A Large-Scale Genome-Wide Gene-Sleep Interaction Study in 732,564 Participants Identifies Novel Lipid Loci Explaining Sleep-Associated Lipid Disturbances

Disturbances in habitual sleep have been associated with lipid levels, which are risk factors for cardiometabolic diseases. However, underlying biomolecular disease mechanisms remain poorly understood. We performed a large-scale genome-wide variant-sleep interaction analyses on lipid levels to identify novel genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances, which also may reveal possible druggable targets. We collected summary-level data from 55 cohorts with a combined sample size of 732,564 participants (87% European population) with data on lipid traits (HDL [HDL-c] and LDL [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) sleep duration were defined by the extreme 20% of the age- and sex-standardized values within each cohort. Cohort-level summary statistics from genome-wide variant-sleep interaction analyses were collected centrally for 1- and 2-degree of freedom interaction meta-analyses. In the cross-population meta-analyses that combines all available data, the 1-degree of freedom variant-sleep interaction test identified 9 lead associations (Pint<5.0e-9) with those mapping to AMPD3 (LDL-c, LTST), ASPH (TG, LTST) and DLEU1 (TG, STST; HDL-c, STST) genes being the most significant. Of interest, ASPH has been a target for aspartic and succinic acid previously shown to improve sleep and cardiovascular risk. The 2-degree of freedom joint test of the main and interaction effect identified an additional 7 lead variants that showed evidence for variant-sleep interaction (Pjoint<5.0e-9 in combination with Pint<6.60e-6) of which the lead variant mapping to SLC8A1 (TG, STST) has been previously identified as a potential treatment target for reduction of ischemic damage after acute myocardial infarction. Collectively, the present large-scale efforts provided insight into the biology underpinning the association between disturbances in habitual sleep duration (9 with STST; 7 with LTST) and lipid levels. The identified druggable targets can provide novel perspectives into the prevention of atherosclerotic cardiovascular disease in people with disturbances in habitual sleep duration.