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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.

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Fig. 1: SNP-based results from the GWAS meta-analysis on insomnia in 1,331,010 individuals.
Fig. 2: Gene-based and gene set analyses of insomnia in 1,331,010 individuals.
Fig. 3: Genome-wide analyses of six sleep-related traits.
Fig. 4: Genetic overlap of insomnia with other sleep-related traits and psychiatric and metabolic traits.
Fig. 5: Overview of brain tissues and cell types associated with insomnia based on the GWAS results in 1,331,010 individuals.

Data availability

The data analyzed in the current study were partly provided by the UK Biobank Study (www.ukbiobank.ac.uk), received under UK Biobank application no. 16406. Our policy is to make genome-wide summary statistics (sumstats) publicly available. Sumstats from the GWAS conducted are available for download from the CNCR Complex Trait Genetics lab at https://ctg.cncr.nl/; see also https://ctg.cncr.nl/software/summary_statistics. Note that our freely available meta-analytic sumstats (insomnia and morningness) represent results excluding the 23andMe sample. This is a non-negotiable clause in the 23andMe data transfer agreement, intended to protect the privacy of the 23andMe research participants. To fully recreate our meta-analytic results for insomnia and morningness: (1) obtain insomnia and morningness sumstats from 23andMe; (2) conduct a meta-analysis of our sumstats with the 23andMe sumstats. 23andMe participant data are shared according to community standards that have been developed to protect against breaches of privacy. Currently, these standards allow for the sharing of summary statistics for at most 10,000 SNPs. The full set of summary statistics can be made available to qualified investigators who enter into an agreement with 23andMe that protects participants’ confidentiality. Interested investigators should email dataset-request@23andme.com for more information.

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Acknowledgements

This work was funded by The Netherlands Organization for Scientific Research (NWO Brain and Cognition 433-09-228, NWO MagW VIDI 452-12-014, NWO VICI 435-13-005 and 453-07-001, and NWO 645-000-003). P.R.J. was funded by the Sophia Foundation for Scientific Research (S14-27), E.J.W.V.S. was funded by the European Research Council (grant no. ERC-ADG-2014-671084 INSOMNIA), and J.B. was funded by the Swiss National Science Foundation (grant no. P2GEP3_165049). N.G.S. was supported by the Wellcome Trust (grant no. 108726/Z/15/Z). J.H.L. was funded by the Swedish Research Council (Vetenskapsrådet, award no. 2014-3863), the Swedish Brain Foundation (Hjärnfonden) and the Wellcome Trust (grant no. 108726/Z/15/Z). Analyses were carried out on the Genetic Cluster Computer, which is financed by the NWO (480-05-003), by the VU University, Amsterdam, and by the Dutch Brain Foundation, and is hosted by the Dutch National Computing and Networking Services SurfSARA. This research has been conducted using the UK Biobank Resource (application no. 16406). We thank the UK Biobank and 23andMe research participants and employees for making this work possible.

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Contributions

D.P. and E.J.W.V.S. conceived the study. D.P. supervised the pre- and post-GWAS analysis pipeline. P.R.J. and K.W. performed the analyses. S.St. performed the quality control on the UKB data and wrote the analysis pipeline. K.W. wrote the online platform (FUMA) that was used for the follow-up analyses. C.d.L. conducted conditional gene-set analyses. J.B., N.S., A.M.M., and J.H.L. contributed single-cell RNA sequencing information. J.Y.T., D.A.H., V.V., X.W., and the 23andMe Research Team contributed and analyzed the 23andMe cohort data. D.P., E.J.W.V.S., and P.R.J. wrote the paper. A.R.H., J.S.B., M.N., J.E.S., P.F.S., S.v.d.S., T.J.C.P. conducted part of the analyses. A.B.S. interpreted the findings in biological context and commented on the manuscript. H.T. and T.W. read the manuscript. All authors discussed the results and approved the final version of the paper.

Corresponding author

Correspondence to Danielle Posthuma.

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Competing interests

P.F.S. is a grant recipient and advisor to Lundbeck A/G. D.A.H., J.Y.T., V.V., and X.W. are employees of 23andMe.

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Supplementary information

Supplementary Text and Figures

Supplementary Note and Supplementary Figs. 1–9

Reporting Summary

Supplementary Tables

Supplementary Tables 1–33

Supplementary Dataset 1

Regional association plots of 202 genome-wide-significant loci in the insomnia meta-analysis in 1,331,010 individuals.

Supplementary Dataset 2

Chromatin interaction maps based on significant loci in the insomnia meta-analysis in 1,331,010 individuals.

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Jansen, P.R., Watanabe, K., Stringer, S. et al. Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways. Nat Genet 51, 394–403 (2019). https://doi.org/10.1038/s41588-018-0333-3

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