Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes

Heming Wang; Jacqueline M Lane; Samuel E Jones; Hassan S Dashti; Hanna M Ollila; Andrew R Wood; Vincent T van Hees; Ben Brumpton; Bendik S Winsvold; Katri Kantojärvi; Teemu Palviainen; Brian E Cade; Tamar Sofer; Yanwei Song; Krunal Patel; Simon G Anderson; David A Bechtold; Jack Bowden; Richard Emsley; Simon D Kyle; Max A Little; Andrew S Loudon; Frank A J L Scheer; Shaun M Purcell; Rebecca C Richmond; Kai Spiegelhalder; Jessica Tyrrell; Xiaofeng Zhu; Christer Hublin; Jaakko A Kaprio; Kati Kristiansson; Sonja Sulkava; Tiina Paunio; Kristian Hveem; Jonas B Nielsen; Cristen J Willer; John-Anker Zwart; Linn B Strand; Timothy M Frayling; David Ray; Deborah A Lawlor; Martin K Rutter; Michael N Weedon; Susan Redline; Richa Saxena

doi:10.1038/s41467-019-11456-7

Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes

Nat Commun. 2019 Aug 13;10(1):3503. doi: 10.1038/s41467-019-11456-7.

Authors

Heming Wang^{1

2}, Jacqueline M Lane^{2

3

4}, Samuel E Jones⁵, Hassan S Dashti^{2

3

4}, Hanna M Ollila^{2

3

6

7}, Andrew R Wood⁵, Vincent T van Hees⁸, Ben Brumpton^{9

10

11}, Bendik S Winsvold^{9

12}, Katri Kantojärvi^{13

14}, Teemu Palviainen¹⁵, Brian E Cade^{1

2}, Tamar Sofer^{1

2}, Yanwei Song^{3

16}, Krunal Patel^{3

16}, Simon G Anderson^{17

18}, David A Bechtold¹⁹, Jack Bowden^{10

20}, Richard Emsley¹⁹, Simon D Kyle²¹, Max A Little^{22

23}, Andrew S Loudon¹⁹, Frank A J L Scheer^{1

2}, Shaun M Purcell^{1

2}, Rebecca C Richmond^{10

24}, Kai Spiegelhalder²⁵, Jessica Tyrrell⁵, Xiaofeng Zhu²⁶, Christer Hublin^{15

27}, Jaakko A Kaprio^{15

27}, Kati Kristiansson¹³, Sonja Sulkava^{13

14}, Tiina Paunio^{13

14}, Kristian Hveem^{9

10}, Jonas B Nielsen²⁸, Cristen J Willer²⁸, John-Anker Zwart¹², Linn B Strand⁹, Timothy M Frayling⁵, David Ray²⁹, Deborah A Lawlor^{10

20}, Martin K Rutter^{19

30}, Michael N Weedon⁵, Susan Redline^{1

2

31}, Richa Saxena^{32

33

34

35}

Affiliations

¹ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
² Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
⁶ Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
⁷ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
⁸ Netherlands eScience Center, Amsterdam, Netherlands.
⁹ K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁰ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
¹¹ Department of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹² Division of Clinical Neuroscience, Oslo University Hospital and University of Oslo, Oslo, Norway.
¹³ Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.
¹⁴ Department of Psychiatry and SleepWell Research Program, Faculty of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
¹⁵ Institute for Molecular Medicine FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
¹⁶ Northeastern University College of Science, Boston, MA, USA.
¹⁷ Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
¹⁸ The George Alleyne Chronic Disease Research Centre, Caribbean Institute for Health Research, University of the West Indies, Cave Hill, Barbados.
¹⁹ Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
²⁰ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
²¹ Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
²² Department of Mathematics, Aston University, Birmingham, UK.
²³ Media Lab, Massachusetts Institute of Technology, Cambridge, MA, USA.
²⁴ School of Social and Community Medicine, University of Bristol, Bristol, UK.
²⁵ Clinic for Psychiatry and Psychotherapy, Medical Centre, University of Freiburg, Freiburg, Germany.
²⁶ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
²⁷ Department of Public Health, University of Helsinki, Helsinki, Finland.
²⁸ Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
²⁹ NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX39DU, UK.
³⁰ Manchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
³¹ Department of Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
³² Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. rsaxena@partners.org.
³³ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. rsaxena@partners.org.
³⁴ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. rsaxena@partners.org.
³⁵ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. rsaxena@partners.org.

Abstract

Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing.

Publication types

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

MeSH terms

Adult
Age Factors
Aged
Datasets as Topic
Female
Genetic Loci*
Genome-Wide Association Study
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Polysomnography
Self Report / statistics & numerical data
Sex Factors
Sleep / genetics*
Sleepiness*
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding