Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms

Samuel E Jones; Jacqueline M Lane; Andrew R Wood; Vincent T van Hees; Jessica Tyrrell; Robin N Beaumont; Aaron R Jeffries; Hassan S Dashti; Melvyn Hillsdon; Katherine S Ruth; Marcus A Tuke; Hanieh Yaghootkar; Seth A Sharp; Yingjie Jie; William D Thompson; Jamie W Harrison; Amy Dawes; Enda M Byrne; Henning Tiemeier; Karla V Allebrandt; Jack Bowden; David W Ray; Rachel M Freathy; Anna Murray; Diego R Mazzotti; Philip R Gehrman; Debbie A Lawlor; Timothy M Frayling; Martin K Rutter; David A Hinds; Richa Saxena; Michael N Weedon

doi:10.1038/s41467-018-08259-7

Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms

Nat Commun. 2019 Jan 29;10(1):343. doi: 10.1038/s41467-018-08259-7.

Authors

Samuel E Jones¹, Jacqueline M Lane^{2

3

4}, Andrew R Wood¹, Vincent T van Hees⁵, Jessica Tyrrell¹, Robin N Beaumont¹, Aaron R Jeffries¹, Hassan S Dashti^{2

4}, Melvyn Hillsdon⁶, Katherine S Ruth¹, Marcus A Tuke¹, Hanieh Yaghootkar¹, Seth A Sharp¹, Yingjie Jie¹, William D Thompson¹, Jamie W Harrison¹, Amy Dawes¹, Enda M Byrne⁷, Henning Tiemeier^{8

9}, Karla V Allebrandt¹⁰, Jack Bowden^{11

12}, David W Ray^{13

14}, Rachel M Freathy¹, Anna Murray¹, Diego R Mazzotti¹⁵, Philip R Gehrman¹⁶, Debbie A Lawlor^{11

12}, Timothy M Frayling¹, Martin K Rutter^{13

14

17}, David A Hinds¹⁸, Richa Saxena^{2

3

19}, Michael N Weedon²⁰

Affiliations

¹ Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, EX2 5DW, UK.
² Center for Genomic Medicine, Massachusetts General Hospital, Boston, 02114, MA, USA.
³ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA.
⁴ Broad Institute, Cambridge, 02142, MA, USA.
⁵ Netherlands eScience Center, Amsterdam, 1098, XG, Netherlands.
⁶ Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter, Exeter, EX1 2LU, UK.
⁷ The University of Queensland, Institute for Molecular Bioscience, Brisbane, 4072, QLD, Australia.
⁸ Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015, GE, Netherlands.
⁹ Department of Psychiatry, Erasmus Medical Center, Rotterdam, 3015, GD, Netherlands.
¹⁰ Department of Translational Informatics, Translational Medicine Early Development, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, 65926, Germany.
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 Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK.
¹⁴ Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK.
¹⁵ Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, 19104, PA, USA.
¹⁶ Perelman School of Medicine of the University of Pennsylvania, Philadelphia, 19104, PA, USA.
¹⁷ Manchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 0JE, UK.
¹⁸ 23andMe Inc., 899W. Evelyn Avenue, Mountain View, CA, 94041, USA.
¹⁹ Departments of Medicine, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02115, USA.
²⁰ Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, EX2 5DW, UK. [email protected].

Abstract

Being a morning person is a behavioural indicator of a person's underlying circadian rhythm. Using genome-wide data from 697,828 UK Biobank and 23andMe participants we increase the number of genetic loci associated with being a morning person from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we find that the chronotype loci associate with sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 min earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.

Publication types

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

MeSH terms

Adult
Aged
Circadian Rhythm*
Cyclic AMP / metabolism
Female
Genetic Loci
Genome-Wide Association Study*
Glutamic Acid / metabolism
Humans
Male
Middle Aged
Sleep
United Kingdom
White People / genetics*

Substances

Glutamic Acid
Cyclic AMP

Abstract

Publication types

MeSH terms

Substances

Grants and funding