The Role of Circadian Rhythms and Sleep in Anorexia Nervosa

Abstract

Importance: Observational studies have associated anorexia nervosa with circadian rhythms and sleep traits. However, the direction of causality and the extent of confounding by psychosocial comorbidities in these associations are unknown.

Objectives: To investigate the association between anorexia nervosa and circadian and sleep traits through mendelian randomization and to test the associations between a polygenic risk score (PRS) for anorexia nervosa and sleep disorders in a clinical biobank.

Design, setting, and participants: This genetic association study used bidirectional 2-sample mendelian randomization with summary-level genetic associations between anorexia nervosa (from the Psychiatric Genomics Consortium) and chronotype and sleep traits (primarily from the UK Biobank). The inverse-variance weighted method, in addition to other sensitivity approaches, was used. From the clinical Mass General Brigham (MGB) Biobank (n = 47 082), a PRS for anorexia nervosa was calculated for each patient and associations were tested with prevalent sleep disorders derived from electronic health records. Patients were of European ancestry. All analyses were performed between February and August 2023.

Exposures: Genetic instruments for anorexia nervosa, chronotype, daytime napping, daytime sleepiness, insomnia, and sleep duration.

Main outcomes and measures: Chronotype, sleep traits, risk of anorexia nervosa, and sleep disorders derived from a clinical biobank.

Results: The anorexia nervosa genome-wide association study included 16 992 cases (87.7%-97.4% female) and 55 525 controls (49.6%-63.4% female). Genetic liability for anorexia nervosa was associated with a more morning chronotype (β = 0.039; 95% CI, 0.006-0.072), and conversely, genetic liability for morning chronotype was associated with increased risk of anorexia nervosa (β = 0.178; 95% CI, 0.042-0.315). Associations were robust in sensitivity and secondary analyses. Genetic liability for insomnia was associated with increased risk of anorexia nervosa (β = 0.369; 95% CI, 0.073-0.666); however, sensitivity analyses indicated bias due to horizontal pleiotropy. The MGB Biobank analysis included 47 082 participants with a mean (SD) age of 60.4 (17.0) years and 25 318 (53.8%) were female. A PRS for anorexia nervosa was associated with organic or persistent insomnia in the MGB Biobank (odds ratio, 1.10; 95% CI, 1.03-1.17). No associations were evident for anorexia nervosa with other sleep traits.

Conclusions and relevance: The results of this study suggest that in contrast to other metabo-psychiatric diseases, anorexia nervosa is a morningness eating disorder and further corroborate findings implicating insomnia in anorexia nervosa. Future studies in diverse populations and with subtypes of anorexia nervosa are warranted.

Figure 1.. Forest Plot of Mendelian Randomization (MR) Primary, Sensitivity, and Secondary Results for the Associations Between Anorexia Nervosa and Morning Chronotype

Forest plot of MR primary, sensitivity, and secondary results for the associations between anorexia nervosa and chronotype (morning), including accelerometer-derived objective chronotype measures of midpoint of least active 5 hours, midpoint of most active 10 hours, and sleep midpoint. β Values reflect the difference in the outcome for each 1-unit increase in the exposure, with blue boxes denoting statistically significant results. Error bars represent 95% CIs. Primary analyses included inverse variance weighted (IVW) MR, weighted median estimator (WME), and MR-Egger, and sensitivity analyses included MR pleiotropy residual sum and outlier (PRESSO).

Figure 2.. Forest Plot of Mendelian Randomization (MR) Primary, Sensitivity, and Secondary Results for Associations Between Anorexia Nervosa and Insomnia

β Values reflect the difference in the outcome for each 1-unit increase in the exposure, with blue boxes denoting statistically significant results. Error bars represent 95% CIs. Primary analyses included inverse variance weighted (IVW) MR, weighted median estimator (WME), and MR-Egger, and sensitivity analyses included MR pleiotropy residual sum and outlier (PRESSO).