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. 2021 Aug 1;78(8):903-910.
doi: 10.1001/jamapsychiatry.2021.0959.

Genetically Proxied Diurnal Preference, Sleep Timing, and Risk of Major Depressive Disorder

Iyas Daghlas  1   2 , Jacqueline M Lane  1   2   3 , Richa Saxena  1   2   3 , Céline Vetter  1   4
Affiliations

Genetically Proxied Diurnal Preference, Sleep Timing, and Risk of Major Depressive Disorder

Iyas Daghlas et al. JAMA Psychiatry. .

Abstract

Importance: Morning diurnal preference is associated with reduced risk of major depressive disorder (MDD); however, causality in this association is uncertain.

Objective: To examine the association of genetically proxied morning diurnal preference with depression risk using mendelian randomization.

Design, setting, and participants: This 2-sample mendelian randomization study used summary-level genetic associations with diurnal preference and MDD. Up to 340 genetic loci associated with diurnal preference in a meta-analysis of the UK Biobank and 23andMe cohorts were considered as genetic proxies for diurnal preference. The effect size of these variants was scaled using genetic associations with accelerometer-based measurement of sleep midpoint. Genetic associations with MDD were obtained from a meta-analysis of genome-wide association studies data from the Psychiatric Genomics Consortium and UK Biobank. The inverse-variance weighted method was used to estimate the association of genetically proxied morning diurnal preference, corresponding to a 1-hour earlier sleep midpoint, with MDD risk.

Exposures: Morning diurnal preference scaled to a 1-hour earlier, objectively measured sleep midpoint.

Main outcomes and measures: Risk of MDD, including self-reported and clinically diagnosed cases, as ascertained in meta-analyses of genome-wide association studies.

Results: A total of 697 828 individuals (all of European ancestry) were in the UK Biobank and 23andMe cohorts; 85 502 in the UK Biobank had measurements of the sleep midpoint. A further 170 756 individuals with MDD and 329 443 control participants (all of European ancestry) were in the Psychiatric Genomics Consortium and UK Biobank data. Genetically proxied earlier diurnal preference was associated with a 23% lower risk of depression (odds ratio [OR] per 1-hour earlier sleep midpoint, 0.77 [95% CI, 0.63-0.94]; P = .01). This association was similar when restricting analysis to individuals with MDD as stringently defined by the Psychiatric Genomics Consortium (OR, 0.73 [95% CI, 0.54-1.00]; P = .05) but not statistically significant when defined by hospital-based billing codes in the UK Biobank (OR, 0.64 [95% CI, 0.39-1.06]; P = .08). Sensitivity analyses examining potential bias due to pleiotropy or reverse causality showed similar findings (eg, intercept [SE], 0.00 [0.001]; P = .66 by Egger intercept test).

Conclusions and relevance: The results of this mendelian randomization study support a protective association of earlier diurnal preference with risk of MDD and provide estimates contextualized to an objective sleep timing measure. Further investigation in the form of randomized clinical trials may be warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Vetter was an unpaid scientific advisory board member of Circadian Light Therapy Inc and Chronsulting during the conduct of the study and served as a paid consultant to the US Department of Energy outside the submitted work; Dr Vetter also reported grants from the National Institutes of Health, Department of Energy, Colorado Clinical and Translational Sciences Institute, and University of Colorado Boulder outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Directed Acyclic Graphs Demonstrating Advantages of Mendelian Randomization (MR)
A, Advantages with respect to potential causal inference. B, Potential bias in mendelian randomization due to pleiotropy. Some genetic variants associated with diurnal preference have also been associated with the independent pathways listed in this section.
Figure 2.
Figure 2.. Mendelian Randomization Estimates for the Association of Morning Diurnal Preference With Major Depressive Disorder
The x-axis shows the odds ratio for the association of genetically proxied morning diurnal preference with depression, scaled to a 1-hour earlier sleep midpoint. Bars represent 95% CIs. GWAS indicates genome-wide association studies; ICD, International Classification of Diseases, Ninth and Tenth Revisions; PGC, Psychiatric Genomics Consortium; UKB, UK Biobank.
Figure 3.
Figure 3.. Mendelian Randomization (MR) Sensitivity Analyses for the Association of Morning Diurnal Preference With Major Depressive Disorder
The x-axis shows the odds ratio for the association of genetically proxied morning diurnal preference with depression, scaled to a 1-hour earlier sleep midpoint. Bars represent 95% CIs. All displayed effect estimates used the outcome of major depressive disorder from the Psychiatric Genomics Consortium–UK Biobank meta-analysis. The diurnal preference–specific single-nucleotide variants were not associated at genome-wide significance (P < 5 × 10−8) with any other sleep traits in the UK Biobank (sleep duration, napping, daytime sleepiness, and insomnia symptoms). IVW indicates inverse-variance weighted; MR-PRESSO, MR pleiotropy residual sum and outlier, MR-RAPSB, MR–robust adjusted profile score; SNV, single-nucleotide variant.
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