Hui-Juan Li1,2, Chen Zhang3,4, Li Hui5, Dong-Sheng Zhou6, Yi Li7,8, Chu-Yi Zhang1,2, Chuang Wang9, Lu Wang1, Wenqiang Li10,11, Yongfeng Yang10,11, Na Qu7,8, Jinsong Tang12,13, Ying He14,15,16,17,18,19, Jun Zhou14,15,16,17,18,19, Zihao Yang14,15,16,17,18,19, Xingxing Li6, Jun Cai3,4, Lu Yang3, Jun Chen3, Weixing Fan20, Wei Tang21, Wenxin Tang22, Qiu-Fang Jia5, Weiqing Liu23, Chuanjun Zhuo24, Xueqin Song25, Fang Liu23, Yan Bai23, Bao-Liang Zhong7,8, Shu-Fang Zhang7,8, Jing Chen7,8, Bin Xia7,8, Luxian Lv10,11,26, Zhongchun Liu27, Shaohua Hu28,29, Xiao-Yan Li1,2, Jie-Wei Liu1, Xin Cai1,2, Yong-Gang Yao1,2,30,31, Yuyanan Zhang32,33, Hao Yan32,33, Suhua Chang32,33, Jing-Ping Zhao14,15,16,17,18,19, Wei-Hua Yue32,33,34, Xiong-Jian Luo1,2,30,35, Xiaogang Chen14,15,16,17,18,19, Xiao Xiao1, Yiru Fang3,4,31, Ming Li1,2,30,31. 1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. 2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China. 3. Clinical Research Center and Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 4. Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China. 5. Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China. 6. Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, Zhejiang, China. 7. Affiliated Wuhan Mental Health Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. 8. Research Center for Psychological and Health Sciences, China University of Geosciences, Wuhan, Hubei, China. 9. Department of Pharmacology and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, China. 10. Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. 11. Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China. 12. Department of Psychiatry, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 13. Key Laboratory of Medical Neurobiology of Zhejiang Province, Hangzhou, Zhejiang, China. 14. Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. 15. National Clinical Research Center for Mental Disorders, Changsha, Hunan, China. 16. National Technology Institute of Mental Disorders, Changsha, Hunan, China. 17. Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan, China. 18. Mental Health Institute of Central South University, Changsha, Hunan, China. 19. Hunan Medical Center for Mental Health, Changsha, Hunan, China. 20. Jinhua Second Hospital, Jinhua, Zhejiang, China. 21. Department of Psychiatry, The Affiliated Kangning Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. 22. Hangzhou Seventh People's Hospital, Hangzhou, Zhejiang, China. 23. Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China. 24. Department of Psychiatric-Neuroimaging-Genetics and Morbidity Laboratory (PNGC-Lab), Nankai University Affiliated Tianjin Anding Hospital, Tianjin Mental Health Center, Mental Health Teaching Hospital, Tianjin Medical University, Tianjin, China. 25. The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. 26. Henan Province People's Hospital, Zhengzhou, Henan, China. 27. Department of Psychiatry, Renmin Hospital, Wuhan University, Wuhan, Hubei, China. 28. Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. 29. The Key Laboratory of Mental Disorder Management in Zhejiang Province, Hangzhou, Zhejiang, China. 30. Kunming Institute of Zoology-The Chinese University of Hong Kong (KIZ-CUHK) Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. 31. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. 32. Peking University Sixth Hospital/Institute of Mental Health, Beijing, China. 33. National Health Commission (NHC) Key Laboratory of Mental Health (Peking University) and National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China. 34. Peking-Tsinghua Joint Center for Life Sciences and Peking University (PKU) International Data Group (IDG)/McGovern Institute for Brain Research, Peking University, Beijing, China. 35. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, China.
Abstract
Importance: The genetic basis of bipolar disorder (BD) in Han Chinese individuals is not fully understood. Objective: To explore the genetic basis of BD in the Han Chinese population. Design, Setting, and Participants: A genome-wide association study (GWAS), followed by independent replication, was conducted to identify BD risk loci in Han Chinese individuals. Individuals with BD were diagnosed based on DSM-IV criteria and had no history of schizophrenia, mental retardation, or substance dependence; individuals without any personal or family history of mental illnesses, including BD, were included as control participants. In total, discovery samples from 1822 patients and 4650 control participants passed quality control for the GWAS analysis. Replication analyses of samples from 958 patients and 2050 control participants were conducted. Summary statistics from the European Psychiatric Genomics Consortium 2 (PGC2) BD GWAS (20 352 cases and 31 358 controls) were used for the trans-ancestry genetic correlation analysis, polygenetic risk score analysis, and meta-analysis to compare BD genetic risk between Han Chinese and European individuals. The study was performed in February 2020. Main Outcomes and Measures: Single-nucleotide variations with P < 5.00 × 10-8 were considered to show genome-wide significance of statistical association. Results: The Han Chinese discovery GWAS sample included 1822 cases (mean [SD] age, 35.43 [14.12] years; 838 [46%] male) and 4650 controls (mean [SD] age, 27.48 [5.97] years; 2465 [53%] male), and the replication sample included 958 cases (mean [SD] age, 37.82 [15.54] years; 412 [43%] male) and 2050 controls (mean [SD] age, 27.50 [6.00] years; 1189 [58%] male). A novel BD risk locus in Han Chinese individuals was found near the gene encoding transmembrane protein 108 (TMEM108, rs9863544; P = 2.49 × 10-8; odds ratio [OR], 0.650; 95% CI, 0.559-0.756), which is required for dendritic spine development and glutamatergic transmission in the dentate gyrus. Trans-ancestry genetic correlation estimation (ρge = 0.652, SE = 0.106; P = 7.30 × 10-10) and polygenetic risk score analyses (maximum liability-scaled Nagelkerke pseudo R2 = 1.27%; P = 1.30 × 10-19) showed evidence of shared BD genetic risk between Han Chinese and European populations, and meta-analysis identified 2 new GWAS risk loci near VRK2 (rs41335055; P = 4.98 × 10-9; OR, 0.849; 95% CI, 0.804-0.897) and RHEBL1 (rs7969091; P = 3.12 × 10-8; OR, 0.932; 95% CI, 0.909-0.956). Conclusions and Relevance: This GWAS study identified several loci and genes involved in the heritable risk of BD, providing insights into its genetic architecture and biological basis.
Importance: The genetic basis of bipolar disorder (BD) in Han Chinese individuals is not fully understood. Objective: To explore the genetic basis of BD in the Han Chinese population. Design, Setting, and Participants: A genome-wide association study (GWAS), followed by independent replication, was conducted to identify BD risk loci in Han Chinese individuals. Individuals with BD were diagnosed based on DSM-IV criteria and had no history of schizophrenia, mental retardation, or substance dependence; individuals without any personal or family history of mental illnesses, including BD, were included as control participants. In total, discovery samples from 1822 patients and 4650 control participants passed quality control for the GWAS analysis. Replication analyses of samples from 958 patients and 2050 control participants were conducted. Summary statistics from the European Psychiatric Genomics Consortium 2 (PGC2) BD GWAS (20 352 cases and 31 358 controls) were used for the trans-ancestry genetic correlation analysis, polygenetic risk score analysis, and meta-analysis to compare BD genetic risk between Han Chinese and European individuals. The study was performed in February 2020. Main Outcomes and Measures: Single-nucleotide variations with P < 5.00 × 10-8 were considered to show genome-wide significance of statistical association. Results: The Han Chinese discovery GWAS sample included 1822 cases (mean [SD] age, 35.43 [14.12] years; 838 [46%] male) and 4650 controls (mean [SD] age, 27.48 [5.97] years; 2465 [53%] male), and the replication sample included 958 cases (mean [SD] age, 37.82 [15.54] years; 412 [43%] male) and 2050 controls (mean [SD] age, 27.50 [6.00] years; 1189 [58%] male). A novel BD risk locus in Han Chinese individuals was found near the gene encoding transmembrane protein 108 (TMEM108, rs9863544; P = 2.49 × 10-8; odds ratio [OR], 0.650; 95% CI, 0.559-0.756), which is required for dendritic spine development and glutamatergic transmission in the dentate gyrus. Trans-ancestry genetic correlation estimation (ρge = 0.652, SE = 0.106; P = 7.30 × 10-10) and polygenetic risk score analyses (maximum liability-scaled Nagelkerke pseudo R2 = 1.27%; P = 1.30 × 10-19) showed evidence of shared BD genetic risk between Han Chinese and European populations, and meta-analysis identified 2 new GWAS risk loci near VRK2 (rs41335055; P = 4.98 × 10-9; OR, 0.849; 95% CI, 0.804-0.897) and RHEBL1 (rs7969091; P = 3.12 × 10-8; OR, 0.932; 95% CI, 0.909-0.956). Conclusions and Relevance: This GWAS study identified several loci and genes involved in the heritable risk of BD, providing insights into its genetic architecture and biological basis.