Genome-Wide Association Study of Circadian Rhythmicity in 71,500 UK Biobank Participants and Polygenic Association with Mood InstabilityResearch in context
Amy Ferguson,
Laura M. Lyall,
Joey Ward,
Rona J. Strawbridge,
Breda Cullen,
Nicholas Graham,
Claire L. Niedzwiedz,
Keira J.A. Johnston,
Daniel MacKay,
Stephany M. Biello,
Jill P. Pell,
Jonathan Cavanagh,
Andrew M. McIntosh,
Aiden Doherty,
Mark E.S. Bailey,
Donald M. Lyall,
Cathy A. Wyse,
Daniel J. Smith
Affiliations
Amy Ferguson
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Laura M. Lyall
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Joey Ward
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Rona J. Strawbridge
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK; Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
Breda Cullen
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Nicholas Graham
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Claire L. Niedzwiedz
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Keira J.A. Johnston
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Daniel MacKay
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Stephany M. Biello
Institute of Neuroscience and Psychology, University of Glasgow, Scotland, UK
Jill P. Pell
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Jonathan Cavanagh
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Andrew M. McIntosh
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Scotland, UK
Aiden Doherty
Big Data Institute, Nuffield Department of Population Health, BHF Centre of Research Excellence, University of Oxford, Oxford, UK; Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, UK
Mark E.S. Bailey
School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, UK
Donald M. Lyall
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK
Cathy A. Wyse
Department of Molecular and Cellular Therapeutics, Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
Daniel J. Smith
Institute of Health & Wellbeing, University of Glasgow, Scotland, UK; Corresponding author.
Background: Circadian rhythms are fundamental to health and are particularly important for mental wellbeing. Disrupted rhythms of rest and activity are recognised as risk factors for major depressive disorder and bipolar disorder. Methods: We conducted a genome-wide association study (GWAS) of low relative amplitude (RA), an objective measure of rest-activity cycles derived from the accelerometer data of 71,500 UK Biobank participants. Polygenic risk scores (PRS) for low RA were used to investigate potential associations with psychiatric phenotypes. Outcomes: Two independent genetic loci were associated with low RA, within genomic regions for Neurofascin (NFASC) and Solute Carrier Family 25 Member 17 (SLC25A17). A secondary GWAS of RA as a continuous measure identified a locus within Meis Homeobox 1 (MEIS1). There were no significant genetic correlations between low RA and any of the psychiatric phenotypes assessed. However, PRS for low RA was significantly associated with mood instability across multiple PRS thresholds (at PRS threshold 0·05: OR = 1·02, 95% CI = 1·01–1·02, p = 9·6 × 10−5), and with major depressive disorder (at PRS threshold 0·1: OR = 1·03, 95% CI = 1·01–1·05, p = 0·025) and neuroticism (at PRS threshold 0·5: Beta = 0·02, 95% CI = 0·007–0·04, p = 0·021). Interpretation: Overall, our findings contribute new knowledge on the complex genetic architecture of circadian rhythmicity and suggest a putative biological link between disrupted circadian function and mood disorder phenotypes, particularly mood instability, but also major depressive disorder and neuroticism. Funding: Medical Research Council (MR/K501335/1). Keywords: Circadian rhythmicity, Mood instability, Relative amplitude, Gwas, Polygenic risk score
