Independent replications and integrative analyses confirmTRANK1as a susceptibility gene for bipolar disorder

作     者：Li, Wenqiang Cai, Xin Li, Hui-Juan Song, Meng Zhang, Chu-Yi Yang, Yongfeng Zhang, Luwen Zhao, Lijuan Liu, Weipeng Wang, Lu Shao, Minglong Zhang, Yan Zhang, Chen Cai, Jun Zhou, Dong-Sheng Li, Xingxing Hui, Li Jia, Qiu-Fang Qu, Na Zhong, Bao-Liang Zhang, Shu-Fang Chen, Jing Xia, Bin Li, Yi Song, Xueqin Fan, Weixing Tang, Wei Tang, Wenxin Tang, Jinsong Chen, Xiaogang Yue, Weihua Zhang, Dai Fang, Yiru Xiao, Xiao Li, Ming Lv, Luxian Chang, Hong 

作者机构：Xinxiang Med Univ Henan Mental Hosp Affiliated Hosp 2 Xinxiang Henan Peoples R China Xinxiang Med Univ Henan Key Lab Biol Psychiat Int Joint Res Lab Psychiat & Neurosci Henan Xinxiang Henan Peoples R China Chinese Acad Sci Chinese Acad Sci & Yunnan Prov Kunming Inst Zool Key Lab Anim Models & Human Dis Mech Kunming Yunnan Peoples R China Univ Chinese Acad Sci Kunming Coll Life Sci Kunming Yunnan Peoples R China Shanghai Jiao Tong Univ Shanghai Mental Hlth Ctr Sch Med Shanghai Peoples R China Ningbo Kangning Hosp Dept Psychiat Ningbo Zhejiang Peoples R China Soochow Univ Suzhou Guangji Hosp Affiliated Guangji Hosp Suzhou Jiangsu Peoples R China Huazhong Univ Sci & Technol Tongji Med Coll Affiliated Wuhan Mental Hlth Ctr Wuhan Hubei Peoples R China China Univ Geosci Res Ctr Psychol & Hlth Sci Wuhan Hubei Peoples R China Zhengzhou Univ Affiliated Hosp 1 Zhengzhou Henan Peoples R China Jinhua Second Hosp Jinhua Zhejiang Peoples R China Wenzhou Med Univ Affiliated Kangning Hosp Dept Psychiat Wenzhou Zhejiang Peoples R China Hangzhou Seventh Peoples Hosp Hangzhou Zhejiang Peoples R China Zhejiang Univ Sir Run Run Shaw Hosp Sch Med Dept Psychiat Hangzhou Zhejiang Peoples R China Key Lab Med Neurobiol Zhejiang Prov Hangzhou Zhejiang Peoples R China Cent South Univ Xiangya Hosp 2 Dept Psychiat Changsha Hunan Peoples R China Natl Clin Res Ctr Mental Disorders Changsha Hunan Peoples R China Natl Technol Inst Mental Disorders Changsha Hunan Peoples R China Hunan Key Lab Psychiat & Mental Hlth Changsha Hunan Peoples R China Cent South Univ Mental Hlth Inst Changsha Hunan Peoples R China Hunan Med Ctr Mental Hlth Changsha Hunan Peoples R China Peking Univ Inst Mental Hlth Hosp 6 Beijing Peoples R China Peking Univ NHC Key Lab Mental Hlth Beijing Peoples R China Peking Univ Hosp 6 Natl Clin Res Ctr Mental Disorders Beijing Peoples R China Peking Univ Peking Tsinghua Joint Ctr Life Sci Beijing Peoples R China Peking Univ PKU IDG McGovern Inst Brain Res Beijing Peoples R China Chinese Acad Sci Kunming Inst Zool KIZ CUHK Joint Lab Bioresources & Mol Res Common Kunming Yunnan Peoples R China Flenan Prov Peoples Hosp Zhengzhou Henan Peoples R China 

出 版 物：《NEUROPSYCHOPHARMACOLOGY》 (神经精神药理学)

年 卷 期：2021年第46卷第6期

页      面：1103-1112页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：National Institute of Mental Health [U01MH116487  U01MH116489  R01MH111721  U01MH116438] Funding Source: NIH RePORTER 

主　　题：Bipolar disorder Gene expression Genetic markers 

摘      要：Genetic analyses for bipolar disorder (BD) have achieved prominent success in Europeans in recent years, whereas its genetic basis in other populations remains relatively less understood. We herein report that the leading risk locus for BD in European genome-wide association studies (GWAS), the single-nucleotide polymorphism (SNP) rs9834970 nearTRANK1at 3p22 region, is also genome-wide significantly associated with BD in a meta-analysis of four independent East Asian samples including 5748 cases and 65,361 controls (p = 2.27 x 10(-8), odds ratio = 1.136). Expression quantitative trait loci (eQTL) analyses and summary data-based Mendelian randomization (SMR) analyses in multiple human brain samples suggest that lowerTRANK1mRNA expression is a principal BD risk factor explaining its genetic risk signals at 3p22. We also identified another SNP rs4789 in the 3 untranslated region (3 UTR) ofTRANK1showing stronger eQTL associations as well as genome-wide significant association with BD. Despite the relatively unclear neuronal function ofTRANK1, our mRNA expression analyses in the human brains and in rat primary cortical neurons reveal that genes highly correlated withTRANK1are significantly enriched in the biological processes related to dendritic spine, synaptic plasticity, axon guidance and circadian entrainment, and are also more likely to exhibit strong associations in psychiatric GWAS (e.g., theCACNA1Cgene). Overall, our results support thatTRANK1is a potential BD risk gene. Further studies elucidating its roles in this illness are needed.