Biological and clinical insights from genetics of insomnia symptoms

Abstract

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal glands. Evidence of shared genetic factors was found between frequent insomnia symptoms and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms, and subjective well-being.

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Fig. 1: Manhattan plots for genome-wide association analyses of insomnia.
Fig. 2: Shared genetic architecture between frequent insomnia symptoms and behavioral and disease traits.
Fig. 3: Causal relationships of insomnia symptoms.

Data availability

GWAS summary statistics are available at the Sleep Disorders Knowledge Portal data download page (http://sleepdisordergenetics.org/informational/data/).

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Acknowledgements

This research was conducted by using the UK Biobank Resource (UK Biobank applications 6818 and 9072). We would like to thank the participants and researchers from the UK Biobank who contributed or collected data. This work was supported by NIH grants R01DK107859 (R.S.), R21HL121728 (R.S.), F32DK102323 (J.M.L.), R01HL113338 (J.M.L., S.R., and R.S.), R01DK102696 (R.S. and F.S.), NHLBI R35 35HL135818 (S.R. and R.S), R01DK105072 (R.S. and F.S.), T32HL007567 (J.M.L.), K01HL136884 (J.M.L.), and HG003054 (H.W.), The MGH Research Scholar Fund (R.S.), The University of Manchester (Research Infrastructure Fund), the Wellcome Trust (salary support for D.W.R. and A.S.L.), UK Medical Research Council MC_UU_12013/5 (D.A.L.), UK Medical Research Council MC_UU_00011/6 (D.A.L.), and UK National Institute of Health Research NF-SI-0611-10196 (D.A.L.). A.R.W. and T.M.F. are supported by a European Research Council grant (SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). S.E.J. is funded by the Medical Research Council (MR/M005070/1). M.N.W. is supported by a Wellcome Trust Institutional Strategic Support Award (WT097835MF). The following groups provided summary statistics to LDHub and MR-base: ADIPOGen (Adiponectin Genetics Consortium), C4D (Coronary Artery Disease Genetics Consortium), CARDIoGRAM (Coronary Artery Disease Genome-wide Replication and Meta-analysis), CKDGen (Chronic Kidney Disease Genetics Consortium), dbGAP (Database of Genotypes and Phenotypes), DIAGRAM (Diabetes Genetics Replication and Meta-analysis), ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis), EAGLE (Early Genetics & Lifecourse Epidemiology Eczema Consortium, excluding 23andMe), EGG (Early Growth Genetics Consortium), GABRIEL (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European community), GCAN (Genetic Consortium for Anorexia Nervosa), GEFOS (Genetic Factors for Osteoporosis Consortium), GIANT (Genetic Investigation of Anthropometric Traits), GIS (Genetics of Iron Status Consortium), GLGC (Global Lipids Genetics Consortium), GPC (Genetics of Personality Consortium), GUGC (Global Urate and Gout Consortium), HaemGen (Haemotological and Platelet Traits Genetics Consortium), HRgene (Heart Rate Consortium), IIBDGC (International Inflammatory Bowel Disease Genetics Consortium), ILCCO (International Lung Cancer Consortium), IMSGC (International Multiple Sclerosis Genetic Consortium), MAGIC (Meta-analyses of Glucose and Insulin-related Traits Consortium), MESA (Multi-ethnic Study of Atherosclerosis), PGC (Psychiatric Genomics Consortium), Project MinE consortium, ReproGen (Reproductive Genetics Consortium), SSGAC (Social Science Genetics Association Consortium), TAG (Tobacco and Genetics Consortium), TRICL (Transdisciplinary Research in Cancer of the Lung Consortium), and UK Biobank. The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration among the HUNT Research Centre (Faculty of Medicine, NTNU, Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority, and Norwegian Institute of Public Health. We are grateful for the contributions from H. Zhang and H. M. Kang. We also acknowledge the support given to us by the Genotyping core and J. Chen. The K.G. Jebsen center for genetic epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), and the Central Norway Regional Health Authority. B.B. and L.B.S. received research grants from The Liaison Committee for education, research and innovation in central Norway. We thank the International EU-RLS-GENE Consortium and KORA for providing RLS GWAS data.

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The study was designed by J.M.L., S.E.J., A.R.W., H.S.D., V.T.V.H., K.H., B.B., L.B.S., B.S.W., K.G.A., H.W., S.G.A., A.S.L., D.W.R., T.M.F., M.N.W., D.A.L., M.K.R., and R.S. J.M.L., S.E.J., A.R.W., H.S.D., V.T.V.H., C.Z., J.B.N., J.-A.Z., M.H., R.N.B., J.T., K.G.A., H.W., Y.S., K.P., S.P., J.W.W., T.M.F., D.A.L., M.K.R., M.N.W., and R.S. participated in acquisition, analysis, and/or interpretation of data. J.M.L., H.S.D., B.B., L.B.S., H.W., and R.S. wrote the manuscript, and all coauthors reviewed and edited the manuscript before approving its submission. R.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Richa Saxena.

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Competing interests

J.W.W. is a consultant for Merck and Flex Pharma. He receives royalties from UpToDate. He has received speaker fees and travel support from Otsuka. He has received research grants from UCB Pharma, NeuroMetrix, NIMH, the RLS Foundation, and Luitpold Pharma. F.A.J.L.S. has received lecture fees from Bayer HealthCare, Sentara HealthCare, Philips, Vanda Pharmaceuticals, and Pfizer. D.A.L. has received funding from Medtronic and Roche Diagnostics for biomarker research unrelated to this study. M.K.R. has acted as a consultant for GlaxoSmithKline, Novo Nordisk, Roche, and Merck Sharp & Dohme (MSD), and also participated in advisory-board meetings on their behalf. M.K.R. has received lecture fees from MSD and grant support from Novo Nordisk, MSD, and GlaxoSmithKline.

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Lane, J.M., Jones, S.E., Dashti, H.S. et al. Biological and clinical insights from genetics of insomnia symptoms. Nat Genet 51, 387–393 (2019). https://doi.org/10.1038/s41588-019-0361-7

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