Sparse whole-genome sequencing identifies two loci for major depressive disorder

被引：657

作者：

Cai, Na ^{[1
]}

Bigdeli, Tim B. ^{[2
]}

Kretzschmar, Warren ^{[1
]}

Li, Yihan ^{[1
]}

Liang, Jieqin ^{[3
]}

Song, Li ^{[3
]}

Hu, Jingchu ^{[3
]}

Li, Qibin ^{[3
]}

Jin, Wei ^{[3
]}

Hu, Zhenfei ^{[3
]}

Wang, Guangbiao ^{[3
]}

Wang, Linmao ^{[3
]}

Qian, Puyi ^{[3
]}

Liu, Yuan ^{[3
]}

Jiang, Tao ^{[3
]}

Lu, Yao ^{[3
]}

Zhang, Xiuqing ^{[3
]}

Yin, Ye ^{[3
]}

Li, Yingrui ^{[3
]}

Xu, Xun ^{[3
]}

Gao, Jingfang ^{[4
]}

Reimers, Mark ^{[2
]}

Webb, Todd ^{[2
]}

Riley, Brien ^{[2
]}

Bacanu, Silviu ^{[2
]}

Peterson, Roseann E. ^{[2
]}

Chen, Yiping ^{[5
]}

Zhong, Hui ^{[6
]}

Liu, Zhengrong ^{[7
]}

Wang, Gang ^{[8
]}

Sun, Jing ^{[9
]}

Sang, Hong ^{[10
]}

Jiang, Guoqing ^{[11
]}

Zhou, Xiaoyan ^{[11
]}

Li, Yi ^{[12
,13
]}

Zhang, Wei ^{[14
]}

Wang, Xueyi ^{[15
]}

Fang, Xiang ^{[16
]}

Pan, Runde ^{[17
]}

Miao, Guodong ^{[18
]}

Zhang, Qiwen ^{[19
]}

Hu, Jian ^{[20
]}

Yu, Fengyu ^{[21
]}

Du, Bo ^{[22
]}

Sang, Wenhua ^{[22
]}

Li, Keqing ^{[22
]}

Chen, Guibing ^{[23
]}

Cai, Min ^{[24
]}

Yang, Lijun ^{[25
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England

[2] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23298 USA

[3] BGI Shenzhen, Shenzhen 518083, Guangdong, Peoples R China

[4] Zhejiang Tradit Chinese Med Hosp, Hangzhou 310000, Zhejiang, Peoples R China

[5] Univ Oxford, CTSU, Oxford OX3 7LF, England

[6] Anhui Mental Hlth Ctr, Hefei 230000, Anhui, Peoples R China

[7] Anshan Psychiat Rehabil Hosp, Anshan 114000, Liaoning, Peoples R China

[8] Capital Univ Med Sci, Beijing Anding Hosp, Beijing 100000, Peoples R China

[9] Nanjing Med Univ, Brain Hosp, Nanjing 210000, Jiangsu, Peoples R China

[10] Changchun Mental Hosp, Changchun 130000, Jilin, Peoples R China

[11] Chongqing Mental Hlth Ctr, Chongqing 404100, Peoples R China

[12] Dalian 7 Hosp, Dalian 116000, Liaoning, Peoples R China

[13] Wuhan Mental Hlth Ctr, Wuhan 430000, Hubei, Peoples R China

[14] Daqing 3 Hosp Heilongjiang, Daqing 163000, Heilongjiang, Peoples R China

[15] Hebei Med Univ, Hosp 1, Shijiazhuang 50000, Hebei, Peoples R China

[16] Fuzhou Psychiat Hosp, Fuzhou 350000, Fujian, Peoples R China

[17] Guangxi Longquanshan Hosp, Guangxi 545000, Zhuangzu, Peoples R China

[18] Guangzhou Psychiat Hosp, Guangzhou Brain Hosp, Guangzhou 510000, Guangdong, Peoples R China

[19] Hainan Anning Hosp, Haikou 570100, Hainan, Peoples R China

[20] Harbin Med Univ, Haerbin 150000, Heilongjiang, Peoples R China

[21] Harbin 1 Special Hosp, Haerbin 150000, Heilongjiang, Peoples R China

[22] Hebei Mental Hlth Ctr, Baoding 71000, Hebei, Peoples R China

[23] Huaian 3 Hosp, Huaian 223001, Jiangsu, Peoples R China

[24] Huzhou 3 Hosp, Huzhou 313000, Zhejiang, Peoples R China

[25] Jilin Brain Hosp, Siping 136000, Jilin, Peoples R China

[26] Jining Psychiat Hosp, Jining 272000, Shandong, Peoples R China

[27] Liaocheng 4 Hosp, Liaocheng 252000, Shandong, Peoples R China

[28] Shantou Univ, Mental Hlth Ctr, Shantou 515000, Guangdong, Peoples R China

[29] Sichuan Univ, West China Hosp, Mental Hlth Ctr, Chengdu 610000, Sichuan, Peoples R China

[30] Jining Med Coll, Mental Hlth Inst, Jining 272000, Shandong, Peoples R China

[31] Mental Hosp Jiangxi Prov, Nanchang 330000, Jiangxi, Peoples R China

[32] Mudanjiang Psychiat Hosp Heilongjiang Prov, Mudanjiang 157000, Heilongjiang, Peoples R China

[33] Ningbo Kang Ning Hosp, Ningbo 315000, Zhejiang, Peoples R China

[34] Sun Yat Sen Univ, Hosp 3, Guangzhou 510630, Guangdong, Peoples R China

[35] ChongqingMed Univ, Hosp 1, Chongqing 400016, Peoples R China

[36] Jinan Univ, Hosp 1, Guangzhou 510000, Guangdong, Peoples R China

[37] Xi An Jiao Tong Univ, Coll Med, Hosp 1, Xian, Shaan Xi, Peoples R China

[38] Shanxi Med Univ, Hosp 1, Taiyuan 30000, Shanxi, Peoples R China

[39] Zhengzhou Univ, Hosp 1, Zhengzhou 450000, Henan, Peoples R China

[40] Lanzhou Univ, Hosp 2, Lanzhou 730000, Gansu, Peoples R China

[41] Zhongnan Univ, Xiangya Hosp 2, Changsha 410000, Hunan, Peoples R China

[42] 3 Hosp Heilongjiang Prov, Beian 164000, Heilongjiang, Peoples R China

[43] Jiangsu Univ, Hosp 4, Zhenjiang 212000, Jiangsu, Peoples R China

[44] Psychiat Hosp Henan Prov, Xinxiang 453000, Henan, Peoples R China

[45] Qingdao Mental Hlth Ctr, Qingdao 266000, Shandong, Peoples R China

[46] Wuhan Univ, Renmin Hosp, Wuhan 430000, Hubei, Peoples R China

[47] Zhejiang Chinese Med Univ, Affiliated Hosp 2, Hangzhou 310000, Zhejiang, Peoples R China

[48] China Med Univ, ShengJing Hosp, Shenyang 110001, Liaoning, Peoples R China

[49] Kangning Hosp, Shenzhen Key Lab Psychol Healthcare, Shenzhen 518000, Guangdong, Peoples R China

[50] Kanazawa Med Univ, Dept Gen Internal Med, Kahoku, Ishikawa 9200293, Japan

来源：

NATURE | 2015年 / 523卷 / 7562期

基金：

欧洲研究理事会; 英国惠康基金;

关键词：

LINEAR MIXED MODELS; EPIDEMIOLOGY; ASSOCIATION; COMORBIDITY; INFERENCE;

D O I：

10.1038/nature14659

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Major depressive disorder (MDD), one of the most frequently encountered forms ofmental illness and a leading cause of disability worldwide(1), poses a major challenge to genetic analysis. To date, no robustly replicated genetic loci have been identified(2), despite analysis of more than 9,000 cases(3). Here, using low-coverage whole-genome sequencing of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified, and subsequently replicated in an independent sample, two loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P = 2.53 x 10(-10)), the other in an intron of the LHPP gene (P = 6.45 x10(-12)). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.

引用

页码：588 / +

页数：15

共 29 条

[1] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[2] Melancholia and atypical depression in the Zurich study:: epidemiology, clinical characteristics, course, comorbidity and personality [J].

Angst, J. ;

Gamma, A. ;

Benazzi, F. ;

Ajdacic, V. ;

Rossler, W. .

ACTA PSYCHIATRICA SCANDINAVICA, 2007, 115 :72-84

[3]

[Anonymous], 2004, LANG ENV STAT COMP

[4]

Association AP, 1994, DIAGN STAT MAN MENT

[5] Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering [J].

Browning, Sharon R. ;

Browning, Brian L. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 81 (05) :1084-1097

[6] Molecular Signatures of Major Depression [J].

Cai, Na ;

Chang, Simon ;

Li, Yihan ;

Li, Qibin ;

Hu, Jingchu ;

Liang, Jieqin ;

Song, Li ;

Kretzschmar, Warren ;

Gan, Xiangchao ;

Nicod, Jerome ;

Rivera, Margarita ;

Deng, Hong ;

Du, Bo ;

Li, Keqing ;

Sang, Wenhu ;

Gao, Jingfang ;

Gao, Shugui ;

Ha, Baowei ;

Ho, Hung-Yao ;

Hu, Chunmei ;

Hu, Jian ;

Hu, Zhenfei ;

Huang, Guoping ;

Jiang, Guoqing ;

Jiang, Tao ;

Jin, Wei ;

Li, Gongying ;

Li, Kan ;

Li, Yi ;

Li, Yingrui ;

Li, Youhui ;

Lin, Yu-Ting ;

Liu, Lanfen ;

Liu, Tiebang ;

Liu, Ying ;

Liu, Yuan ;

Lu, Yao ;

Lv, Luxian ;

Meng, Huaqing ;

Qian, Puyi ;

Sang, Hong ;

Shen, Jianhua ;

Shi, Jianguo ;

Sun, Jing ;

Tao, Ming ;

Wang, Gang ;

Wang, Guangbiao ;

Wang, Jian ;

Wang, Linmao ;

Wang, Xueyi .

CURRENT BIOLOGY, 2015, 25 (09) :1146-1156

[7] Power and Predictive Accuracy of Polygenic Risk Scores [J].

Dudbridge, Frank .

PLOS GENETICS, 2013, 9 (03)

[8]

Flint J, 2014, NEURON, V81, P484, DOI [10.1016/j.neuron.2014.01.027, 10.1016/j.neuron.2014.02.033]

[9] Genetic and environmental risk factors for depression assessed by subject-rated Symptom Check List versus Structured Clinical Interview [J].

Foley, DL ;

Neale, MC ;

Kendler, KS .

PSYCHOLOGICAL MEDICINE, 2001, 31 (08) :1413-1423

[10] Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α [J].

Gerhart-Hines, Zachary ;

Rodgers, Joseph T. ;

Bare, Olivia ;

Lerin, Carles ;

Kim, Seung-Hee ;

Mostoslavsky, Raul ;

Alt, Frederick W. ;

Wu, Zhidan ;

Puigserver, Pere .

EMBO JOURNAL, 2007, 26 (07) :1913-1923

← 1 2 3 →