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, 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 (N = 11 619) data, followed by replication and subsequent meta-analysis in additional Trans-Omics for Precision Medicine-imputed data (N = 8904). The 1 degree-of-freedom (1df) G × E test and the 2df joint G,G × E 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. Statement of Significance Sleep apnea is a complex sleep disorder. Exemplifying this is the disparately varying estimates of presence of excessive daytime sleepiness (EDS) in patients, and persistent EDS that lingers despite treatment. Some data indicate that the excessively sleepy subtype of sleep apnea carries heightened cardiovascular risk. Whether EDS influences genetic risk factors underlying sleep apnea has not yet been investigated. This study addresses this gap, as the first genome-wide gene × EDS interaction study for apnea hypopnea index, the standard sleep apnea severity metric. Genetic loci that have been previously unconsidered for sleep apnea are revealed. Discovered interaction signals highlight pathways in metabolism, genes associated with cardiometabolic traits, and therapeutic agents influencing obesity, blood pressure, oxidative stress, and apnea hypopnea index.