Genome-wide Gene by Sleepiness Interaction Analysis for Sleep Apnea

Study Objectives Excessive daytime sleepiness (EDS), influenced by environmental and social-behavioral factors, is reported by a subset of patients with sleep apnea — a group that may be at elevated cardiovascular risk. However, it is unclear whether sleep apnea with and without EDS have distinct genetic underpinnings. In this study, we perform gene-by-EDS interaction analyses for apnea hypopnea index (AHI), a diagnostic marker of sleep apnea severity, to understand EDS’s influence on its underlying genetic risk. Methods Discovery interaction analyses for common variants and gene-based rare variants were conducted respectively using multi-ethnic Trans-Omics for Precision Medicine (TOPMed) (N=11619) data, followed by replication and subsequent meta-analysis in additional TOPMed-imputed data (N=8904). The 1 degree-of-freedom (1df) GxE test and the 2df joint G, GxE tests were utilized. Sex-stratified analyses were additionally performed. Results Discovery analysis revealed two common intronic variants— rs13118183 (CCDC3) and rs281851 (MARCHF1) — and three rare variant gene sets mapped to SCUBE2, TMEM26, and CPS4FL — to exhibit interaction with EDS. Meta-analysis revealed EDS interaction with 11 rare variant gene sets mapped to UBLCP1, MED31, RAP1GAP, CPNE5, MYMX, YY1, ZNF773, YBEY, IQCB1, PI4K2B, and CORO1A. Conclusion Genetic loci reveal connections to cardiovascular risk, insulin resistance, thiamine deficiency, and resveratrol mechanism. Discovered genetic signals may offer insight into pertinent biological pathways for sleep apnea patients with an excessively sleepy subtype.