Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways

被引：537

作者：

Jansen, Philip R. ^{[1
,2
]}

Watanabe, Kyoko ^{[1
]}

Stringer, Sven ^{[1
]}

Skene, Nathan ^{[3
,4
]}

Bryois, Julien ^{[5
]}

Hammerschlag, Anke R. ^{[1
]}

de Leeuw, Christiaan A. ^{[1
]}

Benjamins, Jeroen S. ^{[6
,7
]}

Munoz-Manchado, Ana B. ^{[3
]}

Nagel, Mats ^{[1
,8
]}

Savage, Jeanne E. ^{[1
]}

Tiemeier, Henning ^{[2
,9
]}

White, Tonya ^{[2
]}

Tung, Joyce Y. ^{[10
]}

Hinds, David A. ^{[10
]}

Vacic, Vladimir ^{[10
]}

Wang, Xin ^{[10
]}

Sullivan, Patrick F. ^{[4
,11
,12
]}

van der Sluis, Sophie ^{[1
,8
]}

Polderman, Tinca J. C. ^{[1
]}

Smit, August B. ^{[13
]}

Hjerling-Leffler, Jens ^{[3
]}

Van Someren, Eus J. W. ^{[14
,15
,16
]}

Posthuma, Danielle ^{[1
,8
]}

Agee, Michelle ^{[10
]}

Alipanahi, Babak ^{[10
]}

Auton, Adam ^{[10
]}

Bell, Robert K. ^{[10
]}

Bryc, Katarzyna ^{[10
]}

Elson, Sarah L. ^{[10
]}

Fontanillas, Pierre ^{[10
]}

Furlotte, Nicholas A. ^{[10
]}

Huber, Karen E. ^{[10
]}

Kleinman, Aaron ^{[10
]}

Litterman, Nadia K. ^{[10
]}

McCreight, Jennifer C. ^{[10
]}

McIntyre, Matthew H. ^{[10
]}

Mountain, Joanna L. ^{[10
]}

Noblin, Elizabeth S. ^{[10
]}

Northover, Carrie A. M. ^{[10
]}

Pitts, Steven J. ^{[10
]}

Sathirapongsasuti, J. Fah ^{[10
]}

Sazonova, Olga, V ^{[10
]}

Shelton, Janie F. ^{[10
]}

Shringarpure, Suyash ^{[10
]}

Tian, Chao ^{[10
]}

Wilson, Catherine H. ^{[10
]}

机构：

[1] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Amsterdam Neurosci, Dept Complex Trait Genet, Amsterdam, Netherlands

[2] Erasmus Univ, Dept Child & Adolescent Psychiat, Med Ctr, Rotterdam, Netherlands

[3] Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Stockholm, Sweden

[4] UCL Inst Neurol, Queen Sq, London, England

[5] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[6] Univ Utrecht, Dept Social Hlth & Org Psychol, Utrecht, Netherlands

[7] Univ Utrecht, Helmholtz Inst, Dept Expt Psychol, Utrecht, Netherlands

[8] Vrije Univ Amsterdam Med Ctr, Amsterdam Neurosci, Dept Clin Genet, Sect Complex Trait Genet, Amsterdam, Netherlands

[9] Erasmus Univ, Dept Psychiat, Med Ctr, Rotterdam, Netherlands

[10] 23andMe Inc, Mountain View, CA USA

[11] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA

[12] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA

[13] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, Amsterdam Neurosci, Amsterdam, Netherlands

[14] Netherlands Inst Neurosci, Dept Sleep & Cognit, Amsterdam, Netherlands

[15] Univ Amsterdam, VU Univ, Ctr Neurogen & Cognit Res, Amsterdam Neurosci,Med Ctr,Dept Psychiat, Amsterdam, Netherlands

[16] Univ Amsterdam, VU Univ, Ctr Neurogen & Cognit Res, Amsterdam Neurosci,Med Ctr,Dept Integrat Neurophy, Amsterdam, Netherlands

来源：

NATURE GENETICS | 2019年 / 51卷 / 03期

基金：

瑞典研究理事会; 瑞士国家科学基金会; 英国惠康基金; 欧洲研究理事会;

关键词：

GENETIC-VARIANTS; MOTOR RESTLESSNESS; SLEEP; ASSOCIATION; SIGNATURES; DATABASE; EPIDEMIOLOGY; METAANALYSIS; COMPLAINTS; BEHAVIOR;

D O I：

10.1038/s41588-018-0333-3

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains limited. Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints. We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.

引用

页码：394 / +

页数：12

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