Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates

Nat Commun. 2019 Mar 7;10(1):1100. doi: 10.1038/s41467-019-08917-4.

Authors

Hassan S Dashti^{1

2}, Samuel E Jones³, Andrew R Wood³, Jacqueline M Lane^{1

2

4}, Vincent T van Hees⁵, Heming Wang^{2

6

7}, Jessica A Rhodes^{1

2}, Yanwei Song^{1

8}, Krunal Patel^{1

8}, Simon G Anderson⁹, Robin N Beaumont³, David A Bechtold¹⁰, Jack Bowden^{11

12}, Brian E Cade^{2

6

7}, Marta Garaulet^{13

14}, Simon D Kyle¹⁵, Max A Little^{16

17}, Andrew S Loudon¹⁰, Annemarie I Luik¹⁵, Frank A J L Scheer^{2

7

18}, Kai Spiegelhalder¹⁹, Jessica Tyrrell³, Daniel J Gottlieb^{6

7

20}, Henning Tiemeier^{21

22}, David W Ray¹⁰, Shaun M Purcell²³, Timothy M Frayling³, Susan Redline²⁴, Deborah A Lawlor^{11

12}, Martin K Rutter^{10

25}, Michael N Weedon³, Richa Saxena^{26

27

28}

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA.
² Broad Institute, Cambridge, 02142, MA, USA.
³ Genetics of Complex Traits, University of Exeter Medical School, Exeter, EX2 5DW, UK.
⁴ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA.
⁵ Netherlands eScience Center, Amsterdam, 1098 XG, The Netherlands.
⁶ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, 02115, MA, USA.
⁷ Division of Sleep Medicine, Harvard Medical School, Boston, 02115, MA, USA.
⁸ Northeastern University College of Science, 176 Mugar Life Sciences, 360 Huntington Avenue, Boston, MA, 02015, USA.
⁹ Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PL, UK.
¹⁰ Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK.
¹¹ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, BS8 2BN, UK.
¹² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.
¹³ Department of Physiology, University of Murcia, Murcia, 30100, Spain.
¹⁴ IMIB-Arrixaca, Murcia, 30120, Spain.
¹⁵ Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 7LF, UK.
¹⁶ Department of Mathematics, Aston University, Birmingham, B4 7ET, UK.
¹⁷ Media Lab, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA.
¹⁸ Medical Chronobiology Program, Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, 02115, MA, USA.
¹⁹ Clinic for Psychiatry and Psychotherapy, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany.
²⁰ VA Boston Healthcare System, Boston, 02132, MA, USA.
²¹ Deprtment of Social and Behavioral Science, Harvard TH Chan School of Public Health, Boston, 02115, MA, USA.
²² Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015, The Netherlands.
²³ Department of Psychiatry, Brigham & Women's Hospital, Harvard Medical School, 02115, Boston, MA, USA.
²⁴ Departments of Medicine, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02115, MA, USA.
²⁵ Manchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9PL, UK.
²⁶ Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA. rsaxena@partners.org.
²⁷ Broad Institute, Cambridge, 02142, MA, USA. rsaxena@partners.org.
²⁸ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA. rsaxena@partners.org.

Abstract

Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration (p < 5 × 10^-8; 43 loci at p < 6 × 10^-9). Replication is observed for PAX8, VRK2, and FBXL12/UBL5/PIN1 loci in the CHARGE study (n = 47,180; p < 6.3 × 10^-4), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis (n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Accelerometry
Adult
Aged
Female
Genetic Loci*
Genome-Wide Association Study
Humans
Linkage Disequilibrium
Male
Middle Aged
Polymorphism, Single Nucleotide
Schizophrenia / genetics
Schizophrenia / physiopathology
Self Report
Sleep / genetics*
Sleep / physiology
United Kingdom
White People

Abstract

Publication types

MeSH terms

Grants and funding