut and DUET servers were applied to determine protein stability due to the amino acid change by integrating protein structure information. Missense variations associated with AD were annotated to 26 proteins and further analyzed in our study. Following rigorous data filtration steps, 15 candidate variants (13 proteins) were identified and subjected to sequence and structure-based analysis. Finally in this in-silico study, five deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) were identified in ACKR2(V41A), APOE(R176C), ATP8B4(G395S), LAMB2(E987K), and TOMM40(R239W), and these findings were subsequently backed-up by existing in-vivo and in-vitro literature. This study not only provides invaluable insight into the intricate pathogenic mechanisms underlying AD but also offers a distinctive perspective that paves the way for future, more comprehensive investigations aimed at unraveling the molecular intricacies responsible for the development and progression of AD. Nonetheless, it is imperative that further rigorous in vivo and in vitro experiments are conducted to validate and expand upon the findings presented here.
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Affiliation(s)
- Betul Akcesme
- Department of Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
- Hamidiye Faculty of Medicine, Program of Medical Biology, University of Health Sciences, İstanbul, Türkiye.
| | - Nadia Islam
- Department of Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Delila Lekic
- Department of Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Raisa Cutuk
- Department of Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Nejla Basovic
- Department of Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina
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14
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Sidorenko J, Couvy-Duchesne B, Kemper KE, Moen GH, Bhatta L, Åsvold BO, Mägi R, Ani A, Wang R, Nolte IM, Gordon S, Hayward C, Campbell A, Benjamin DJ, Cesarini D, Evans DM, Goddard ME, Haley CS, Porteous D, Medland SE, Martin NG, Snieder H, Metspalu A, Hveem K, Brumpton B, Visscher PM, Yengo L. Genetic architecture reconciles linkage and association studies of complex traits. Nat Genet 2024; 56:2352-2360. [PMID: 39375568 PMCID: PMC11835202 DOI: 10.1038/s41588-024-01940-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/26/2023] [Accepted: 08/30/2024] [Indexed: 10/09/2024]
Abstract
Linkage studies have successfully mapped loci underlying monogenic disorders, but mostly failed when applied to common diseases. Conversely, genome-wide association studies (GWASs) have identified replicable associations between thousands of SNPs and complex traits, yet capture less than half of the total heritability. In the present study we reconcile these two approaches by showing that linkage signals of height and body mass index (BMI) from 119,000 sibling pairs colocalize with GWAS-identified loci. Concordant with polygenicity, we observed the following: a genome-wide inflation of linkage test statistics; that GWAS results predict linkage signals; and that adjusting phenotypes for polygenic scores reduces linkage signals. Finally, we developed a method using recombination rate-stratified, identity-by-descent sharing between siblings to unbiasedly estimate heritability of height (0.76 ± 0.05) and BMI (0.55 ± 0.07). Our results imply that substantial heritability remains unaccounted for by GWAS-identified loci and this residual genetic variation is polygenic and enriched near these loci.
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Affiliation(s)
- Julia Sidorenko
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
| | - Baptiste Couvy-Duchesne
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- Sorbonne University, Paris Brain Institute-ICM, CNRS, INRIA, INSERM, AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France
| | - Kathryn E Kemper
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
| | - Gunn-Helen Moen
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- The Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Laxmi Bhatta
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Bjørn Olav Åsvold
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
- Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim, Norway
| | - Reedik Mägi
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Alireza Ani
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rujia Wang
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ilja M Nolte
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Scott Gordon
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Daniel J Benjamin
- Human Genetics Department, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Behavioral Decision Making Group, Anderson School of Management, University of California Los Angeles, Los Angeles, CA, USA
- National Bureau of Economic Research, Cambridge, MA, USA
| | - David Cesarini
- National Bureau of Economic Research, Cambridge, MA, USA
- Department of Economics, New York University, New York, NY, USA
- Center for Experimental Social Science, New York University, New York, NY, USA
| | - David M Evans
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
- The Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Michael E Goddard
- Centre for AgriBioscience, Agriculture Victoria, Bundoora, Victoria, Australia
- Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia
| | - Chris S Haley
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
- Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, UK
- Coupland Craft Cider, Coupland, Northumberland, UK
| | - David Porteous
- MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Sarah E Medland
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Nicholas G Martin
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Andres Metspalu
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Kristian Hveem
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
| | - Ben Brumpton
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
| | - Peter M Visscher
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
| | - Loic Yengo
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
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15
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Ortiz-Valladares M, Gonzalez-Perez O, Pedraza-Medina R. Bridging the gap: Prenatal nutrition, myelination, and schizophrenia etiopathogenesis. Neuroscience 2024; 558:58-69. [PMID: 39159841 DOI: 10.1016/j.neuroscience.2024.08.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/26/2024] [Revised: 08/02/2024] [Accepted: 08/13/2024] [Indexed: 08/21/2024]
Abstract
Schizophrenia (SZ) is a complex mental illness characterized by disturbances in thinking, emotionality, and behavior, significantly impacting the quality of life for individuals affected and those around them. The etiology of SZ involves intricate interactions between genetic and environmental factors, although the precise mechanisms remain incompletely understood. Genetic predisposition, neurotransmitter dysregulation (particularly involving dopamine and serotonin), and structural brain abnormalities, including impaired prefrontal cortex function, have been implicated in SZ development. However, increasing evidence reveals the role of environmental factors, such as nutrition, during critical periods like pregnancy and lactation. Epidemiological studies suggest that early malnutrition significantly increases the risk of SZ symptoms manifesting in late adolescence, a crucial period coinciding with peak myelination and brain maturation. Prenatal undernutrition may disrupt myelin formation, rendering individuals more susceptible to SZ pathology. This review explores the potential relationship between prenatal undernutrition, myelin alterations, and susceptibility to SZ. By delineating the etiopathogenesis, examining genetic and environmental factors associated with SZ, and reviewing the relationship between SZ and myelination disorders, alongside the impact of malnutrition on myelination, we aim to examine how malnutrition might be linked to SZ by altering myelination processes, which contribute to increasing the understanding of SZ etiology and help identify targets for intervention and management.
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Affiliation(s)
| | - Oscar Gonzalez-Perez
- Laboratory of Neuroscience, School of Psychology, University of Colima, Colima 28040. México
| | - Ricardo Pedraza-Medina
- Medical Science Postgraduate Program, School of Medicine, University of Colima, Colima 28040. México
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16
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Wang Z, Grosvenor L, Ray D, Ruczinski I, Beaty TH, Volk H, Ladd-Acosta C, Chatterjee N. Estimation of Direct and Indirect Polygenic Effects and Gene-Environment Interactions using Polygenic Scores in Case-Parent Trio Studies. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.10.08.24315066. [PMID: 39417123 PMCID: PMC11482979 DOI: 10.1101/2024.10.08.24315066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Academic Contribution Register] [Indexed: 10/19/2024]
Abstract
Family-based studies provide a unique opportunity to characterize genetic risks of diseases in the presence of population structure, assortative mating, and indirect genetic effects. We propose a novel framework, PGS-TRI, for the analysis of polygenic scores (PGS) in case-parent trio studies for estimation of the risk of an index condition associated with direct effects of inherited PGS, indirect effects of parental PGS, and gene-environment interactions. Extensive simulation studies demonstrate the robustness of PGS-TRI in the presence of complex population structure and assortative mating compared to alternative methods. We apply PGS-TRI to multi-ancestry trio studies of autism spectrum disorders (Ntrio = 1,517) and orofacial clefts (Ntrio = 1,904) to establish the first transmission-based estimates of risk associated with pre-defined PGS for these conditions and other related traits. For both conditions, we further explored offspring risk associated with polygenic gene-environment interactions, and direct and indirect effects of genetically predicted levels of gene expression and metabolite traits.
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Affiliation(s)
- Ziqiao Wang
- Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
| | - Luke Grosvenor
- Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, United States of America 94588
- Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
| | - Debashree Ray
- Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
| | - Ingo Ruczinski
- Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
| | - Terri H. Beaty
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
| | - Heather Volk
- Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
| | - Christine Ladd-Acosta
- Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
| | - Nilanjan Chatterjee
- Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America 21205
- Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America 21205
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17
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Lv F, Li X, Wang Z, Wang X, Liu J. Identification and validation of Rab GTPases RAB13 as biomarkers for peritoneal metastasis and immune cell infiltration in colorectal cancer patients. Front Immunol 2024; 15:1403008. [PMID: 39192986 PMCID: PMC11347351 DOI: 10.3389/fimmu.2024.1403008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/18/2024] [Accepted: 07/29/2024] [Indexed: 08/29/2024] Open
Abstract
Background As one of the most common cancer, colorectal cancer (CRC) is with high morbidity and mortality. Peritoneal metastasis (PM) is a fatal state of CRC, and few patients may benefit from traditional therapies. There is a complex interaction between PM and immune cell infiltration. Therefore, we aimed to determine biomarkers associated with colorectal cancer peritoneal metastasis (CRCPM) and their relationship with immune cell infiltration. Methods By informatic analysis, differently expressed genes (DEGs) were selected and hub genes were screened out. RAB13, one of the hub genes, was identificated from public databases and validated in CRC tissues. The ESTIMATE, CEBERSORT and TIMER algorithms were applied to analyze the correlation between RAB13 and immune infiltration in CRC. RAB13's expression in different cells were analyzed at the single-cell level in scRNA-Seq. The Gene Set Enrichment Analysis (GSEA) was performed for RAB13 enrichment and further confirmed. Using oncoPredict algorithm, RAB13's impact on drug sensitivity was evaluated. Results High RAB13 expression was identified in public databases and led to a poor prognosis. RAB13 was found to be positively correlated with the macrophages and other immune cells infiltration and from scRNA-Seq, RAB13 was found to be located in CRC cells and macrophages. GSEA revealed that high RAB13 expression enriched in a various of biological signaling, and oncoPredict algorithm showed that RAB13 expression was correlated with paclitaxel sensitivity. Conclusion Our study indicated clinical role of RAB13 in CRC-PM, suggesting its potential as a therapeutic target in the future.
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Affiliation(s)
- Fei Lv
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaoqi Li
- Oncology Department III, People’s Hospital of Liaoning Province, Shenyang, Liaoning, China
| | - Zhe Wang
- Department of Digestive Diseases 1, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
| | - Xiaobo Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jing Liu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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18
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Shi X, Feng C, Qin H, Wang J, Zhao Q, Jiao C, Zhang Y. Identification of QTNs and Their Candidate Genes for Boll Number and Boll Weight in Upland Cotton. Genes (Basel) 2024; 15:1032. [PMID: 39202392 PMCID: PMC11353353 DOI: 10.3390/genes15081032] [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] [Academic Contribution Register] [Received: 07/02/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/03/2024] Open
Abstract
Genome-wide association study (GWAS) has identified numerous significant loci for boll number (BN) and boll weight (BW), which play an essential role in cotton (Gossypium spp.) yield. The North Carolina design II (NC II) genetic mating population exhibits a greater number of genetic variations than other populations, which may facilitate the identification of additional genes. Accordingly, the 3VmrMLM method was employed for the analysis of upland cotton (Gossypium hirsutum L.) in an incomplete NC II genetic mating population across three environments. A total of 204 quantitative trait nucleotides (QTNs) were identified, of which 25 (24.75%) BN and 30 (29.13%) BW QTNs were of small effect (<1%) and 24 (23.76%) BN and 20 (19.42%) BW QTNs were rare (<10%). In the vicinity of these QTNs, two BN-related genes and two BW-related genes reported in previous studies were identified, in addition to five BN candidate genes and six BW candidate genes, which were obtained using differential expression analysis, gene function annotation, and haplotype analysis. Among these, six candidate genes were identified as homologs of Arabidopsis genes. The present study addresses the limitation of heritability missing and uncovers several new candidate genes. The findings of this study can provide a basis for further research and marker-assisted selection in upland cotton.
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Affiliation(s)
- Xiaoshi Shi
- College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (J.W.); (Q.Z.)
| | - Changhui Feng
- Institute of Industrual Crops, Hubei Academy of Agricultural Sciences, Wuhan 430064, China; (C.F.); (H.Q.)
| | - Hongde Qin
- Institute of Industrual Crops, Hubei Academy of Agricultural Sciences, Wuhan 430064, China; (C.F.); (H.Q.)
| | - Jingtian Wang
- College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (J.W.); (Q.Z.)
| | - Qiong Zhao
- College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (J.W.); (Q.Z.)
| | - Chunhai Jiao
- Hubei Academy of Agricultural Sciences, Wuhan 430064, China
| | - Yuanming Zhang
- College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (J.W.); (Q.Z.)
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Xiao Z, Li Y, Yang L, Cui M, Wang Z, Sun W, Wang J, Chen S, Lai S, Jia X. Genome-Wide Association Studies of Growth Trait Heterosis in Crossbred Meat Rabbits. Animals (Basel) 2024; 14:2096. [PMID: 39061558 PMCID: PMC11273820 DOI: 10.3390/ani14142096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/07/2024] [Revised: 07/07/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
The application of heterosis can not only effectively improve the disease resistance and meat quality of livestock, but also significantly enhance the reproduction and growth of livestock and poultry. We conducted genome-wide association studies using data from F2 crossbred meat rabbits to screen out candidate genes with significant dominant effects associated with economic trait variation. High-throughput sequencing technology was used to obtain SNPs covering the whole genome to evaluate the homozygosity of the population genome, and analyze the number, length, frequency, and distribution of ROHs in the population. Candidate genes related to economic traits of meat rabbits were searched based on high-frequency ROH regions. After quality control filtering of genotype data, 380 F2 crossbred rabbits were identified with 78,579 SNPs and 42,018 ROHs on the autosomes. The fitting of the Logistic growth curve model showed that 49-day-old rabbits were a growth inflection point. Then, through genome-wide association studies, 10 SNP loci and seven growth trait candidate genes were found to be significantly related to body weight in meat rabbits at 84 days of age. In addition, we revealed the functional roles and locations of 20 candidate genes in the high-frequency ROH region associated with economic traits in meat rabbits. This study identified potential genes associated with growth and development in the high-frequency ROH region of meat rabbits. In this study, the identified candidate genes can be used as molecular markers for assisted selection in meat rabbits. At the same time, the inbreeding situation based on ROH assessment can provide reference for breeding and breeding preservation of meat rabbits.
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Affiliation(s)
- Zhanjun Xiao
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Z.X.); (M.C.); (Z.W.); (W.S.); (S.C.); (S.L.)
| | - Yuchao Li
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 610000, China; (Y.L.); (L.Y.); (J.W.)
| | - Li Yang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 610000, China; (Y.L.); (L.Y.); (J.W.)
| | - Mingyan Cui
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Z.X.); (M.C.); (Z.W.); (W.S.); (S.C.); (S.L.)
| | - Zicheng Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Z.X.); (M.C.); (Z.W.); (W.S.); (S.C.); (S.L.)
| | - Wenqiang Sun
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Z.X.); (M.C.); (Z.W.); (W.S.); (S.C.); (S.L.)
| | - Jie Wang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 610000, China; (Y.L.); (L.Y.); (J.W.)
| | - Shiyi Chen
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Z.X.); (M.C.); (Z.W.); (W.S.); (S.C.); (S.L.)
| | - Songjia Lai
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Z.X.); (M.C.); (Z.W.); (W.S.); (S.C.); (S.L.)
| | - Xianbo Jia
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Z.X.); (M.C.); (Z.W.); (W.S.); (S.C.); (S.L.)
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Espitia-Pérez L, Brango H, Peñata-Taborda A, Galeano-Páez C, Jaramillo-García M, Espitia-Pérez P, Pastor-Sierra K, Bru-Cordero O, Hoyos-Giraldo LS, Reyes-Carvajal I, Saavedra-Trujillo D, Ricardo-Caldera D, Coneo-Pretelt A. Influence of genetic polymorphisms of Hg metabolism and DNA repair on the frequencies of micronuclei, nucleoplasmic bridges, and nuclear buds in communities living in gold mining areas. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2024; 897:503790. [PMID: 39054006 DOI: 10.1016/j.mrgentox.2024.503790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 02/29/2024] [Revised: 06/07/2024] [Accepted: 06/12/2024] [Indexed: 07/27/2024]
Abstract
Fishing communities living near gold mining areas are at increased risk of mercury (Hg) exposure via bioaccumulation of methylmercury (MeHg) in fish. This exposure has been linked to health effects that may be triggered by genotoxic events. Genetic polymorphisms play a role in the risk associated with Hg exposure. This study evaluated the effect of single nucleotide polymorphisms (SNPs) in metabolic and DNA repair genes on genetic instability and total hair Hg (T-Hg) levels in 78 individuals from "La Mojana" in northern Colombia and 34 individuals from a reference area. Genetic instability was assessed by the frequency of micronuclei (MNBN), nuclear buds (NBUDS), and nucleoplasmic bridges (NPB). We used a Poisson regression to assess the influence of SNPs on T-Hg levels and genetic instability, and a Bayesian regression to examine the interaction between Hg detoxification and DNA repair. Among exposed individuals, carriers of XRCC1Arg399Gln had a significantly higher frequency of MNBN. Conversely, the XRCC1Arg194Trp and OGG1Ser326Cys polymorphisms were associated with lower frequencies of MNBN. XRCC1Arg399Gln, XRCC1Arg280His, and GSTM1Null carriers showed lower NPB frequencies. Our results also indicated that individuals with the GSTM1Nulland GSTT1null polymorphisms had a 1.6-fold risk for higher T-Hg levels. The Bayesian model showed increased MNBN frequencies in carriers of the GSTM1Null polymorphism in combination with XRCC1Arg399Gln and increased NBUDS frequencies in the GSTM1Null carriers with the XRCC3Thr241Met and OGG1Ser326Cys alleles. The GSTM1+ variant was found to be a protective factor in individuals carrying OGG1Ser326Cys (MNBN) and XRCC1Arg280His (NPB); the GSTT1+ polymorphism combined with XRCCArg194Trp also modulated lower MNBN frequencies, while GSTT1+ carriers with the XRCC1Arg399Gln allele showed lower NPB frequencies. Consistent with GSTM1, GSTT1Null carriers with XRCC3Thr241Met showed increased NBUDS frequency. With the rise of gold mining activities, these approaches are vital to identify and safeguard populations vulnerable to Hg's toxic effects.
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Affiliation(s)
- Lyda Espitia-Pérez
- Facultad de Ciencias de la Salud, Laboratorio de Investigación Biomédica y Biología Molecular, Universidad del Sinú, Montería, Córdoba, Colombia.
| | - Hugo Brango
- Departamento de Matemáticas y Estadística, Universidad del Norte, Barranquilla, Colombia
| | - Ana Peñata-Taborda
- Facultad de Ciencias de la Salud, Laboratorio de Investigación Biomédica y Biología Molecular, Universidad del Sinú, Montería, Córdoba, Colombia
| | - Claudia Galeano-Páez
- Facultad de Ciencias de la Salud, Laboratorio de Investigación Biomédica y Biología Molecular, Universidad del Sinú, Montería, Córdoba, Colombia
| | - Manolo Jaramillo-García
- Facultad de Ciencias de la Salud, Laboratorio de Investigación Biomédica y Biología Molecular, Universidad del Sinú, Montería, Córdoba, Colombia (Postmorten)
| | - Pedro Espitia-Pérez
- Facultad de Ciencias de la Salud, Laboratorio de Investigación Biomédica y Biología Molecular, Universidad del Sinú, Montería, Córdoba, Colombia
| | - Karina Pastor-Sierra
- Facultad de Ciencias de la Salud, Laboratorio de Investigación Biomédica y Biología Molecular, Universidad del Sinú, Montería, Córdoba, Colombia
| | - Osnamir Bru-Cordero
- Universidad Nacional de Colombia, Dirección académica, kilómetro 9, vía Valledupar-La Paz, La Paz, Cesar, Colombia
| | - Luz Stella Hoyos-Giraldo
- Department of Biology, Research Group Genetic Toxicology and Cytogenetics, Faculty of Natural Sciences and Education, Universidad del Cauca, Popayán, Cauca, Colombia
| | - Ingrid Reyes-Carvajal
- Department of Biology, Research Group Genetic Toxicology and Cytogenetics, Faculty of Natural Sciences and Education, Universidad del Cauca, Popayán, Cauca, Colombia
| | - Diana Saavedra-Trujillo
- Department of Biology, Research Group Genetic Toxicology and Cytogenetics, Faculty of Natural Sciences and Education, Universidad del Cauca, Popayán, Cauca, Colombia
| | - Dina Ricardo-Caldera
- Grupo de Investigación Enfermedades Tropicales y Resistencia Bacteriana, Universidad del Sinú, Montería, Córdoba, Colombia
| | - Andrés Coneo-Pretelt
- Facultad de Ciencias de la Salud, Laboratorio de Investigación Biomédica y Biología Molecular, Universidad del Sinú, Montería, Córdoba, Colombia
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Singh KP, Kumari P, Rai PK. GWAS for the identification of introgressed candidate genes of Sinapis alba with increased branching numbers in backcross lines of the allohexaploid Brassica. FRONTIERS IN PLANT SCIENCE 2024; 15:1381387. [PMID: 38978520 PMCID: PMC11228338 DOI: 10.3389/fpls.2024.1381387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Academic Contribution Register] [Received: 02/03/2024] [Accepted: 06/11/2024] [Indexed: 07/10/2024]
Abstract
Plant architecture is a crucial determinant of crop yield. The number of primary (PB) and secondary branches (SB) is particularly significant in shaping the architecture of Indian mustard. In this study, we analyzed a panel of 86 backcross introgression lines (BCILs) derived from the first stable allohexaploid Brassicas with 170 Sinapis alba genome-specific SSR markers to identify associated markers with higher PB and SB through association mapping. The structure analysis revealed three subpopulations, i.e., P1, P2, and P3, in the association panel containing a total of 11, 33, and 42 BCILs, respectively. We identified five novel SSR markers linked to higher PB and SB. Subsequently, we explored the 20 kb up- and downstream regions of these SSR markers to predict candidate genes for improved branching and annotated them through BLASTN. As a result, we predicted 47 complete genes within the 40 kb regions of all trait-linked markers, among which 35 were identified as candidate genes for higher PB and SB numbers in BCILs. These candidate genes were orthologous to ANT, RAMOSUS, RAX, MAX, MP, SEU, REV, etc., branching genes. The remaining 12 genes were annotated for additional roles using BLASTP with protein databases. This study identified five novel S. alba genome-specific SSR markers associated with increased PB and SB, as well as 35 candidate genes contributing to plant architecture through improved branching numbers. To the best of our knowledge, this is the first report of introgressive genes for higher branching numbers in B. juncea from S. alba.
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Affiliation(s)
- Kaushal Pratap Singh
- Plant Protection Unit, Indian Council of Agricultural Research (ICAR)-Directorate of Rapeseed Mustard Research, Sewar, Bharatpur, India
| | - Preetesh Kumari
- Genetics Division, ICAR-Indian Agricultural Research Institute, New Delhi, India
- School of Agriculture, Sanskriti University, Mathura - Delhi Highway, Chhata, Mathura, India
| | - Pramod Kumar Rai
- Plant Protection Unit, Indian Council of Agricultural Research (ICAR)-Directorate of Rapeseed Mustard Research, Sewar, Bharatpur, India
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Chen WC, Chen YC, Chen YH, Liu TY, Tsai CH, Tsai FJ. Identification of novel genetic susceptibility loci for calcium-containing kidney stone disease by genome-wide association study and polygenic risk score in a Taiwanese population. Urolithiasis 2024; 52:94. [PMID: 38896256 DOI: 10.1007/s00240-024-01577-0] [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] [Academic Contribution Register] [Received: 01/23/2024] [Accepted: 05/04/2024] [Indexed: 06/21/2024]
Abstract
Approximately 80% of kidney stone diseases contain calcium. Inherited genetic factors are among the variables that influence the development of calcium-containing kidney stone diseases (CKSD). Previous genome-wide association studies (GWAS) on stone diseases have been reported worldwide; however, these are not focused on calcium-containing stones. We conducted a GWAS to identify germline genetic polymorphisms associated with CKSD in a Medical Center in Taiwan; hence, this study was based primarily on a hospital-based database. CKSD was diagnosed using the chart records. Patients infected with urea-splitting-microorganisms and those with at least two urinary pH value below 5.5 were excluded. None of the patients had cystic stones based on stone analysis. Those over 40 years of age with no history of CKSD and no microscopic hematuria on urinalysis were considered as controls. The DNA isolated from the blood of 14,934 patients (63.7% male and 36.3% female) with CKSD and 29,868 controls (10,830 men and 19,038 women) at a medical center was genotyped for approximately 714,457 single nucleotide polymorphisms (SNPs) with minor allele frequency of ≥ 0.05. We used PLINK 1.9 to calculate the polygenic risk score (PRS) to investigate the association between CKSD and controls. The accuracy of the PRS was verified by dividing it into the training and testing groups. The statistical analyses were calculated with the area under the curve (AUC) using IBM SPSS version 22. We identified 432 susceptibility loci that reached a genome-wide threshold of P < 1.0 × 10- 5. A total of 132 SNPs reached a threshold of P < 5 × 10- 8 using a stricter definition of significance on chromosomes 4, 13, 16, 17, and 18. At the top locus of our study, SNPs in DGKH, PDILT, BCAS3, and ABCG2 have been previously reported. RN7SKP27, HDAC4, PCDH15, AP003068.2, and NFATC1 were novel findings in this study. PRS was adjusted for sex and age, resulting in an AUC of 0.65. The number of patients in the top quartile of PRS was 1.39 folds in the risk of CKSD than patients in the bottom quartile. Our data identified the significance of GWAS for patients with CKSD in a hospital-based study. The PRS also had a high AUC for discriminating patients with CKSD from controls. A total of 132 SNP loci of SNPs significantly associated with the development of CKSD. This first survey, which focused on patients with CKSD, will provide novel insights specific to CKSD and its potential clinical biomarkers.
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Affiliation(s)
- Wen-Chi Chen
- Department of Urology, Department of Medical Research, Department of Medical Genetics, Million-Person Precision Medicine Initiative, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Integrated Medicine, School of Chinese Medicine, College of Chinese Medicine, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Yu-Chia Chen
- Department of Urology, Department of Medical Research, Department of Medical Genetics, Million-Person Precision Medicine Initiative, China Medical University Hospital, Taichung, Taiwan
| | - Yung-Hsiang Chen
- Department of Urology, Department of Medical Research, Department of Medical Genetics, Million-Person Precision Medicine Initiative, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Integrated Medicine, School of Chinese Medicine, College of Chinese Medicine, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan
| | - Ting-Yuan Liu
- Department of Urology, Department of Medical Research, Department of Medical Genetics, Million-Person Precision Medicine Initiative, China Medical University Hospital, Taichung, Taiwan
| | - Chang-Hai Tsai
- Department of Urology, Department of Medical Research, Department of Medical Genetics, Million-Person Precision Medicine Initiative, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Integrated Medicine, School of Chinese Medicine, College of Chinese Medicine, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Fuu-Jen Tsai
- Department of Urology, Department of Medical Research, Department of Medical Genetics, Million-Person Precision Medicine Initiative, China Medical University Hospital, Taichung, Taiwan.
- Graduate Institute of Integrated Medicine, School of Chinese Medicine, College of Chinese Medicine, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
- Division of Medical Genetics, China Medical University Children's Hospital, Taichung, Taiwan.
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Jin L, Li Z, Zhang J. Research on Plant Genomics and Breeding 2.0. Int J Mol Sci 2024; 25:6659. [PMID: 38928365 PMCID: PMC11203404 DOI: 10.3390/ijms25126659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/13/2024] [Revised: 05/29/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Plant genomics and breeding is one among the several highly regarded disciplines in today's field of biological sciences [...].
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Affiliation(s)
| | - Zhiyong Li
- State Key Laboratory of Rice Biology and Breeding, China National Rice Research Institute, Hangzhou 311400, China;
| | - Jian Zhang
- State Key Laboratory of Rice Biology and Breeding, China National Rice Research Institute, Hangzhou 311400, China;
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24
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Xu IRL, Danzi MC, Ruiz A, Raposo J, De Jesus YA, Reilly MM, Cortese A, Shy ME, Scherer SS, Hermann D, Fridman V, Baets J, Saporta M, Seyedsadjadi R, Stojkovic T, Claeys KG, Patel P, Feely S, Rebelo A, Dohrn MF, Züchner S. A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A. J Peripher Nerv Syst 2024; 29:202-212. [PMID: 38581130 PMCID: PMC11209807 DOI: 10.1111/jns.12621] [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] [Academic Contribution Register] [Received: 01/24/2024] [Revised: 03/01/2024] [Accepted: 03/07/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets. In this study, we present a comprehensive analysis of clinical examination results from 1564 CMT1A patients sourced from a prospective natural history study conducted by the RDCRN-INC (Inherited Neuropathy Consortium). Our primary objective is to delineate extreme phenotype profiles (mild and severe) within this patient cohort, thereby enhancing our ability to detect genetic modifiers with large effects. METHODS We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics. RESULTS We defined patients below the 10th (mild) and above the 90th (severe) percentiles of age-normalized disease severity based on the CMT Examination Score V2 and foot dorsiflexion strength (MRC scale). Based on extreme phenotype categories, we defined a statistically justified recruitment strategy, which we propose to use in future modifier studies. INTERPRETATION Leveraging whole genome sequencing with base pair resolution, a future genetic modifier evaluation will include single nucleotide association, gene burden tests, and structural variant analysis. The present work not only provides insight into the severity and course of CMT1A, but also elucidates the statistical foundation and practical considerations for a cost-efficient and straightforward patient enrollment strategy that we intend to conduct on additional patients recruited globally.
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Affiliation(s)
- Isaac R. L. Xu
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Matt C. Danzi
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Ariel Ruiz
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Jacquelyn Raposo
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Yeisha Arcia De Jesus
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Mary M Reilly
- Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square
| | - Andrea Cortese
- Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square
| | - Michael E Shy
- Department of Neurology, University of Iowa, Iowa City, Iowa, USA
| | - Steven S. Scherer
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States
| | - David Hermann
- Department of Neurology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 673, Rochester, New York, 14642, USA
| | - Vera Fridman
- Department of Neurology, University of Colorado Anschutz Medical Campus, 12631 E 17th Avenue, Mailstop B185, Room 5113C, Aurora, CO, 80045, USA
| | - Jonathan Baets
- Department of Neurology, Neuromuscular Reference Centre, Antwerp University Hospital, Antwerp, Belgium
- Faculty of Medicine and Health Sciences, Translational Neurosciences, University of Antwerp, Antwerp, Belgium
- Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
| | - Mario Saporta
- Department of Neurology, University of Miami Miller School of Medicine, United States
| | - Reza Seyedsadjadi
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Tanya Stojkovic
- AP-HP, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, Hôpital Pitié-Salpêtrière, 47-83, boulevard de l’Hôpital, 75013 Paris, France
| | - Kristl G. Claeys
- Department of Neurology, University Hospitals Leuven, Leuven, Belgium
- Department of Neurosciences, Laboratory for Muscle Diseases and Neuropathies, KU Leuven, Leuven, Belgium
| | - Pooja Patel
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Shawna Feely
- Department of Neurology, University of Iowa, Iowa City, Iowa, USA
| | - Adriana Rebelo
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | | | - Maike F. Dohrn
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
- Department of Neurology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Stephan Züchner
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
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Álvarez-Machancoses Ó, Faraggi E, deAndrés-Galiana EJ, Fernández-Martínez JL, Kloczkowski A. Prediction of Deleterious Single Amino Acid Polymorphisms with a Consensus Holdout Sampler. Curr Genomics 2024; 25:171-184. [PMID: 39086995 PMCID: PMC11288160 DOI: 10.2174/0113892029236347240308054538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/03/2023] [Revised: 08/03/2023] [Accepted: 09/22/2023] [Indexed: 08/02/2024] Open
Abstract
Background Single Amino Acid Polymorphisms (SAPs) or nonsynonymous Single Nucleotide Variants (nsSNVs) are the most common genetic variations. They result from missense mutations where a single base pair substitution changes the genetic code in such a way that the triplet of bases (codon) at a given position is coding a different amino acid. Since genetic mutations sometimes cause genetic diseases, it is important to comprehend and foresee which variations are harmful and which ones are neutral (not causing changes in the phenotype). This can be posed as a classification problem. Methods Computational methods using machine intelligence are gradually replacing repetitive and exceedingly overpriced mutagenic tests. By and large, uneven quality, deficiencies, and irregularities of nsSNVs datasets debase the convenience of artificial intelligence-based methods. Subsequently, strong and more exact approaches are needed to address these problems. In the present work paper, we show a consensus classifier built on the holdout sampler, which appears strong and precise and outflanks all other popular methods. Results We produced 100 holdouts to test the structures and diverse classification variables of diverse classifiers during the training phase. The finest performing holdouts were chosen to develop a consensus classifier and tested using a k-fold (1 ≤ k ≤5) cross-validation method. We also examined which protein properties have the biggest impact on the precise prediction of the effects of nsSNVs. Conclusion Our Consensus Holdout Sampler outflanks other popular algorithms, and gives excellent results, highly accurate with low standard deviation. The advantage of our method emerges from using a tree of holdouts, where diverse LM/AI-based programs are sampled in diverse ways.
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Affiliation(s)
- Óscar Álvarez-Machancoses
- Group of Inverse Problems, Optimization and Machine Learning, Department of Mathematics, University of Oviedo, C. Federico García Lorca, 18, 33007, Oviedo, Spain
| | - Eshel Faraggi
- School of Science, Indiana University-Purdue University Indianapolis, IN, USA
| | - Enrique J deAndrés-Galiana
- Group of Inverse Problems, Optimization and Machine Learning, Department of Mathematics, University of Oviedo, C. Federico García Lorca, 18, 33007, Oviedo, Spain
- Department of Computer Science, University of Oviedo, C. Federico García Lorca, 18, 33007, Oviedo, Spain
| | - Juan L Fernández-Martínez
- Group of Inverse Problems, Optimization and Machine Learning, Department of Mathematics, University of Oviedo, C. Federico García Lorca, 18, 33007, Oviedo, Spain
| | - Andrzej Kloczkowski
- Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
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Damena D, Barry A, Morrison R, Gaoussou S, Mahamar A, Attaher O, Issiaka D, Dicko Y, Dicko A, Duffy P, Fried M. A novel locus in CSMD1 gene is associated with increased susceptibility to severe malaria in Malian children. Front Genet 2024; 15:1390786. [PMID: 38854427 PMCID: PMC11157005 DOI: 10.3389/fgene.2024.1390786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/23/2024] [Accepted: 05/02/2024] [Indexed: 06/11/2024] Open
Abstract
Background Plasmodium falciparum malaria is still a leading cause of child mortality in sub-Saharan Africa. The clinical manifestations of malaria range from asymptomatic infection to severe disease. The variation in clinical presentation is partly attributed to host genetic factors with estimated narrow-sense heritability of 23%. Here, we investigate the associations between candidate gene polymorphisms and the likelihood of severe malaria (SM) in a cohort of Malian children. Methods Based on our previous genome-wide association studies (GWAS) analysis, candidate genes were selected for in-depth analysis using several criteria including gene-level GWAS scores, functional overlap with malaria pathogenesis, and evidence of association with protection or susceptibility to other infectious or inflammatory diseases. Single Nucleotide Polymorphisms (SNPs) residing within these genes were selected mainly based on p-values from previous severe malaria susceptibility GWAS studies and minor allele frequency (MAF) in West African populations. Results Of 182 candidate genes reported in our previous study, 11 genes and 22 SNPs residing in these genes were selected. The selected SNPs were genotyped using KASP technology in 477 DNA samples (87 SM and 390 controls). Logistic regression analysis revealed that a common intron variant, rs13340578 in CUB and Sushi Multi Domain (CSMD1) gene, is associated with increased odds of SM in recessive mode of inheritance (MAF = 0.42, OR = 1.8, 95% CI = [1.78, 1.84], p = 0.029). The SNP is in linkage disequilibrium (LD) with multiple variants with regulatory features. Conclusion Taken together, the current study showed that an intron variant rs13340578, residing in CSMD1 gene, is associated with increased susceptibility to malaria. This finding suggests that modified regulation of complement may contribute to malaria disease severity. Further studies are needed to identify the causal variants and the underlying molecular mechanisms.
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Affiliation(s)
- Delesa Damena
- Molecular Pathogenesis and Biomarkers Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Amadou Barry
- Malaria Research and Training Center, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali
| | - Robert Morrison
- Pathogenesis and Immunity Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Santara Gaoussou
- Malaria Research and Training Center, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali
| | - Almahamoudou Mahamar
- Malaria Research and Training Center, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali
| | - Oumar Attaher
- Malaria Research and Training Center, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali
| | - Djibrilla Issiaka
- Malaria Research and Training Center, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali
| | - Yahia Dicko
- Malaria Research and Training Center, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali
| | - Alassane Dicko
- Malaria Research and Training Center, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali
| | - Patrick Duffy
- Pathogenesis and Immunity Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Michal Fried
- Molecular Pathogenesis and Biomarkers Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
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Kim SB, Kang JH, Cheon M, Kim DJ, Lee BC. Stacked neural network for predicting polygenic risk score. Sci Rep 2024; 14:11632. [PMID: 38773257 PMCID: PMC11109142 DOI: 10.1038/s41598-024-62513-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/17/2023] [Accepted: 05/17/2024] [Indexed: 05/23/2024] Open
Abstract
In recent years, the utility of polygenic risk scores (PRS) in forecasting disease susceptibility from genome-wide association studies (GWAS) results has been widely recognised. Yet, these models face limitations due to overfitting and the potential overestimation of effect sizes in correlated variants. To surmount these obstacles, we devised the Stacked Neural Network Polygenic Risk Score (SNPRS). This novel approach synthesises outputs from multiple neural network models, each calibrated using genetic variants chosen based on diverse p-value thresholds. By doing so, SNPRS captures a broader array of genetic variants, enabling a more nuanced interpretation of the combined effects of these variants. We assessed the efficacy of SNPRS using the UK Biobank data, focusing on the genetic risks associated with breast and prostate cancers, as well as quantitative traits like height and BMI. We also extended our analysis to the Korea Genome and Epidemiology Study (KoGES) dataset. Impressively, our results indicate that SNPRS surpasses traditional PRS models and an isolated deep neural network in terms of accuracy, highlighting its promise in refining the efficacy and relevance of PRS in genetic studies.
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Affiliation(s)
- Sun Bin Kim
- Genoplan Korea Inc., Seoul, Republic of Korea
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28
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Pirruccello JP, Di Achille P, Choi SH, Rämö JT, Khurshid S, Nekoui M, Jurgens SJ, Nauffal V, Kany S, Ng K, Friedman SF, Batra P, Lunetta KL, Palotie A, Philippakis AA, Ho JE, Lubitz SA, Ellinor PT. Deep learning of left atrial structure and function provides link to atrial fibrillation risk. Nat Commun 2024; 15:4304. [PMID: 38773065 PMCID: PMC11109224 DOI: 10.1038/s41467-024-48229-w] [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] [Academic Contribution Register] [Received: 09/03/2021] [Accepted: 04/24/2024] [Indexed: 05/23/2024] Open
Abstract
Increased left atrial volume and decreased left atrial function have long been associated with atrial fibrillation. The availability of large-scale cardiac magnetic resonance imaging data paired with genetic data provides a unique opportunity to assess the genetic contributions to left atrial structure and function, and understand their relationship with risk for atrial fibrillation. Here, we use deep learning and surface reconstruction models to measure left atrial minimum volume, maximum volume, stroke volume, and emptying fraction in 40,558 UK Biobank participants. In a genome-wide association study of 35,049 participants without pre-existing cardiovascular disease, we identify 20 common genetic loci associated with left atrial structure and function. We find that polygenic contributions to increased left atrial volume are associated with atrial fibrillation and its downstream consequences, including stroke. Through Mendelian randomization, we find evidence supporting a causal role for left atrial enlargement and dysfunction on atrial fibrillation risk.
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Affiliation(s)
- James P Pirruccello
- Division of Cardiology, University of California San Francisco, San Francisco, CA, USA.
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
- Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA, USA.
- Cardiovascular Genetics Center, University of California San Francisco, San Francisco, CA, USA.
| | - Paolo Di Achille
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Seung Hoan Choi
- Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, USA
| | - Joel T Rämö
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Shaan Khurshid
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiology Division, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Mahan Nekoui
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Sean J Jurgens
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, NL, Netherlands
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, University of Amsterdam, Amsterdam, NL, Netherlands
| | - Victor Nauffal
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Shinwan Kany
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Cardiology, University Heart and Vascular Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Samuel F Friedman
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Puneet Batra
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Kathryn L Lunetta
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Aarno Palotie
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
- Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA
| | | | - Jennifer E Ho
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- CardioVascular Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Steven A Lubitz
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiology Division, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Patrick T Ellinor
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiology Division, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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Lv F, Li X, Wang Y, Hao L. MAGP1 maintains tumorigenicity and angiogenesis of laryngeal cancer by activating Wnt/β-catenin/MMP7 pathway. Carcinogenesis 2024; 45:220-234. [PMID: 36645203 DOI: 10.1093/carcin/bgad003] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/14/2022] [Revised: 10/17/2022] [Accepted: 01/16/2023] [Indexed: 01/17/2023] Open
Abstract
Microfibril-associated glycoprotein-1 (MAGP1), a crucial extracellular matrix protein, contributes to the initiation and progression of different cancers. However, the role of MAGP1 in laryngeal cancer is not clear. The purpose of this study was to investigate the clinical significance and biological function of MAGP1 in laryngeal cancer. MAGP1 was upregulated in public databases and laryngeal cancer tissues, and high MAGP1 expression led to a poor prognosis and was identified as an independent prognostic marker. Knocking-down MAGP1 inhibited laryngeal cancer cell growth and metastasis. According to gene set enrichment analysis, high MAGP1 expression revealed enrichment in Wnt/β-catenin signaling and knocking-down MAGP1 in laryngeal cancer cells also caused degradation, de-activation, re-location and loss of stability of β-catenin. Additionally, we observed MAGP1 in laryngeal cancer cells inhibits angiogenesis in an MMP7-dependent way. In conclusion, our study suggests a clinical role of MAGP1 in laryngeal cancer, signifying its potential as a therapeutic target in the future.
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Affiliation(s)
- Fei Lv
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaoqi Li
- Oncology Department III, People's Hospital of Liaoning Province, Shenyang, Liaoning, China
| | - Ying Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Liying Hao
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
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Ran F, Wang Y, Jiang F, Yin X, Bi Y, Shaw RK, Fan X. Studies on Candidate Genes Related to Flowering Time in a Multiparent Population of Maize Derived from Tropical and Temperate Germplasm. PLANTS (BASEL, SWITZERLAND) 2024; 13:1032. [PMID: 38611561 PMCID: PMC11013272 DOI: 10.3390/plants13071032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 03/01/2024] [Revised: 03/31/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024]
Abstract
A comprehensive study on maize flowering traits, focusing on the regulation of flowering time and the elucidation of molecular mechanisms underlying the genes controlling flowering, holds the potential to significantly enhance our understanding of the associated regulatory gene network. In this study, three tropical maize inbreds, CML384, CML171, and CML444, were used, along with a temperate maize variety, Shen137, as parental lines to cross with Ye107. The resulting F1s underwent seven consecutive generations of self-pollination through the single-seed descent (SSD) method to develop a multiparent population. To investigate the regulation of maize flowering time-related traits and to identify loci and candidate genes, a genome-wide association study (GWAS) was conducted. GWAS analysis identified 556 SNPs and 12 candidate genes that were significantly associated with flowering time-related traits. Additionally, an analysis of the effect of the estimated breeding values of the subpopulations on flowering time was conducted to further validate the findings of the present study. Collectively, this study offers valuable insights into novel candidate genes, contributing to an improved understanding of maize flowering time-related traits. This information holds practical significance for future maize breeding programs aimed at developing high-yielding hybrids.
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Affiliation(s)
- Fengyun Ran
- College of Agronomy and Biotechnology, Yunnan Agricultural University, Kunming 650500, China; (F.R.); (Y.W.)
| | - Yizhu Wang
- College of Agronomy and Biotechnology, Yunnan Agricultural University, Kunming 650500, China; (F.R.); (Y.W.)
| | - Fuyan Jiang
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming 650205, China; (F.J.); (X.Y.); (Y.B.); (R.K.S.)
| | - Xingfu Yin
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming 650205, China; (F.J.); (X.Y.); (Y.B.); (R.K.S.)
| | - Yaqi Bi
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming 650205, China; (F.J.); (X.Y.); (Y.B.); (R.K.S.)
| | - Ranjan K. Shaw
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming 650205, China; (F.J.); (X.Y.); (Y.B.); (R.K.S.)
| | - Xingming Fan
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming 650205, China; (F.J.); (X.Y.); (Y.B.); (R.K.S.)
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Risch N. 2023 lifetime achievement award: "If you want to go fast, go alone; if you want to go far, go together". Am J Hum Genet 2024; 111:412-423. [PMID: 38458162 PMCID: PMC10995461 DOI: 10.1016/j.ajhg.2024.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/06/2024] [Accepted: 02/06/2024] [Indexed: 03/10/2024] Open
Abstract
This article is based on the address given by the author at the 2023 meeting of The American Society of Human Genetics (ASHG). A video of the original address can be found at the ASHG website.
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Affiliation(s)
- Neil Risch
- Institute for Human Genetics, University of California San Francisco, San Fransisco, CA, USA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Fransisco, CA, USA; Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
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32
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Klein O. 2023 ASHG Lifetime Achievement Award: Neil Risch. Am J Hum Genet 2024; 111:410-411. [PMID: 38458161 PMCID: PMC10995462 DOI: 10.1016/j.ajhg.2023.12.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/22/2023] [Accepted: 12/22/2023] [Indexed: 03/10/2024] Open
Abstract
This article is based on the address given by the author for the 2023 meeting of The American Society of Human Genetics (ASHG) in Washington, D.C. A video of the original address can be found at the ASHG website.
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Affiliation(s)
- Ophir Klein
- Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA; Program in Craniofacial Biology; Department of Orofacial Sciences; and Institute for Human Genetics, University of California San Fransisco, San Francisco, CA, USA.
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33
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Karam ZM, Yari A, Najmadini A, Khorasani NN, Attari R, Jafarinejad-Farsangi S, Karam MAM, Najafipour H, Saeidi K. Association of the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) Polymorphisms With Risk of Coronary Artery Disease in Iranian Patients. J Clin Lab Anal 2024; 38:e25026. [PMID: 38506378 PMCID: PMC10997818 DOI: 10.1002/jcla.25026] [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] [Academic Contribution Register] [Received: 12/03/2023] [Revised: 02/06/2024] [Accepted: 02/25/2024] [Indexed: 03/21/2024] Open
Abstract
BACKGROUND Coronary artery disease (CAD) is a devastating illness and a leading cause of death worldwide, primarily caused by atherosclerosis resulting from a genetic-environmental interaction. This study aimed to investigate the relationship between the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) polymorphisms, lipid profile parameters, and CAD risk in a southeast Iranian population. METHODS A total of 400 subjects (200 CAD patients with hyperlipidemia and 200 healthy controls) were enrolled in this case-control study. Five selected polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS For all single nucleotide polymorphisms (SNPs), the population under study was in the Hardy-Weinberg equilibrium. The T-risk allele frequency of rs2228570 was associated with an increased risk of CAD. The TT and CT genotypes of rs2228570 had also been associated with the risk of CAD. Additionally, the TT genotype was associated with higher serum low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels. The GG genotype of the rs3736234 was associated with higher body mass index (BMI) and triglyceride (TG) levels, and the AA genotype of the rs708272 was associated with higher HDL-c levels. Based on these findings, we propose that the VDR (rs2228570) polymorphism was associated with serum HDL-c and LDL-c levels and may serve as potential risk factors for CAD within the Iranian population. Moreover, rs3736234 and rs708272 influence the concentrations of TG and HDL-c, respectively. CONCLUSION These findings provided insights into the complex interplay between genetic variations, cardiovascular risk, and lipid metabolism.
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Affiliation(s)
- Zahra Miri Karam
- Department of Medical Genetics, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Abolfazl Yari
- Department of Medical Genetics, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Atefeh Najmadini
- Department of Medical Immunology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Nima Norouzi Khorasani
- Department of Biology, Faculty of Life Sciences, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Rezvan Attari
- Department of Biology, University of Guilan, Rasht, Iran
| | | | - Mohammad Ali Miri Karam
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Hamid Najafipour
- Cardiovascular Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Kolsoum Saeidi
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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Thomas NS, Gillespie NA, Chan G, Edenberg HJ, Kamarajan C, Kuo SIC, Miller AP, Nurnberger JI, Tischfield J, Dick DM, Salvatore JE. A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency. Behav Genet 2024; 54:151-168. [PMID: 38108996 PMCID: PMC10913412 DOI: 10.1007/s10519-023-10170-x] [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] [Academic Contribution Register] [Received: 06/27/2023] [Accepted: 12/01/2023] [Indexed: 12/19/2023]
Abstract
Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.
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Affiliation(s)
- Nathaniel S Thomas
- Department of Psychology, Virginia Commonwealth University, Box 842018, Richmond, VA, 23284-2018, USA.
| | - Nathan A Gillespie
- Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA
| | - Grace Chan
- Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
- Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
| | - Howard J Edenberg
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chella Kamarajan
- Department of Psychiatry & Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
| | - Sally I-Chun Kuo
- Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA
| | - Alex P Miller
- Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | | | - Jay Tischfield
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA
| | - Danielle M Dick
- Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA
| | - Jessica E Salvatore
- Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA
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Qiao L, Gao X, Jia Z, Liu X, Wang H, Kong Y, Qin P, Yang B. Identification of adult resistant genes to stripe rust in wheat from southwestern China based on GWAS and WGCNA analysis. PLANT CELL REPORTS 2024; 43:67. [PMID: 38341832 DOI: 10.1007/s00299-024-03148-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 11/09/2023] [Accepted: 01/02/2024] [Indexed: 02/13/2024]
Abstract
KEY MESSAGE In this study, genome-wide association studies combined with transcriptome data analysis were utilized to reveal potential candidate genes for stripe rust resistance in wheat, providing a basis for screening wheat varieties for stripe rust resistance. Wheat stripe rust, which is caused by the wheat stripe rust fungus (Puccinia striiformis f. sp. tritici, Pst) is one of the world's most devastating diseases of wheat. Genetic resistance is the most effective strategy for controlling diseases. Although wheat stripe rust resistance genes have been identified to date, only a few of them confer strong and broad-spectrum resistance. Here, the resistance of 335 wheat germplasm resources (mainly wheat landraces) from southwestern China to wheat stripe rust was evaluated at the adult stage. Combined genome-wide association study (GWAS) and weighted gene co-expression network analysis (WGCNA) based on RNA sequencing from stripe rust resistant accession Y0337 and susceptible accession Y0402, five candidate resistance genes to wheat stripe rust (TraesCS1B02G170200, TraesCS2D02G181000, TraesCS4B02G117200, TraesCS6A02G189300, and TraesCS3A02G122300) were identified. The transcription level analyses showed that these five genes were significantly differentially expressed between resistant and susceptible accessions post inoculation with Pst at different times. These candidate genes could be experimentally transformed to validate and manipulate fungal resistance, which is beneficial for the development of the wheat cultivars resistant to stripe rust.
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Affiliation(s)
- Liang Qiao
- College of Agronomy and Biotechnology, Yunnan Agricultural University, Kunming, 650201, China
| | - Xue Gao
- College of Agronomy and Biotechnology, Yunnan Agricultural University, Kunming, 650201, China
| | - Zhiqiang Jia
- College of Agronomy and Biotechnology, Yunnan Agricultural University, Kunming, 650201, China
| | - Xingchen Liu
- College of Agronomy and Biotechnology, Yunnan Agricultural University, Kunming, 650201, China
| | - Huiyutang Wang
- College of Agronomy and Biotechnology, Yunnan Agricultural University, Kunming, 650201, China
| | - Yixi Kong
- College of Agronomy and Biotechnology, Yunnan Agricultural University, Kunming, 650201, China
| | - Peng Qin
- College of Agronomy and Biotechnology, Yunnan Agricultural University, Kunming, 650201, China
| | - Baoju Yang
- College of Agronomy and Biotechnology, Yunnan Agricultural University, Kunming, 650201, China.
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36
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Yang S, Ning C, Yang C, Li W, Zhang Q, Wang D, Tang H. Identify Candidate Genes Associated with the Weight and Egg Quality Traits in Wenshui Green Shell-Laying Chickens by the Copy Number Variation-Based Genome-Wide Association Study. Vet Sci 2024; 11:76. [PMID: 38393094 PMCID: PMC10892766 DOI: 10.3390/vetsci11020076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/18/2023] [Revised: 02/03/2024] [Accepted: 02/04/2024] [Indexed: 02/25/2024] Open
Abstract
Copy number variation (CNV), as an essential source of genetic variation, can have an impact on gene expression, genetic diversity, disease susceptibility, and species evolution in animals. To better understand the weight and egg quality traits of chickens, this paper aimed to detect CNVs in Wenshui green shell-laying chickens and conduct a copy number variation regions (CNVRs)-based genome-wide association study (GWAS) to identify variants and candidate genes associated with their weight and egg quality traits to support related breeding efforts. In our paper, we identified 11,035 CNVRs in Wenshui green shell-laying chickens, which collectively spanned a length of 13.1 Mb, representing approximately 1.4% of its autosomal genome. Out of these CNVRs, there were 10,446 loss types, 491 gain types, and 98 mixed types. Notably, two CNVRs showed significant correlations with egg quality, while four CNVRs exhibited significant associations with body weight. These significant CNVRs are located on chromosome 4. Further analysis identified potential candidate genes that influence weight and egg quality traits, including FAM184B, MED28, LAP3, ATOH8, ST3GAL5, LDB2, and SORCS2. In this paper, the CNV map of the Wenshui green shell-laying chicken genome was constructed for the first time through population genotyping. Additionally, CNVRs can be employed as molecular markers to genetically improve chickens' weight and egg quality traits.
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Affiliation(s)
- Suozhou Yang
- Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China; (S.Y.); (C.N.); (C.Y.); (W.L.)
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China;
| | - Chao Ning
- Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China; (S.Y.); (C.N.); (C.Y.); (W.L.)
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China;
| | - Cheng Yang
- Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China; (S.Y.); (C.N.); (C.Y.); (W.L.)
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China;
| | - Wenqiang Li
- Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China; (S.Y.); (C.N.); (C.Y.); (W.L.)
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China;
| | - Qin Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China;
- College of Animal Science and Technology, China Agricultural University, Beijing 100083, China
| | - Dan Wang
- Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China; (S.Y.); (C.N.); (C.Y.); (W.L.)
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China;
| | - Hui Tang
- Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China; (S.Y.); (C.N.); (C.Y.); (W.L.)
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai’an 271018, China;
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Lu J, Toro C, Adams DR, Moreno CAM, Lee WP, Leung YY, Harms MB, Vardarajan B, Heinzen EL. LUSTR: a new customizable tool for calling genome-wide germline and somatic short tandem repeat variants. BMC Genomics 2024; 25:115. [PMID: 38279154 PMCID: PMC10811831 DOI: 10.1186/s12864-023-09935-9] [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] [Academic Contribution Register] [Received: 05/18/2023] [Accepted: 12/21/2023] [Indexed: 01/28/2024] Open
Abstract
BACKGROUND Short tandem repeats (STRs) are widely distributed across the human genome and are associated with numerous neurological disorders. However, the extent that STRs contribute to disease is likely under-estimated because of the challenges calling these variants in short read next generation sequencing data. Several computational tools have been developed for STR variant calling, but none fully address all of the complexities associated with this variant class. RESULTS Here we introduce LUSTR which is designed to address some of the challenges associated with STR variant calling by enabling more flexibility in defining STR loci, allowing for customizable modules to tailor analyses, and expanding the capability to call somatic and multiallelic STR variants. LUSTR is a user-friendly and easily customizable tool for targeted or unbiased genome-wide STR variant screening that can use either predefined or novel genome builds. Using both simulated and real data sets, we demonstrated that LUSTR accurately infers germline and somatic STR expansions in individuals with and without diseases. CONCLUSIONS LUSTR offers a powerful and user-friendly approach that allows for the identification of STR variants and can facilitate more comprehensive studies evaluating the role of pathogenic STR variants across human diseases.
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Affiliation(s)
- Jinfeng Lu
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- The Taub Institute for Research On Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, Department of Neurology, College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, New York, NY, 10032, USA.
| | - Camilo Toro
- NIH Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD, 20892, USA
| | - David R Adams
- NIH Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD, 20892, USA
| | | | - Wan-Ping Lee
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory MedicinePerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Yuk Yee Leung
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory MedicinePerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Mathew B Harms
- Department of Neurology, Division of Neuromuscular Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Badri Vardarajan
- The Taub Institute for Research On Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, Department of Neurology, College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, New York, NY, 10032, USA
| | - Erin L Heinzen
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
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Hu C, Kuang T, Shaw RK, Zhang Y, Fan J, Bi Y, Jiang F, Guo R, Fan X. Genetic dissection of resistance to gray leaf spot by genome-wide association study in a multi-parent maize population. BMC PLANT BIOLOGY 2024; 24:10. [PMID: 38163896 PMCID: PMC10759574 DOI: 10.1186/s12870-023-04701-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 06/23/2023] [Accepted: 12/19/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Understanding the genetic mechanisms underlying gray leaf spot (GLS) resistance in maize is crucial for breeding GLS-resistant inbred lines and commercial hybrids. Genome-wide association studies (GWAS) and gene functional annotation are valuable methods for identifying potential SNPs (single nucleotide polymorphism) and candidate genes associated with GLS resistance in maize. RESULTS In this study, a total of 757 lines from five recombinant inbred line (RIL) populations of maize at the F7 generation were used to construct an association mapping panel. SNPs obtained through genotyping-by-sequencing (GBS) were used to perform GWAS for GLS resistance using a linear mixture model in GEMMA. Candidate gene screening was performed by analyzing the 10 kb region upstream and downstream of the significantly associated SNPs linked to GLS resistance. Through GWAS analysis of multi-location phenotypic data, we identified ten candidate genes that were consistently detected in two locations or from one location along with best linear unbiased estimates (BLUE). One of these candidate genes, Zm00001d003257 that might impact GLS resistance by regulating gibberellin content, was further identified through haplotype-based association analysis, candidate gene expression analysis, and previous reports. CONCLUSIONS The discovery of the novel candidate gene provides valuable genomic resources for elucidating the genetic mechanisms underlying GLS resistance in maize. Additionally, these findings will contribute to the development of new genetic resources by utilizing molecular markers to facilitate the genetic improvement and breeding of maize for GLS resistance.
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Affiliation(s)
- Can Hu
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming, China
- School of Agriculture, Yunnan University, Kunming, China
| | - Tianhui Kuang
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming, China
| | - Ranjan K Shaw
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming, China
| | - Yudong Zhang
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming, China
| | - Jun Fan
- School of Agriculture, Yunnan University, Kunming, China
| | - Yaqi Bi
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming, China
| | - Fuyan Jiang
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming, China
| | - Ruijia Guo
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming, China
| | - Xingming Fan
- Institute of Food Crops, Yunnan Academy of Agricultural Sciences, Kunming, China.
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Liu J, Xu L, Ding X, Ma Y. Genome-Wide Association Analysis of Reproductive Traits in Chinese Holstein Cattle. Genes (Basel) 2023; 15:12. [PMID: 38275594 PMCID: PMC10815438 DOI: 10.3390/genes15010012] [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] [Academic Contribution Register] [Received: 10/28/2023] [Revised: 12/15/2023] [Accepted: 12/17/2023] [Indexed: 01/27/2024] Open
Abstract
This study was to explore potential SNP loci for reproductive traits in Chinese Holstein cattle and identify candidate genes. Genome-wide Association Study based on mixed linear model was performed on 643 Holstein cattle using GeneSeek Bovine 50 K SNP chip. Our results detected forty significant SNP loci after Bonferroni correction. We identified five genes (VWC2L, STAT1, PPP3CA, LDB3, and CTNNA3) as being associated with pregnancy ratio of young cows, five genes (PAEP, ACOXL, EPAS1, GLRB, and MARVELD1) as being associated with pregnancy ratio of adult cows, and nine genes (PDE1B, SLCO1A2, ARHGAP26, ADAM10, APBB1, MON1B, COQ9, CDC42BPB, MARVELD1, and HPSE2) as being associated with daughter pregnancy rate. Our study may provide valuable insights into identifying genes related to reproductive traits and help promote the application of molecular breeding in dairy cows.
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Affiliation(s)
- Jiashuang Liu
- Tianjin Key Laboratory of Animal Molecular Breeding and Biotechnology, Tianjin Engineering Research Center of Animal Healthy Farming, Institute of Animal Science and Veterinary, Tianjin Academy of Agricultural Sciences, Tianjin 300381, China;
- College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China;
| | - Lingyang Xu
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China;
| | - Xiangbin Ding
- College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China;
| | - Yi Ma
- Tianjin Key Laboratory of Animal Molecular Breeding and Biotechnology, Tianjin Engineering Research Center of Animal Healthy Farming, Institute of Animal Science and Veterinary, Tianjin Academy of Agricultural Sciences, Tianjin 300381, China;
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Wang C, Lan J, Wang J, He W, Lu W, Lin Y, Luo J. Population structure and genetic diversity in Eucalyptus pellita based on SNP markers. FRONTIERS IN PLANT SCIENCE 2023; 14:1278427. [PMID: 38162312 PMCID: PMC10757378 DOI: 10.3389/fpls.2023.1278427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Academic Contribution Register] [Received: 08/24/2023] [Accepted: 10/25/2023] [Indexed: 01/03/2024]
Abstract
Eucalyptus pellita has the characteristics of rapid growth and high resistance. However, there is little research on molecular breeding of E. pellita, which is essential to shortening breeding life and selecting quality varieties. Therefore, a crucial step before selective breeding can be carried out to increase the wood quality of E. pellita is identifying genetic diversity and population structure using single nucleotide polymorphism (SNP) markers. In this study, the genetic diversity of 1st generation 196 E. pellita families from 23 geographically defined was assessed using 1,677,732 SNP markers identified by whole genome resequencing. SNP annotation showed that the ratio of non-synonymous to synonymous coding mutations was 0.83. Principal component analysis (PCA), phylogenetic tree, and population structure analysis permitted the families to be categorized into three groups, one of which (G2) contains most of the Indonesian (IDN) and Papua New Guinea (PNG) families. Genetic relationship analysis showed that IDN was closely related to PNG. Genetic diversity analysis showed that He, PIC, I, and H mean values were 0.2502, 0.2027, 0.3815, and 0.2680, respectively. PCA analysis classified various provenances in QLD into two categories (G1 and G3). The genetic diversity of G3 was higher than that of G2. The results of genetic differentiation (Fst) showed that PNG region was divided into two groups (PNG1 and PNG2), the Fst (0.172) between QLD and PNG2 region was higher than QLD and PNG1, and the Fst (0.024) between IDN and PNG1 is smaller than IDN and PNG2. A Mantel test revealed a positive correlation between the genetic and geographic distance of E. pellita. This study has a certain reference value for genetic identification, germplasm preservation, and breeding of E. pellita. Also, it provides a basis for subsequent association analysis to explore excellent alleles and introduction.
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Affiliation(s)
- Chubiao Wang
- Research Institute of Fast-growing Trees, Chinese Academy of Forestry, Zhanjiang, China
| | - Jun Lan
- Forestry Science Research Institute, Guangxi Dongmen Forest Farm, Fusui, China
| | - Jianzhong Wang
- Forestry Science Research Institute, Guangxi Dongmen Forest Farm, Fusui, China
| | - Wenliang He
- Research Institute of Fast-growing Trees, Chinese Academy of Forestry, Zhanjiang, China
| | - Wanhong Lu
- Research Institute of Fast-growing Trees, Chinese Academy of Forestry, Zhanjiang, China
| | - Yan Lin
- Research Institute of Fast-growing Trees, Chinese Academy of Forestry, Zhanjiang, China
| | - Jianzhong Luo
- Research Institute of Fast-growing Trees, Chinese Academy of Forestry, Zhanjiang, China
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Cox EGM, Zhang W, van der Voort PHJ, Lunter G, Keus F, Snieder H. Genetic association studies in critically ill patients: protocol for a systematic review. Syst Rev 2023; 12:233. [PMID: 38093336 PMCID: PMC10716946 DOI: 10.1186/s13643-023-02401-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/28/2022] [Accepted: 11/23/2023] [Indexed: 12/17/2023] Open
Abstract
INTRODUCTION Patients in the intensive care unit (ICU) are highly heterogeneous in characteristics, their clinical course, and outcomes. Genetic variability may partly explain the variability and similarity in disease courses observed among critically ill patients and may identify clusters of subgroups. The aim of this study is to conduct a systematic review of all genetic association studies of critically ill patients with their outcomes. METHODS AND ANALYSIS This systematic review will be conducted and reported according to the HuGE Review Handbook V1.0. We will search PubMed, Embase, and the Cochrane Library for relevant studies. All types of genetic association studies that included acutely admitted medical and surgical adult ICU patients will be considered for this review. All studies will be selected according to predefined selection criteria, evaluated and assessed for risk of bias independently by two reviewers. Risk of bias will be assessed according to the HuGE Review Handbook V1.0 with some modifications reflecting recent insights. We will provide an overview of all included studies by reporting the characteristics of the study designs, the patients included in the studies, the genetic variables, and the outcomes evaluated. ETHICS AND DISSEMINATION We will use data from peer-reviewed published articles, and hence, there is no requirement for ethics approval. The results of this systematic review will be disseminated through publication in a peer-reviewed scientific journal. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42021209744.
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Affiliation(s)
- Eline G M Cox
- Department of Critical Care, University Medical Center Groningen, Groningen, 9713 GZ, the Netherlands.
| | - Wenbo Zhang
- Department of Epidemiology, University Medical Center Groningen, Groningen, 9713 GZ, the Netherlands
| | - Peter H J van der Voort
- Department of Critical Care, University Medical Center Groningen, Groningen, 9713 GZ, the Netherlands
| | - Gerton Lunter
- Department of Epidemiology, University Medical Center Groningen, Groningen, 9713 GZ, the Netherlands
| | - Frederik Keus
- Department of Critical Care, University Medical Center Groningen, Groningen, 9713 GZ, the Netherlands
| | - Harold Snieder
- Department of Epidemiology, University Medical Center Groningen, Groningen, 9713 GZ, the Netherlands
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Doesburg-van Kleffens M, Zimmermann-Klemd AM, Gründemann C. An Overview on the Hallucinogenic Peyote and Its Alkaloid Mescaline: The Importance of Context, Ceremony and Culture. Molecules 2023; 28:7942. [PMID: 38138432 PMCID: PMC10746114 DOI: 10.3390/molecules28247942] [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] [Academic Contribution Register] [Received: 10/26/2023] [Revised: 11/27/2023] [Accepted: 12/02/2023] [Indexed: 12/24/2023] Open
Abstract
Peyote (Lophophora williamsii) is a cactus that contains various biologically active alkaloids-such as pellotine, anhalonidine, hordenine and mescaline. Here, mescaline induces the psychoactive effects of peyote through the activation of the serotonin 5-HT2A receptor and the subsequent release of calcium (Ca2+) from the endoplasmic reticulum (ER). Moreover, an evaluation of the therapeutic benefits of mescaline is also currently the subject of research. It is important to consider that the outcome of taking a psychedelic drug strongly depends on the mindset of the recipient and the context (set and setting principle), including ceremonies and culture. This overview serves to summarise the current state of the knowledge of the metabolism, mechanism of action and clinical application studies of peyote and mescaline. Furthermore, the benefits of the potential of peyote and mescaline are presented in a new light, setting an example for combining a form of treatment embedded in nature and ritually enriched with our current highly innovative Western medicine.
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Tang H, Liu J, Wang Z, Zhang L, Yang M, Huang J, Wen X, Luo J. Genome-wide association study (GWAS) analysis of black color trait in the leopard coral grouper (Plectropomus leopardus) using whole genome resequencing. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2023; 48:101138. [PMID: 37683359 DOI: 10.1016/j.cbd.2023.101138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 05/28/2023] [Revised: 08/28/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023]
Abstract
The leopard coral grouper (Plectropomus leopardus) is a coral reef fish species that exhibits rapid and diverse color variation. However, the presence of melanoma and the high proportion of individuals displaying black color in artificial breeding have led to reduced economic and ornamental value. To pinpoint single nucleotide polymorphisms (SNPs) and potential genes linked to the black pigmentation characteristic in this particular species, This study gathered a cohort of 360 specimens from diverse origins and conducted a comprehensive genome-wide association analysis (GWAS) employing whole-genome resequencing. As a result, 57 SNPs related to the black skin trait were identified, and a grand total of 158 genes were annotated within 50 kb of these SNPs. Subsequently, GWAS was applied to three populations (LED, QHH, and QHL), and the corresponding results were compared with the analysis results of the total population. The results of the four GWAS models showed significant enrichment in Rap1 signaling pathway, melanin biosynthesis, metabolic pathways, tyrosine metabolism, cAMP signaling pathway, AMPK signaling pathway, PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, HIF-1 signaling pathway, Ras signaling pathway, MAPK signaling pathway, etc. (p < 0.05), which were mainly associated with eleven genes (POL4, MET, E2F2, COMT, ZBED1, TYRP2, FOXP2, THIKA, LORF2, MYH16 and SOX2). Significant differences (p < 0.05) were observed in the expression of all 11 genes in the dorsal skin tissue, in 10 genes except COMT in the ventral skin tissue, and in all 11 genes in the caudal fin tissue. These findings imply that the control of body color in the P. leopardus is the result of the joint action of multiple genes and signaling pathways. These findings will contribute to a more profound comprehension of the genetic attributes that underlie the development of black skin in the vibrant P. leopardus, thus furnishing a theoretical foundation for genetic enhancement.
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Affiliation(s)
- Haizhan Tang
- Sanya Nanfan Research Institute of Hainan University, Hainan Aquaculture Breeding Engineering Research Center, Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Hainan Academician Team Innovation Center, Hainan University, Haikou 570228, China
| | - Junchi Liu
- Sanya Nanfan Research Institute of Hainan University, Hainan Aquaculture Breeding Engineering Research Center, Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Hainan Academician Team Innovation Center, Hainan University, Haikou 570228, China
| | - Zirui Wang
- Sanya Nanfan Research Institute of Hainan University, Hainan Aquaculture Breeding Engineering Research Center, Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Hainan Academician Team Innovation Center, Hainan University, Haikou 570228, China
| | - Lianjie Zhang
- Sanya Nanfan Research Institute of Hainan University, Hainan Aquaculture Breeding Engineering Research Center, Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Hainan Academician Team Innovation Center, Hainan University, Haikou 570228, China
| | - Min Yang
- Sanya Nanfan Research Institute of Hainan University, Hainan Aquaculture Breeding Engineering Research Center, Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Hainan Academician Team Innovation Center, Hainan University, Haikou 570228, China
| | - Jie Huang
- Sanya Nanfan Research Institute of Hainan University, Hainan Aquaculture Breeding Engineering Research Center, Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Hainan Academician Team Innovation Center, Hainan University, Haikou 570228, China
| | - Xin Wen
- Sanya Nanfan Research Institute of Hainan University, Hainan Aquaculture Breeding Engineering Research Center, Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Hainan Academician Team Innovation Center, Hainan University, Haikou 570228, China.
| | - Jian Luo
- Sanya Nanfan Research Institute of Hainan University, Hainan Aquaculture Breeding Engineering Research Center, Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Hainan Academician Team Innovation Center, Hainan University, Haikou 570228, China.
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Biswas R, Boyd EK, Eaton N, Steenackers A, Schulte ML, Reusswig F, Yu H, Drew C, Kahr WHA, Shi Q, Plomann M, Hoffmeister KM, Falet H. PACSIN2 regulates platelet integrin β1 hemostatic function. J Thromb Haemost 2023; 21:3619-3632. [PMID: 37678551 PMCID: PMC10841284 DOI: 10.1016/j.jtha.2023.08.026] [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] [Academic Contribution Register] [Received: 04/25/2023] [Revised: 08/11/2023] [Accepted: 08/25/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND Upon vessel injury, platelets adhere to exposed matrix constituents via specific membrane receptors, including the von Willebrand factor receptor glycoprotein (GP)Ib-IX-V complex and integrins β1 and β3. In platelets, the Fes/CIP4-homology Bin-Amphiphysin-Rvs protein PACSIN2 associates with the cytoskeletal and scaffolding protein filamin A (FlnA), linking GPIbα and integrins to the cytoskeleton. OBJECTIVES Here we investigated the role of PACSIN2 in platelet function. METHODS Platelet parameters were evaluated in mice lacking PACSIN2 and platelet integrin β1. RESULTS Pacsin2-/- mice displayed mild thrombocytopenia, prolonged bleeding time, and delayed thrombus formation in a ferric chloride-mediated carotid artery injury model, which was normalized by injection of control platelets. Pacsin2-/- platelets formed unstable thrombi that embolized abruptly in a laser-induced cremaster muscle injury model. Pacsin2-/- platelets had hyperactive integrin β1, as evidenced by increased spreading onto surfaces coated with the collagen receptor α2β1-specific peptide GFOGER and increased binding of the antibody 9EG7 directed against active integrin β1. By contrast, Pacsin2-/- platelets had normal integrin αIIbβ3 function and expressed P-selectin normally following stimulation through the collagen receptor GPVI or with thrombin. Deletion of platelet integrin β1 in Pacsin2-/- mice normalized platelet count, hemostasis, and thrombus formation. A PACSIN2 peptide mimicking the FlnA-binding site mediated the pull-down of a FlnA rod 2 construct by integrin β7, a model for integrin β-subunits. CONCLUSIONS Pacsin2-/- mice displayed severe thrombus formation defects due to hyperactive platelet integrin β1. The data suggest that PACSIN2 binding to FlnA negatively regulates platelet integrin β1 hemostatic function.
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Affiliation(s)
- Ratnashree Biswas
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA
| | - Emily K Boyd
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Nathan Eaton
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Agata Steenackers
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA
| | | | - Friedrich Reusswig
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA
| | - Hongyin Yu
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Caleb Drew
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA
| | - Walter H A Kahr
- Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Qizhen Shi
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Children's Research Institute, Children's Wisconsin, Milwaukee, Wisconsin, USA
| | - Markus Plomann
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Karin M Hoffmeister
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA; Departments of Biochemistry and Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Hervé Falet
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Translational Glycomics Center, Milwaukee, Wisconsin, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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Zhang YM, Jia Z, Dunwell JM. Editorial: The applications of new multi-locus GWAS methodologies in the genetic dissection of complex traits, volume II. FRONTIERS IN PLANT SCIENCE 2023; 14:1340767. [PMID: 38146269 PMCID: PMC10749431 DOI: 10.3389/fpls.2023.1340767] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 11/19/2023] [Accepted: 11/27/2023] [Indexed: 12/27/2023]
Affiliation(s)
- Yuan-Ming Zhang
- College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Zhenyu Jia
- Department of Botany and Plant Sciences, University of California, Riverside, Riverside, CA, United States
| | - Jim M. Dunwell
- School of Agriculture, Policy and Development, University of Reading, Reading, United Kingdom
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Aparicio A, Sun Z, Gold DR, Litonjua AA, Weiss ST, Lee-Sarwar K, Liu YY. Genotype-microbiome-metabolome associations in early childhood, and their link to BMI and childhood obesity. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.11.13.23298467. [PMID: 38014043 PMCID: PMC10680902 DOI: 10.1101/2023.11.13.23298467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 11/29/2023]
Abstract
The influence of genotype on defining the human gut microbiome has been extensively studied, but definite conclusions have not yet been found. To fill this knowledge gap, we leverage data from children enrolled in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) from 6 months to 8 years old. We focus on a pool of 12 genes previously found to be associated with the gut microbiome in independent studies, establishing a Bonferroni corrected significance level of p-value < 2.29 × 10 -6 . We identified significant associations between SNPs in the FHIT gene (known to be associated with obesity and type 2 diabetes) and obesity-related microbiome features, and the children's BMI through their childhood. Based on these associations, we defined a set of SNPs of interest and a set of taxa of interest. Taking a multi-omics approach, we integrated plasma metabolome data into our analysis and found simultaneous associations among children's BMI, the SNPs of interest, and the taxa of interest, involving amino acids, lipids, nucleotides, and xenobiotics. Using our association results, we constructed a quadripartite graph where each disjoint node set represents SNPs in the FHIT gene, microbial taxa, plasma metabolites, or BMI measurements. Network analysis led to the discovery of patterns that identify several genetic variants, microbial taxa and metabolites as new potential markers for obesity, type 2 diabetes, or insulin resistance risk.
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Trebes H, Wang Y, Reynolds E, Tiplady K, Harland C, Lopdell T, Johnson T, Davis S, Harris B, Spelman R, Couldrey C. Identification of candidate novel production variants on the Bos taurus chromosome X. J Dairy Sci 2023; 106:7799-7815. [PMID: 37562645 DOI: 10.3168/jds.2022-23095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/01/2022] [Accepted: 04/26/2023] [Indexed: 08/12/2023]
Abstract
Chromosome X is often excluded from bovine genetic studies due to complications caused by the sex specific nature of the chromosome. As chromosome X is the second largest cattle chromosome and makes up approximately 6% of the female genome, finding ways to include chromosome X in dairy genetic studies is important. Using female animals and treating chromosome X as an autosome, we performed X chromosome inclusive genome-wide association studies in the selective breeding environment of the New Zealand dairy industry, aiming to identify chromosome X variants associated with milk production traits. We report on the findings of these genome-wide association studies and their potential effect within the dairy industry. We identify missense mutations in the MOSPD1 and CCDC160 genes that are associated with decreased milk volume and protein production and increased fat production. Both of these mutations are exonic SNP that are more prevalent in the Jersey breed than in Holstein-Friesians. Of the 2 candidates proposed it is likely that only one is causal, though we have not been able to identify which is more likely.
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Affiliation(s)
- H Trebes
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand.
| | - Y Wang
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand
| | - E Reynolds
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand
| | - K Tiplady
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand
| | - C Harland
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand
| | - T Lopdell
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand
| | - T Johnson
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand
| | - S Davis
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand
| | - B Harris
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand
| | - R Spelman
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand
| | - C Couldrey
- Research and Development, Livestock Improvement Corporation, Hamilton 3240, New Zealand
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48
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Nakahara S, Male AG, Turner JA, Calhoun VD, Lim KO, Mueller BA, Bustillo JR, O'Leary DS, Voyvodic J, Belger A, Preda A, Mathalon DH, Ford JM, Guffanti G, Macciardi F, Potkin SG, Van Erp TGM. Auditory oddball hypoactivation in schizophrenia. Psychiatry Res Neuroimaging 2023; 335:111710. [PMID: 37690161 DOI: 10.1016/j.pscychresns.2023.111710] [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] [Academic Contribution Register] [Received: 03/15/2022] [Revised: 06/30/2023] [Accepted: 08/26/2023] [Indexed: 09/12/2023]
Abstract
Individuals with schizophrenia (SZ) show aberrant activations, assessed via functional magnetic resonance imaging (fMRI), during auditory oddball tasks. However, associations with cognitive performance and genetic contributions remain unknown. This study compares individuals with SZ to healthy volunteers (HVs) using two cross-sectional data sets from multi-center brain imaging studies. It examines brain activation to auditory oddball targets, and their associations with cognitive domain performance, schizophrenia polygenic risk scores (PRS), and genetic variation (loci). Both sample 1 (137 SZ vs. 147 HV) and sample 2 (91 SZ vs. 98 HV), showed hypoactivation in SZ in the left-frontal pole, and right frontal orbital, frontal pole, paracingulate, intracalcarine, precuneus, supramarginal and hippocampal cortices, and right thalamus. In SZ, precuneus activity was positively related to cognitive performance. Schizophrenia PRS showed a negative correlation with brain activity in the right-supramarginal cortex. GWA analyses revealed significant single-nucleotide polymorphisms associated with right-supramarginal gyrus activity. RPL36 also predicted right-supramarginal gyrus activity. In addition to replicating hypoactivation for oddball targets in SZ, this study identifies novel relationships between regional activity, cognitive performance, and genetic loci that warrant replication, emphasizing the need for continued data sharing and collaborative efforts.
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Affiliation(s)
- Soichiro Nakahara
- Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, 92617, United States; Discovery Accelerator Venture Unit Direct Reprogramming, Astellas Pharma Inc, 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan
| | - Alie G Male
- Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, 92617, United States
| | - Jessica A Turner
- Department of Psychiatry and Behavioral Health, Ohio State University, Columbus, OH, 43210, United States
| | - Vince D Calhoun
- Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, and Emory University 55 Park Pl NE, Atlanta, GA 30303, USA
| | - Kelvin O Lim
- Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, 55454, United States
| | - Bryon A Mueller
- Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, 55454, United States
| | - Juan R Bustillo
- Departments of Psychiatry & Neurosciences, University of New Mexico, Albuquerque, NM, 87131, United States
| | - Daniel S O'Leary
- Department of Psychiatry, University of Iowa, Iowa City, IA, 52242, United States
| | - James Voyvodic
- Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC, 27710, United States
| | - Aysenil Belger
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States
| | - Adrian Preda
- Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, 92617, United States
| | - Daniel H Mathalon
- Department of Psychiatry, University of California, San Francisco, San Francisco, CA, 94143, United States; Veterans Affairs San Francisco Healthcare System, San Francisco, CA, 94121, United States
| | - Judith M Ford
- Department of Psychiatry, University of California, San Francisco, San Francisco, CA, 94143, United States; Veterans Affairs San Francisco Healthcare System, San Francisco, CA, 94121, United States; San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, United States
| | - Guia Guffanti
- Department of Psychiatry at McLean Hospital - Harvard Medical School, Boston, MA, 02478, United States
| | - Fabio Macciardi
- Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, 92617, United States
| | - Steven G Potkin
- Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, 92617, United States
| | - Theo G M Van Erp
- Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, 92617, United States; Center for the Neurobiology of Learning and Memory, University of California Irvine, 309 Qureshey Research Lab, Irvine, CA, 92697, United States.
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49
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Moscati A, Faucon AB, Arnaiz-Yépez C, Lönn SL, Sundquist J, Sundquist K, Belbin GM, Nadkarni G, Cho JH, Loos RJF, Davis LK, Kendler KS. Life is pain: Fibromyalgia as a nexus of multiple liability distributions. Am J Med Genet B Neuropsychiatr Genet 2023; 192:171-182. [PMID: 37334860 DOI: 10.1002/ajmg.b.32949] [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] [Academic Contribution Register] [Received: 01/08/2022] [Revised: 03/20/2023] [Accepted: 05/23/2023] [Indexed: 06/21/2023]
Abstract
Fibromyalgia is a complex disease of unclear etiology that is complicated by difficulties in diagnosis, treatment, and clinical heterogeneity. To clarify this etiology, healthcare-based data are leveraged to assess the influences on fibromyalgia in several domains. Prevalence is less than 1% of females in our population register data, and about 1/10th that in males. Fibromyalgia often presents with co-occurring conditions including back pain, rheumatoid arthritis, and anxiety. More comorbidities are identified with hospital-associated biobank data, falling into three broad categories of pain-related, autoimmune, and psychiatric disorders. Selecting representative phenotypes with published genome-wide association results for polygenic scoring, we confirm genetic predispositions to psychiatric, pain sensitivity, and autoimmune conditions show associations with fibromyalgia, although these may differ by ancestry group. We conduct a genome-wide association analysis of fibromyalgia in biobank samples, which did not result in any genome-wide significant loci; further studies with increased sample size are necessary to identify specific genetic effects on fibromyalgia. Overall, fibromyalgia appears to have strong clinical and likely genetic links to several disease categories, and could usefully be understood as a composite manifestation of these etiological sources.
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Affiliation(s)
- Arden Moscati
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Annika B Faucon
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Cayetana Arnaiz-Yépez
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sara Larsson Lönn
- Center for Primary Health Care Research, Lund University, Lund, Sweden
| | - Jan Sundquist
- Center for Primary Health Care Research, Lund University, Lund, Sweden
- Department of Family Medicine and Community Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Functional Pathology, School of Medicine, Center for Community-based Healthcare Research and Education (CoHRE), Shimane University, Matsue, Japan
| | - Kristina Sundquist
- Center for Primary Health Care Research, Lund University, Lund, Sweden
- Department of Family Medicine and Community Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Functional Pathology, School of Medicine, Center for Community-based Healthcare Research and Education (CoHRE), Shimane University, Matsue, Japan
| | - Gillian M Belbin
- The Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Girish Nadkarni
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Judy H Cho
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ruth J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Lea K Davis
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kenneth S Kendler
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
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50
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Chi J, Xu M, Sheng X, Zhou Y. Association detection between multiple traits and rare variants based on family data via a nonparametric method. PeerJ 2023; 11:e16040. [PMID: 37780393 PMCID: PMC10541022 DOI: 10.7717/peerj.16040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/20/2023] [Accepted: 08/15/2023] [Indexed: 10/03/2023] Open
Abstract
Background The rapid development of next-generation sequencing technologies allow people to analyze human complex diseases at the molecular level. It has been shown that rare variants play important roles for human diseases besides common variants. Thus, effective statistical methods need to be proposed to test for the associations between traits (e.g., diseases) and rare variants. Currently, more and more rare genetic variants are being detected throughout the human genome, which demonstrates the possibility to study rare variants. Yet complex diseases are usually measured as a variety of forms, such as binary, ordinal, quantitative, or some mixture of them. Therefore, the genetic mapping problem can be attributable to the association detection between multiple traits and multiple loci, with sufficiently considering the correlated structure among multiple traits. Methods In this article, we construct a new non-parametric statistic by the generalized Kendall's τ theory based on family data. The new test statistic has an asymptotic distribution, it can be used to study the associations between multiple traits and rare variants, which broadens the way to identify genetic factors of human complex diseases. Results We apply our method (called Nonp-FAM) to analyze simulated data and GAW17 data, and conduct comprehensive comparison with some existing methods. Experimental results show that the proposed family-based method is powerful and robust for testing associations between multiple traits and rare variants, even if the data has some population stratification effect.
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Affiliation(s)
- Jinling Chi
- Department of Statistics, Heilongjiang University, Harbin, China
- School of Mathematics and Statistics, Xidian University, Xi’an, China
| | - Meijuan Xu
- Department of Statistics, Heilongjiang University, Harbin, China
| | - Xiaona Sheng
- School of Information Engineering, Harbin University, Harbin, China
| | - Ying Zhou
- Department of Statistics, Heilongjiang University, Harbin, China
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