The relationship between alcohol- and sleep-related traits: Results from polygenic risk score and Mendelian randomization analyses

We investigated whether genetic risk for insomnia and sleep duration abnormalities are associated with AUD and alcohol consumption. We also evaluated the causal relationships between sleep- and alcohol-related traits.Individual-level phenotype and genotype data from the Million Veteran Program were used. Polygenic risk scores (PRS) were computed using summary statistics from two recent discovery GWAS of insomnia (N= 453,379 European-ancestry (EA) individuals) and sleep duration (N= 446,118 EAs) and tested for association with lifetime AUD diagnosis (N= 34,658 EA cases) and past-year Alcohol Use Disorders Identification Test-Consumption scale scores (AUDIT-C, N= 200,680 EAs). Bi-directional two-sample Mendelian Randomization (MR) analyses assessed causal associations between the two sleep traits and the two alcohol-related traits.The insomnia PRS was positively associated with AUD at 2/9 PRS thresholds, with p<0.01 being the most significant (OR = 1.02, p = 3.48 × 10-5). Conversely, insomnia PRS was negatively associated with AUDIT-C at 6/9 PRS thresholds (most significant threshold being p = 0.001 (β = -0.02, p = 5.6 × 10-8). Sleep duration PRS was positively associated with AUDIT-C at 2/9 PRS thresholds, with the most significant threshold being p = 1 × 10-6 (β = 0.01, p = 0.0009). MR analyses supported a significant positive causal effect of insomnia on AUD (14 SNPs; β = 104.14; SE = 16.19; p = 2.22 × 10-5), although with significant heterogeneity. MR analyses also showed that shorter sleep duration had a causal effect on the risk of AUD (27 SNPs; β = -63.05; SE = 3.54; p = 4.55 × 10-16), which was robust to sensitivity analyses.The genetic risk for insomnia shows pleiotropy with AUD, and sleep continuity abnormalities have a causal influence on the development of AUD.