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 language | English |
|---|---|
| Pages (from-to) | 394-403 |
| Number of pages | 10 |
| Journal | Nature Genetics |
| Volume | 51 |
| Issue number | 3 |
| Early online date | 25 Feb 2019 |
| DOIs | |
| Publication status | Published - Mar 2019 |
Funding
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.
| Funders | Funder number |
|---|---|
| Dutch Brain Foundation | |
| Dutch National Computing and Networking Services | |
| Sophia Foundation for Scientific Research | S14-27 |
| Swedish Brain Foundation | 480-05-003 |
| Wellcome Trust | 108726/Z/15/Z |
| Horizon 2020 Framework Programme | 671084 |
| European Research Council | ERC-ADG-2014-671084 INSOMNIA |
| Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung | P2GEP3_165049 |
| Vrije Universiteit Amsterdam | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 645-000-003, 453-07-001, VICI 435-13-005, MagW VIDI 452-12-014 |
| Vetenskapsrådet | 2014-3863 |
