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Original Investigation
December 2, 2020

Novel Risk Loci Associated With Genetic Risk for Bipolar Disorder Among Han Chinese Individuals: A Genome-Wide Association Study and Meta-analysis

Author Affiliations
  • 1Key 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
  • 2Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China
  • 3Clinical Research Center and Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • 4Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
  • 5Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China
  • 6Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, Zhejiang, China
  • 7Affiliated Wuhan Mental Health Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  • 8Research Center for Psychological and Health Sciences, China University of Geosciences, Wuhan, Hubei, China
  • 9Department of Pharmacology and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, China
  • 10Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
  • 11Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China
  • 12Department of Psychiatry, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
  • 13Key Laboratory of Medical Neurobiology of Zhejiang Province, Hangzhou, Zhejiang, China
  • 14Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
  • 15National Clinical Research Center for Mental Disorders, Changsha, Hunan, China
  • 16National Technology Institute of Mental Disorders, Changsha, Hunan, China
  • 17Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan, China
  • 18Mental Health Institute of Central South University, Changsha, Hunan, China
  • 19Hunan Medical Center for Mental Health, Changsha, Hunan, China
  • 20Jinhua Second Hospital, Jinhua, Zhejiang, China
  • 21Department of Psychiatry, The Affiliated Kangning Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
  • 22Hangzhou Seventh People’s Hospital, Hangzhou, Zhejiang, China
  • 23Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
  • 24Department 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
  • 25The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
  • 26Henan Province People’s Hospital, Zhengzhou, Henan, China
  • 27Department of Psychiatry, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
  • 28Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  • 29The Key Laboratory of Mental Disorder Management in Zhejiang Province, Hangzhou, Zhejiang, China
  • 30Kunming 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
  • 31CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
  • 32Peking University Sixth Hospital/Institute of Mental Health, Beijing, China
  • 33National Health Commission (NHC) Key Laboratory of Mental Health (Peking University) and National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
  • 34Peking-Tsinghua Joint Center for Life Sciences and Peking University (PKU) International Data Group (IDG)/McGovern Institute for Brain Research, Peking University, Beijing, China
  • 35Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, China
JAMA Psychiatry. 2021;78(3):320-330. doi:10.1001/jamapsychiatry.2020.3738
Key Points

Question  What is the genetic architecture of bipolar disorder (BD) in the Han Chinese population?

Findings  In this genome-wide association study of 6472 individuals of Han Chinese ancestry (1822 cases and 4650 controls), several novel risk loci for BD were found, and trans-ancestry genetic correlation estimation and polygenic risk score analyses of Han Chinese and European individuals suggested a shared genetic risk of BD.

Meaning  Findings of this study highlighted novel genome-wide significant risk loci for BD that can provide insight into the genetic architecture of this disorder.

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.

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