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Liu H, Bai Q, Wang X, Jin Y, Ju X, Lu C. Immune signature of gene expression pattern shared by autism spectrum disorder and Huntington's disease. IBRO Neurosci Rep 2024; 17:311-319. [PMID: 39398347 PMCID: PMC11471255 DOI: 10.1016/j.ibneur.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/25/2024] [Accepted: 09/25/2024] [Indexed: 10/15/2024] Open
Abstract
Autism spectrum disorder (ASD) and Huntington's disease (HD) are complex neurological conditions with unclear causes and limited treatments, affecting individuals, families, and society. Despite ASD and HD representing two opposing stages of neuronal development and degeneration, they share similar clinical-pathological features in motor function. In this study, we leveraged transcriptomic data from the prefrontal cortex available in public databases to identify shared transcriptional characteristics of ASD and HD. Differential expression analysis revealed that the majority of differentially expressed genes (DEGs) were up-regulated in ASD carriers, whereas most DEGs were down-regulated in HD carriers. Among the DEGs shared between both diseases, three out of seven protein-coding genes were related to the immune system. Furthermore, we identified two enriched pathways shared between ASD and HD DEGs. The gene interaction network analysis unveiled four hub genes shared by both diseases, all of which are associated with immune functions. The findings suggest a shared gene expression pattern in the prefrontal cortex of people with ASD and HD, closely linked to the immune system. These findings will contribute to exploring the biological mechanisms underlying the shared phenotypes of these two diseases from an immunological perspective.
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Affiliation(s)
- Huanhuan Liu
- School of Psychology, Northeast Normal University, Changchun, China
| | - Qiuyu Bai
- Yancheng College of Mechatronic Technology, Yancheng, China
| | | | - Yunlei Jin
- Children’ s Hospital of Changchun, Changchun, China
| | - Xingda Ju
- School of Psychology, Northeast Normal University, Changchun, China
- Jilin Provincial Key Laboratory of Cognitive Neuroscience and Brain Development, Changchun, China
| | - Chang Lu
- School of Psychology, Northeast Normal University, Changchun, China
- Jilin Provincial Key Laboratory of Cognitive Neuroscience and Brain Development, Changchun, China
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Bonk S, Eszlari N, Kirchner K, Gezsi A, Garvert L, Kuokkanen M, Cano I, Grabe HJ, Antal P, Juhasz G, Van der Auwera S. Impact of gene-by-trauma interaction in MDD-related multimorbidity clusters. J Affect Disord 2024; 359:382-391. [PMID: 38806065 DOI: 10.1016/j.jad.2024.05.126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 05/23/2024] [Accepted: 05/24/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUND Major depressive disorder (MDD) is considerably heterogeneous in terms of comorbidities, which may hamper the disentanglement of its biological mechanism. In a previous study, we classified the lifetime trajectories of MDD-related multimorbidities into seven distinct clusters, each characterized by unique genetic and environmental risk-factor profiles. The current objective was to investigate genome-wide gene-by-environment (G × E) interactions with childhood trauma burden, within the context of these clusters. METHODS We analyzed 77,519 participants and 6,266,189 single-nucleotide polymorphisms (SNPs) of the UK Biobank database. Childhood trauma burden was assessed using the Childhood Trauma Screener (CTS). For each cluster, Plink 2.0 was used to calculate SNP × CTS interaction effects on the participants' cluster membership probabilities. We especially focused on the effects of 31 candidate genes and associated SNPs selected from previous G × E studies for childhood maltreatment's association with depression. RESULTS At SNP-level, only the high-multimorbidity Cluster 6 revealed a genome-wide significant SNP rs145772219. At gene-level, MPST and PRH2 were genome-wide significant for the low-multimorbidity Clusters 1 and 3, respectively. Regarding candidate SNPs for G × E interactions, individual SNP results could be replicated for specific clusters. The candidate genes CREB1, DBH, and MTHFR (Cluster 5) as well as TPH1 (Cluster 6) survived multiple testing correction. LIMITATIONS CTS is a short retrospective self-reported measurement. Clusters could be influenced by genetics of individual disorders. CONCLUSIONS The first G × E GWAS for MDD-related multimorbidity trajectories successfully replicated findings from previous G × E studies related to depression, and revealed risk clusters for the contribution of childhood trauma.
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Affiliation(s)
- Sarah Bonk
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Nora Eszlari
- Department of Pharmacodynamics, Faculty of Pharmaceutical Sciences, Semmelweis University, Nagyvárad tér 4., H-1089 Budapest, Hungary; NAP3.0-SE Neuropsychopharmacology Research Group, Hungarian Brain Research Program, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary
| | - Kevin Kirchner
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Andras Gezsi
- Department of Measurement and Information Systems, Budapest University of Technology and Economics, Műegyetem rkp. 3., H-1111 Budapest, Hungary
| | - Linda Garvert
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Mikko Kuokkanen
- Department of Public Health and Welfare, Finnish Health and Welfare Institute. Biomedicum 1, Haartmaninkatu 8, 00290 Helsinki, Finland; Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine at University of Texas Rio Grande Valley, Brownsville, TX, United States; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland
| | - Isaac Cano
- Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Villarroel 170, Barcelona 08036. Spain
| | - Hans J Grabe
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, 17475 Greifswald, Germany
| | - Peter Antal
- Department of Measurement and Information Systems, Budapest University of Technology and Economics, Műegyetem rkp. 3., H-1111 Budapest, Hungary
| | - Gabriella Juhasz
- Department of Pharmacodynamics, Faculty of Pharmaceutical Sciences, Semmelweis University, Nagyvárad tér 4., H-1089 Budapest, Hungary; NAP3.0-SE Neuropsychopharmacology Research Group, Hungarian Brain Research Program, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary
| | - Sandra Van der Auwera
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, 17475 Greifswald, Germany.
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Jiang R, Huang W, Qiu X, Chen J, Luo R, Zeng R, Tong S, Lyu Y, Sun P, Lian Q, Leung FW, Liu Y, Sha W, Chen H. Unveiling promising drug targets for autism spectrum disorder: insights from genetics, transcriptomics, and proteomics. Brief Bioinform 2024; 25:bbae353. [PMID: 39038939 PMCID: PMC11262832 DOI: 10.1093/bib/bbae353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/20/2024] [Accepted: 07/09/2024] [Indexed: 07/24/2024] Open
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder for which current treatments are limited and drug development costs are prohibitive. Identifying drug targets for ASD is crucial for the development of targeted therapies. Summary-level data of expression quantitative trait loci obtained from GTEx, protein quantitative trait loci data from the ROSMAP project, and two ASD genome-wide association studies datasets were utilized for discovery and replication. We conducted a combined analysis using Mendelian randomization (MR), transcriptome-wide association studies, Bayesian colocalization, and summary-data-based MR to identify potential therapeutic targets associated with ASD and examine whether there are shared causal variants among them. Furthermore, pathway and drug enrichment analyses were performed to further explore the underlying mechanisms and summarize the current status of pharmacological targets for developing drugs to treat ASD. The protein-protein interaction (PPI) network and mouse knockout models were performed to estimate the effect of therapeutic targets. A total of 17 genes revealed causal associations with ASD and were identified as potential targets for ASD patients. Cathepsin B (CTSB) [odd ratio (OR) = 2.66 95, confidence interval (CI): 1.28-5.52, P = 8.84 × 10-3], gamma-aminobutyric acid type B receptor subunit 1 (GABBR1) (OR = 1.99, 95CI: 1.06-3.75, P = 3.24 × 10-2), and formin like 1 (FMNL1) (OR = 0.15, 95CI: 0.04-0.58, P = 5.59 × 10-3) were replicated in the proteome-wide MR analyses. In Drugbank, two potential therapeutic drugs, Acamprosate (GABBR1 inhibitor) and Bryostatin 1 (CASP8 inhibitor), were inferred as potential influencers of autism. Knockout mouse models suggested the involvement of the CASP8, GABBR1, and PLEKHM1 genes in neurological processes. Our findings suggest 17 candidate therapeutic targets for ASD and provide novel drug targets for therapy development and critical drug repurposing opportunities.
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Affiliation(s)
- Rui Jiang
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan 2nd Road, Guangzhou 510080, China
- The Second School of Clinical Medicine, Southern Medical University, No. 1023 Shatainan Road, Guangzhou 510515, China
- School of Medicine, South China University of Technology, No. 230, West Waihuan Road, Higher Education Mega Centre, Panyu District, Guangzhou 510006, China
| | - Wentao Huang
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan 2nd Road, Guangzhou 510080, China
- The Second School of Clinical Medicine, Southern Medical University, No. 1023 Shatainan Road, Guangzhou 510515, China
| | - Xinqi Qiu
- Cancer Prevention Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng East Road, Guangzhou 510060, China
| | - Jianyi Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan 2nd Road, Guangzhou 510080, China
- School of Medicine, South China University of Technology, No. 230, West Waihuan Road, Higher Education Mega Centre, Panyu District, Guangzhou 510006, China
| | - Ruibang Luo
- Department of Computer Science, The University of Hong Kong, Pokfulam Road, Hong Kong 999077, China
| | - Ruijie Zeng
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan 2nd Road, Guangzhou 510080, China
| | - Shuangshuang Tong
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan 2nd Road, Guangzhou 510080, China
- Shantou University Medical College, Shantou University, No. 22 Xinling Road, Shantou 515041, Guangdong, China
| | - Yanlin Lyu
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan 2nd Road, Guangzhou 510080, China
- Shantou University Medical College, Shantou University, No. 22 Xinling Road, Shantou 515041, Guangdong, China
| | - Panpan Sun
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, No. 1068 Xueyuan Avenue, Shenzhen University Town, Shenzhen 518055, China
| | - Qizhou Lian
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, No. 1068 Xueyuan Avenue, Shenzhen University Town, Shenzhen 518055, China
- Cord Blood Bank, Guangzhou Institute of Eugenics and Perinatology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, No. 9 Jinsui Road, Guangzhou 510623, China
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pokfulam Road, Hong Kong 999077, China
| | - Felix W Leung
- Sepulveda Ambulatory Care Center, VA Greater Los Angeles Healthcare System, 16111 Plummer Street, Los Angeles 91343, California, United States
- University of California Los Angeles David Geffen School of Medicine, 10833 Le Conte Avenue, Los Angeles 90095, California, United States
| | - Yufeng Liu
- Center for Medical Research on Innovation and Translation, Guangzhou First People's Hospital, the Second Affiliated Hospital of South China University of Technology, No 1 Panfu Road, Guangzhou 510000, China
| | - Weihong Sha
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan 2nd Road, Guangzhou 510080, China
- The Second School of Clinical Medicine, Southern Medical University, No. 1023 Shatainan Road, Guangzhou 510515, China
- School of Medicine, South China University of Technology, No. 230, West Waihuan Road, Higher Education Mega Centre, Panyu District, Guangzhou 510006, China
- Shantou University Medical College, Shantou University, No. 22 Xinling Road, Shantou 515041, Guangdong, China
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan 2nd Road, Guangzhou 510080, China
- The Second School of Clinical Medicine, Southern Medical University, No. 1023 Shatainan Road, Guangzhou 510515, China
- School of Medicine, South China University of Technology, No. 230, West Waihuan Road, Higher Education Mega Centre, Panyu District, Guangzhou 510006, China
- Shantou University Medical College, Shantou University, No. 22 Xinling Road, Shantou 515041, Guangdong, China
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Lathakumari S, Seenipandian S, Balakrishnan S, Raj APMS, Sugiyama H, Namasivayam GP, Sivasubramaniam S. Identification of genes responsible for the social skill in the earthworm, Eudrilus eugeniae. GENE REPORTS 2023. [DOI: 10.1016/j.genrep.2023.101774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2023]
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Wang Z, Xu Y, Peng D, Gao J, Lu F. Brain functional activity-based classification of autism spectrum disorder using an attention-based graph neural network combined with gene expression. Cereb Cortex 2022; 33:6407-6419. [PMID: 36587290 DOI: 10.1093/cercor/bhac513] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/02/2022] [Accepted: 12/03/2022] [Indexed: 01/02/2023] Open
Abstract
Autism spectrum disorder (ASD) is a complex brain neurodevelopmental disorder related to brain activity and genetics. Most of the ASD diagnostic models perform feature selection at the group level without considering individualized information. Evidence has shown the unique topology of the individual brain has a fundamental impact on brain diseases. Thus, a data-constructing method fusing individual topological information and a corresponding classification model is crucial in ASD diagnosis and biomarker discovery. In this work, we trained an attention-based graph neural network (GNN) to perform the ASD diagnosis with the fusion of graph data. The results achieved an accuracy of 79.78%. Moreover, we found the model paid high attention to brain regions mainly involved in the social-brain circuit, default-mode network, and sensory perception network. Furthermore, by analyzing the covariation between functional magnetic resonance imaging data and gene expression, current studies detected several ASD-related genes (i.e. MUTYH, AADAT, and MAP2), and further revealed their links to image biomarkers. Our work demonstrated that the ASD diagnostic framework based on graph data and attention-based GNN could be an effective tool for ASD diagnosis. The identified functional features with high attention values may serve as imaging biomarkers for ASD.
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Affiliation(s)
- Zhengning Wang
- School of Information and Communication Engineering, University of Electronic Science and Technology of China, Chengdu 611731, PR China
| | - Yuhang Xu
- School of Information and Communication Engineering, University of Electronic Science and Technology of China, Chengdu 611731, PR China
| | - Dawei Peng
- School of Information and Communication Engineering, University of Electronic Science and Technology of China, Chengdu 611731, PR China
| | - Jingjing Gao
- School of Information and Communication Engineering, University of Electronic Science and Technology of China, Chengdu 611731, PR China
| | - Fengmei Lu
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 611731, PR China
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Li X, Han YR, Xuefeng X, Ma YX, Xing GS, Yang ZW, Zhang Z, Shi L, Wu XL. Lentivirus-mediated short hairpin RNA interference of CENPK inhibits growth of colorectal cancer cells with overexpression of Cullin 4A. World J Gastroenterol 2022; 28:5420-5443. [PMID: 36312839 PMCID: PMC9611705 DOI: 10.3748/wjg.v28.i37.5420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/24/2022] [Accepted: 09/12/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. The identification of novel diagnostic and prognostic biomarkers for CRC is a key research imperative. Immunohistochemical analysis has revealed high expression of centromere protein K (CENPK) in CRC. However, the role of CENPK in the progression of CRC is not well characterized. AIM To evaluate the effects of knockdown of CENPK and overexpression of Cullin 4A (CUL4A) in RKO and HCT116 cells. METHODS Human colon cancer samples were collected and tested using a human gene expression chip. We identified CENPK as a potential oncogene for CRC based on bioinformatics analysis. In vitro experiments verified the function of this gene. We investigated the expression of CENPK in RKO and HCT116 cells using quantitative polymerase chain reaction (qPCR), western blot, and flow cytometry. The effect of short hairpin RNA (shRNA) virus-infected RKO cells on tumor growth was evaluated in vivo using quantitative analysis of fluorescence imaging. To evaluate the effects of knockdown of CENPK and overexpression of CUL4A in RKO and HCT116 cells, we performed a series of in vitro experiments, using qPCR, western blot, MTT assay, and flow cytometry. RESULTS We demonstrated overexpression of CENPK in human colon cancer samples. CENPK was an independent risk factor in patients with CRC. The downstream genes FBX32, CUL4A, and Yes-associated protein isoform 1 were examined to evaluate the regulatory action of CENPK in RKO cells. Significantly delayed xenograft tumor emergence, slower growth rate, and lower final tumor weight and volume were observed in the CENPK short hairpin RNA virus infected group compared with the CENPK negative control group. The CENPK gene interference inhibited the proliferation of RKO cells in vitro and in vivo. The lentivirus-mediated shRNA interference of CENPK inhibited the proliferation of RKO and HCT116 colon cancer cells, with overexpression of the CUL4A. CONCLUSION We indicated a potential role of CENPK in promoting tumor proliferation, and it may be a novel diagnostic and prognostic biomarker for CRC.
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Affiliation(s)
- Xian Li
- Clinical Medical Research Center, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Yi-Ru Han
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Xuefeng Xuefeng
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Yong-Xiang Ma
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Guo-Sheng Xing
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Zhi-Wen Yang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Zhen Zhang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Lin Shi
- Department of Pathology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Xin-Lin Wu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
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Yuan J, Wang T, Wang L, Li P, Shen H, Mo Y, Zhang Q, Ni C. Transcriptome-wide association study identifies PSMB9 as a susceptibility gene for coal workers' pneumoconiosis. ENVIRONMENTAL TOXICOLOGY 2022; 37:2103-2114. [PMID: 35506645 DOI: 10.1002/tox.23554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 04/13/2022] [Accepted: 04/23/2022] [Indexed: 06/14/2023]
Abstract
Coal workers' pneumoconiosis (CWP) is a type of typical occupational lung disease caused by prolonged inhalation of coal mine dust. The individuals' different genetic background may underlie their different susceptibility to develop pneumoconiosis, even under the same exposure level. This study aimed to identify susceptibility genes associated with CWP. Based on our previous genome-wide association study (GWAS, 202 CWP cases vs. 198 controls) and gene expression data obtained by analyzing human lungs and whole blood from the Genotype-Tissue Expression (GTEx) Portal, a transcriptome-wide association study (TWAS) was applied to identify CWP risk-related genes. Luciferase report gene assay, qRT-PCR, Western blot, immunofluorescence assay, and TUNEL assay were conducted to explore the potential role of the candidate gene in CWP. Proteasome 20S subunit beta 9 (PSMB9) was identified as a strong risk-related gene of CWP in both lungs and whole blood (Lungs: PTWAS = 4.22 × 10-4 ; Whole blood: PTWAS = 2.11 × 10-4 ). Single nucleotide polymorphisms (SNPs) rs2071480 and rs1351383, which locate in the promoter region and the first intron of the PSMB9 gene, were in high linkage disequilibrium (LD, r2 = 0.98) with the best GWAS SNP rs4713600 (G>T, OR = 0.55, 95% CI: 0.42-0.74, P = 6.86 × 10-5 ). Both rs2071480 and rs1351383 significantly enhanced the transcriptional activity of PSMB9. Functional experiments revealed that silica exposure remarkably reduced the PSMB9 expression and caused cell apoptosis, while overexpression of PSMB9 markedly abolished silica-induced cell apoptosis. We here identified PSMB9 as a novel susceptibility gene for CWP and provided important insights into the further exploration of the CWP pathogenesis.
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Affiliation(s)
- Jiali Yuan
- Center for Global Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ting Wang
- Department of Pathology, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lijuan Wang
- Center for Global Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ping Li
- Center for Global Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hongbing Shen
- Center for Global Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yiqun Mo
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
| | - Qunwei Zhang
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
| | - Chunhui Ni
- Center for Global Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
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Cheng Y, Li L, Qin Z, Li X, Qi F. Identification of castration-resistant prostate cancer-related hub genes using weighted gene co-expression network analysis. J Cell Mol Med 2020; 24:8006-8017. [PMID: 32485038 PMCID: PMC7348158 DOI: 10.1111/jcmm.15432] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 05/07/2020] [Accepted: 05/08/2020] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer is the most common malignancy in urinary system and brings heavy burdens in men. We downloaded gene expression profile of mRNA and related clinical data of GSE70768 data set from public database. Weighted gene co‐expression network analysis (WGCNA) was used to identify the relationships between gene modules and clinical features, as well as the candidate genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were developed to investigate the potential functions of related hub genes. Importantly, basic experiments were performed to verify the relationship between hub genes and the phenotype previously identified. Lastly, copy number variation (CNV) analysis was conducted to explore the genetical alteration. WGCNA identified that black module was the most relevant module which was tightly related to castration‐resistant prostate cancer (CRPC) phenotype. KEGG and GO analysis results revealed genes in black module were mainly related to RNA splicing. Additionally, 9 genes were chosen as hub genes and heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), golgin A8 family member B (GOLGA8B) and mitogen‐activated protein kinase 8 interacting protein 3 (MAPK8IP3) were identified to be associated with PCa progression and prognosis. Moreover, all above three genes were highly expressed in CRPC‐like cells and their suppression led to hindered cell proliferation in vitro. Finally, CNV analysis found that amplification was the main type of alteration of the 3 hub genes. Our study found that HNRNPA2B1, GOLGA8B and MAPK8IP3 were identified to be tightly associated with tumour progression and prognosis, and further researches are needed before clinical application.
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Affiliation(s)
- Yifei Cheng
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lu Li
- Nanjing Medical University, Nanjing, China
| | - Zongshi Qin
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xiao Li
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Qi
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Herrero MJ, Velmeshev D, Hernandez-Pineda D, Sethi S, Sorrells S, Banerjee P, Sullivan C, Gupta AR, Kriegstein AR, Corbin JG. Identification of amygdala-expressed genes associated with autism spectrum disorder. Mol Autism 2020; 11:39. [PMID: 32460837 PMCID: PMC7251751 DOI: 10.1186/s13229-020-00346-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 05/10/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development. METHODS Focusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20 years to elucidate cell type specificity of amygdala-expressed genes and their dysregulation in ASD. RESULTS Our analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline. LIMITATIONS We were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages. CONCLUSIONS Our pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala.
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Affiliation(s)
- Maria Jesus Herrero
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC, USA
| | - Dmitry Velmeshev
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California-San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California-San Francisco, San Francisco, CA, USA
| | - David Hernandez-Pineda
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC, USA
| | - Saarthak Sethi
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC, USA
| | - Shawn Sorrells
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California-San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California-San Francisco, San Francisco, CA, USA
- Present Address: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
| | - Payal Banerjee
- Center for Genetic Medicine, Children's Research Institute, Children's National Hospital, Washington, DC, USA
| | - Catherine Sullivan
- Department of Pediatrics and Child Study Center, Yale School of Medicine, New Haven, Connecticut, USA
| | - Abha R Gupta
- Department of Pediatrics and Child Study Center, Yale School of Medicine, New Haven, Connecticut, USA
| | - Arnold R Kriegstein
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California-San Francisco, San Francisco, CA, USA.
- Department of Neurology, University of California-San Francisco, San Francisco, CA, USA.
| | - Joshua G Corbin
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC, USA.
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Tan X, Tang H, Gong L, Xie L, Lei Y, Luo Z, He C, Ma J, Han S. Integrating Genome-Wide Association Studies and Gene Expression Profiles With Chemical-Genes Interaction Networks to Identify Chemicals Associated With Colorectal Cancer. Front Genet 2020; 11:385. [PMID: 32391058 PMCID: PMC7193025 DOI: 10.3389/fgene.2020.00385] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 03/27/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and has the second highest mortality rate in global cancer. Exploring the associations between chemicals and CRC has great significance in prophylaxis and therapy of tumor diseases. This study aims to explore the relationships between CRC and environmental chemicals on genetic basis by bioinformatics analysis. The genome-wide association study (GWAS) datasets for CRC were obtained from the UK Biobank. The GWAS data for colon cancer (category C18) includes 2,581 individuals and 449,683 controls, while that of rectal cancer (category C20) includes 1,244 individuals and 451,020 controls. In addition, we derived CRC gene expression datasets from the NCBI-GEO (GSE106582). The chemicals related gene sets were acquired from the comparative toxicogenomics database (CTD). Transcriptome-wide association study (TWAS) analysis was applied to CRC GWAS summary data and calculated the expression association testing statistics by FUSION software. We performed chemicals related gene set enrichment analysis (GSEA) by integrating GWAS summary data, mRNA expression profiles of CRC and the CTD chemical-gene interaction networks to identify relationships between chemicals and genes of CRC. We observed several significant correlations between chemicals and CRC. Meanwhile, we also detected 5 common chemicals between colon and rectal cancer, including methylnitronitrosoguanidine, isoniazid, PD 0325901, sulindac sulfide, and importazole. Our study performed TWAS and GSEA analysis, linked prior knowledge to newly generated data and thereby helped identifying chemicals related to tumor genes, which provides new clues for revealing the associations between environmental chemicals and cancer.
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Affiliation(s)
- Xinyue Tan
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Hanmin Tang
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Liuyun Gong
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Lina Xie
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Yutiantian Lei
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Zhenzhen Luo
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Chenchen He
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Jinlu Ma
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Suxia Han
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
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11
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Abstract
Major psychiatric disorders are heritable but they are genetically complex. This means that, with certain exceptions, single gene markers will not be helpful for diagnosis. However, we are learning more about the large number of gene variants that, in combination, are associated with risk for disorders such as schizophrenia, bipolar disorder, and other psychiatric conditions. The presence of those risk variants may now be combined into a polygenic risk score (PRS). Such a score provides a quantitative index of the genomic burden of risk variants in an individual, which relates to the likelihood that a person has a particular disorder. Currently, such scores are quite useful in research, and they are telling us much about the relationships between different disorders and other indices of brain function. In the future, as the datasets supporting the development of such scores become larger and more diverse and as methodological developments improve predictive capacity, we expect that PRS will have substantial clinical utility in the assessment of risk for disease, subtypes of disease, and even treatment response. Here, we provide an overview of PRS in general terms (including a glossary suitable for informed non-geneticists) and discuss the use of PRS in psychiatry, including their limitations and cautions for interpretation, as well as their applications now and in the future.
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Affiliation(s)
- Janice M Fullerton
- Neuroscience Research Australia, Margarete Ainsworth Building, 139 Barker Street, Randwick, Sydney, NSW, 2031, Australia.,School of Medical Sciences, University of New South Wales, High St, Kensington, Sydney, NSW, 2052, Australia
| | - John I Nurnberger
- Department of Psychiatry, Indiana University School of Medicine, 355 W. 16th Street, Indianapolis, IN, 46202, USA.,Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 W. 15th Street, Indianapolis, IN, 46202-2266, USA
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