Genome-Wide Association Study of Circadian Rhythmicity in 71,500 UK Biobank Participants and Polygenic Association with Mood Instability

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, 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

Abstract

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; Gwas; Mood instability; Polygenic risk score; Relative amplitude.

Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
SNP Manhattan plot and QQ plot (inset) of low RA GWAS (N = 2700 cases verses N = 68,300 controls). Red line of Manhattan plot represents genome-wide significance (p −8).
Fig. 2
Fig. 2
SNP Manhattan plot and QQ plot (inset) of continuous RA GWAS (N = 77,440). Red line of Manhattan plot represents genome-wide significance (p −8).

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