机构：[1]1Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China[2]2Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China[3]3Key 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[4]4Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China[5]5Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China[6]6Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, Zhejiang, China[7]7Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China[8]8Affiliated Wuhan Mental Health Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China[9]9Research Center for Psychological and Health Sciences, China University of Geosciences, Wuhan, Hubei, China[10]10The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China[11]11Jinhua Second Hospital, Jinhua, Zhejiang, China[12]12Department of Psychiatry, The Affiliated Kangning Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China[13]13Hangzhou Seventh People’s Hospital, Hangzhou, Zhejiang, China[14]14Department of Psychiatry, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China[15]15Key Laboratory of Medical Neurobiology of Zhejiang Province, Hangzhou, Zhejiang, China[16]16Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China[17]17National Clinical Research Center for Mental Disorders, Changsha, Hunan, China[18]18National Technology Institute of Mental Disorders, Changsha, Hunan, China[19]19Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan, China[20]20Mental Health Institute of Central South University, Changsha, Hunan, China[21]21Hunan Medical Center for Mental Health, Changsha, Hunan, China[22]22Peking University Sixth Hospital/Institute of Mental Health, Beijing, China[23]23NHC Key Laboratory of Mental Health (Peking University) and National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China[24]24Peking-Tsinghua Joint Center for Life Sciences and PKU IDG/McGovern Institute for Brain Research, Peking University, Beijing, China[25]25KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China[26]Henan Province People’s Hospital, Zhengzhou, Henan, China
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 near TRANK1 at 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 × 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 lower TRANK1 mRNA 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) of TRANK1 showing stronger eQTL associations as well as genome-wide significant association with BD. Despite the relatively unclear neuronal function of TRANK1, our mRNA expression analyses in the human brains and in rat primary cortical neurons reveal that genes highly correlated with TRANK1 are 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., the CACNA1C gene). Overall, our results support that TRANK1 is a potential BD risk gene. Further studies elucidating its roles in this illness are needed.
基金：
The authors declare no competing financial interests. This work
was supported by grants from National Natural Science
Foundation of China (81871067 to H.C., 81671330 and
81971252 to L.L., U1904130 to W.L., 81771439 to L.H.); Open
Program of Henan Key Laboratory of Biological Psychiatry
(ZDSYS2018001 to H.C.); the Science and Technology Project of
Henan Province (192102310086 to W.L.); the High Scientific and
Technological Research Fund of Xinxiang Medical University
(2017ZDCG-04 to L.L.); Hubei Province health and family
planning scientific research project (WJ2015Q033 to N.Q.);
Population and Family Planning Commission of Wuhan
(WX14B34 to N.Q.); and the medical and health science and
technology project in Zhejiang (2018KY721 to D.-S.Z.). The
Genotype-Tissue Expression (GTEx) Project was supported by
the Common Fund of the Office of the Director of the National
Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and
NINDS. The data used for the analyses described in this
manuscript were obtained from the GTEx Portal on 11/16/
2019. Data were generated as part of the PsychENCODE
Consortium, supported by: U01MH103392, U01MH103365,
U01MH103346, U01MH103340, U01MH103339, R21MH109956,
R21MH105881, R21MH105853, R21MH103877, R21MH102791,
R01MH111721, R01MH110928, R01MH110927, R01MH110926,
R01MH110921, R01MH110920, R01MH110905, R01MH109715,
R01MH109677, R01MH105898, R01MH105898, R01MH094714,
P50MH106934, U01MH116488, U01MH116487, U01MH116492,
U01MH116489, U01MH116438, U01MH116441, U01MH116442,
R01MH114911, R01MH114899, R01MH114901, R01MH117293,
R01MH117291, R01MH117292. The awardees of members in
PsychENCODE Consortium are listed in Supplementary Materials.
Data were generated as part of the CommonMind
Consortium supported by funding from Takeda Pharmaceuticals
Company Limited, F. Hoffman-La Roche Ltd, and NIH grants
R01MH085542, R01MH093725, P50MH066392, P50MH080405,
R01MH097276, RO1-MH-075916, P50M096891,
P50MH084053S1, R37MH057881 and R37MH057881S1,
HHSN271201300031C, AG02219, AG05138, and MH06692. Brain
tissue for the study was obtained from the following brain bank
collections: the Mount Sinai NIH Brain and Tissue Repository,
the University of Pennsylvania Alzheimer’s Disease Core Center,
the University of Pittsburgh NeuroBioBank and Brain and Tissue
Repositories, and the NIMH Human Brain Collection Core. The
members of CommonMind Consortium leadership are listed in
Supplementary Materials.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类|2 区医学
小类|1 区药学2 区神经科学2 区精神病学
最新[2023]版：
大类|1 区医学
小类|1 区神经科学1 区药学1 区精神病学
第一作者：
第一作者机构：[1]1Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China[2]2Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China
通讯作者：
通讯机构：[1]1Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China[2]2Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China[3]3Key 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[4]4Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China[25]25KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China[26]Henan Province People’s Hospital, Zhengzhou, Henan, China
推荐引用方式(GB/T 7714)：
Li Wenqiang,Cai Xin,Li Hui-Juan,et al.Independent replications and integrative analyses confirm TRANK1 as a susceptibility gene for bipolar disorder[J].Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.2021,46(6):1103-1112.doi:10.1038/s41386-020-00788-4.
APA：
Li Wenqiang,Cai Xin,Li Hui-Juan,Song Meng,Zhang Chu-Yi...&Chang Hong.(2021).Independent replications and integrative analyses confirm TRANK1 as a susceptibility gene for bipolar disorder.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology,46,(6)
MLA：
Li Wenqiang,et al."Independent replications and integrative analyses confirm TRANK1 as a susceptibility gene for bipolar disorder".Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 46..6(2021):1103-1112
医学