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

The 23andMe Research Team, Philip R. Jansen, Kyoko Watanabe, Sven Stringer, Nathan Skene, Julien Bryois, Anke R. Hammerschlag, Christiaan A. de Leeuw, Jeroen S. Benjamins, Ana B. Muñoz-Manchado, Mats Nagel, Jeanne E. Savage, Henning Tiemeier, Tonya White, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson & 29 others Pierre Fontanillas, Nicholas A. Furlotte, David A. Hinds, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Jennifer C. McCreight, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Catherine H. Wilson, Joyce Y. Tung, David A. Hinds, Vladimir Vacic, Xin Wang, Patrick F. Sullivan, Sophie van der Sluis, Tinca J.C. Polderman, August B. Smit, Jens Hjerling-Leffler, Eus J.W. Van Someren, Danielle Posthuma

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

LanguageEnglish
Pages394-403
Number of pages10
JournalNature Genetics
Volume51
Issue number3
Early online date25 Feb 2019
DOIs
Publication statusPublished - Mar 2019

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Sleep Initiation and Maintenance Disorders
Genome
Sleep
Genes
Neurons
Corpus Striatum
Quantitative Trait Loci
Random Allocation
Basal Ganglia
Mental Disorders
Chromatin
Psychiatry
Meta-Analysis
Cardiovascular Diseases
Depression
Brain
Therapeutics

Cite this

@article{08af5d9e862141f197c5e77a1063495f,
title = "Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways",
abstract = "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.",
author = "{The 23andMe Research Team} and Jansen, {Philip R.} and Kyoko Watanabe and Sven Stringer and Nathan Skene and Julien Bryois and Hammerschlag, {Anke R.} and {de Leeuw}, {Christiaan A.} and Benjamins, {Jeroen S.} and Mu{\~n}oz-Manchado, {Ana B.} and Mats Nagel and Savage, {Jeanne E.} and Henning Tiemeier and Tonya White and Michelle Agee and Babak Alipanahi and Adam Auton and Bell, {Robert K.} and Katarzyna Bryc and Elson, {Sarah L.} and Pierre Fontanillas and Furlotte, {Nicholas A.} and Hinds, {David A.} and Huber, {Karen E.} and Aaron Kleinman and Litterman, {Nadia K.} and McCreight, {Jennifer C.} and McIntyre, {Matthew H.} and Mountain, {Joanna L.} and Noblin, {Elizabeth S.} and Northover, {Carrie A.M.} and Pitts, {Steven J.} and Sathirapongsasuti, {J. Fah} and Sazonova, {Olga V.} and Shelton, {Janie F.} and Suyash Shringarpure and Chao Tian and Wilson, {Catherine H.} and Tung, {Joyce Y.} and Hinds, {David A.} and Vladimir Vacic and Xin Wang and Sullivan, {Patrick F.} and {van der Sluis}, Sophie and Polderman, {Tinca J.C.} and Smit, {August B.} and Jens Hjerling-Leffler and {Van Someren}, {Eus J.W.} and Danielle Posthuma",
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Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways. / The 23andMe Research Team.

In: Nature Genetics, Vol. 51, No. 3, 03.2019, p. 394-403.

Research output: Contribution to JournalArticleAcademicpeer-review

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