Characterization of the genetic relationship between the domains of sleep and circadian-related behaviors with substance use phenotypes

Abstract

Sleep problems and substance use frequently cooccur. While substance use can often manifest as specific sleep deficits, genetic pleiotropy could also explain part of the relationship between sleep and substance use. Here we assess the genetic overlap between substance use behaviors and both sleep and circadian-related activity measures by deriving genetic clusters between these domains and testing processes of causality vs. horizontal pleiotropy using the largest publicly available genome-wide summary statistics of substance use behaviors (N= 79,729 - 632,802) and sleep/activity phenotypes/endophenotypes to date (N=85,502 - 449,734). We found 31 genetic correlations between substance use and sleep/activity measures after Bonferroni correction. Two specific genetic clusters explained our patterns of overlap. Genes associated with tobacco use severity (age of first regular tobacco use and smoking cessation) share overlap with elements of sleep health (sleep duration, sleep efficiency, and chronotype). Substance consumption (drinks per day and cigarettes per day) and problematic substance use behaviors (cannabis use disorder, opioid use disorder, and problematic alcohol use) clustered strongly with problematic measures of sleep (insomnia, self-reported short sleep duration, increased number of sleep episodes, increased sleep duration variability, diurnal inactivity) as well as measures of circadian-related activity (L5, M10, and sleep midpoint). Latent causal variable analyses determined that horizontal pleiotropy (rather than causality) underlies a majority of the associations between substance use and sleep/circadian related measures, except one plausible genetically causal relationship for opioid use disorder on self-reported long sleep duration. Results indeed show significant genetic overlap between substance use and sleep/circadian-related activity measures.