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

Philip R. Jansen, Kyoko Watanabe, Sven Stringer, Nathan Skene, Julien Bryois, Anke R. Hammerschlag, Christiaan A. de Leeuw, Jeroen S. Benjamins, Ana B. Munoz-Manchado, Mats Nagel, Jeanne E. Savage, Henning Tiemeier, Tonya White, Joyce Y. Tung, David A. Hinds, Vladimir Vacic, Xin Wang, Patrick F. Sullivan, Sophie van der Sluis, Tinca J. C. PoldermanAugust B. Smit, Jens Hjerling-Leffler, Eus J. W. Van Someren, Danielle Posthuma, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, 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

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.

Original languageEnglish
Pages (from-to)394-403
Number of pages10
JournalNature Genetics
Volume51
Issue number3
DOIs
Publication statusPublished - 1 Mar 2019

Cite this

Jansen, P. R., Watanabe, K., Stringer, S., Skene, N., Bryois, J., Hammerschlag, A. R., ... Wilson, C. H. (2019). Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways. Nature Genetics, 51(3), 394-403. https://doi.org/10.1038/s41588-018-0333-3