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

Study objectives: 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. Methods: 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 TestConsumption 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. Results: 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 x 10(-5)). Conversely, insomnia PRS was negatively associated with AUDIT-C at 6/9 PRS thresholds (most significant threshold being p = 0.001 (beta = -0.02, p = 5.6 x 10(-8)). Sleep duration PRS was positively associated with AUDIT-C at 2/9 PRS thresholds, with the most significant threshold being p = 1 x 10(-6) (beta = 0.01, p = 0.0009). MR analyses supported a significant positive causal effect of insomnia on AUD (14 SNPs; beta = 104.14; SE = 16.19; p = 2.22 x 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; beta = -63.05; SE = 3.54; p = 4.55 x 10(-16)), which was robust to sensitivity analyses. Conclusion: The genetic risk for insomnia shows pleiotropy with AUD, and sleep continuity abnormalities have a causal influence on the development of AUD.