Clustering bipolar disorder risk variants by their effect on sleep and circadian traits.

Bipolar disorder (BD) is a common, severe, and recurrent familial psychiatric disorder that causes unusual shifts in mood, energy, activity levels, concentration, and the ability to carry out day-to-day tasks. Genetic studies (GWAS) have identified multiple risk variants for BD. To enable new insights into disease-causing pathways, we clustered BD risk variants by their effect on sleep and circadian traits. We tested the association of 63 BD risk variants from a recent GWAS with traits related to sleep timing, quality, and quantity both self-reported and objectively measured using Clustergrammer for hierarchical clustering. We found BD risk variants cluster into four bins based on their association with sleep and circadian traits. These clusters indicate bipolar genetic risk may function through four distinct mechanisms related to early chronotype, sleep efficiency, late chronotype, and sleep duration. This finding may allow the classification of BD-patients by genetic pathways potentially offering a way forward toward genetically informed diagnosis, surveillance, and management of BD-patients using sleep and circadian interventions. Additionally, this confirms that genetic heterogeneity contributes to the clinical heterogeneity of BD, thus consideration of sleep and circadian traits’ contribution to psychopathologic components of BD may improve genetic prediction of complex psychiatric disorders.