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Genome-wide gene by sleepiness interaction analysis for sleep apnea.
Pavithra Nagarajan1, Nuzulul Kurniansyah1, Jiwon Lee1
1Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Sleep
|July 30, 2025
Summary
This study investigated the genetic basis of sleep apnea with excessive daytime sleepiness (EDS). Gene interaction analyses identified specific genetic variants and pathways linked to EDS in sleep apnea patients, offering insights into cardiovascular risk.
Area of Science:
- Genetics
- Sleep Medicine
- Cardiovascular Health
Background:
- Excessive daytime sleepiness (EDS) affects some sleep apnea patients, who may face higher cardiovascular risks.
- The distinct genetic factors contributing to sleep apnea with and without EDS remain unclear.
- Apnea-hypopnea index (AHI) is a key marker for sleep apnea severity.
Purpose of the Study:
- To conduct gene-by-EDS interaction analyses for AHI.
- To understand how EDS influences the genetic risk of sleep apnea severity.
- To identify genetic underpinnings distinguishing sleep apnea with and without EDS.
Main Methods:
- Utilized multi-ethnic Trans-Omics for Precision Medicine (TOPMed) data (N=11619) for discovery.
- Performed interaction analyses for common and rare variants using 1-degree-of-freedom (1df) GxE and 2df joint G, GxE tests.
- Conducted replication and meta-analysis in additional TOPMed-imputed data (N=8904), including sex-stratified analyses.
Main Results:
- Discovery analysis identified two common variants (rs13118183 in CCDC3, rs281851 in MARCHF1) and three rare variant gene sets (SCUBE2, TMEM26, CPS4FL) interacting with EDS.
- Meta-analysis revealed EDS interaction with 11 additional rare variant gene sets (UBLCP1, MED31, RAP1GAP, CPNE5, MYMX, YY1, ZNF773, YBEY, IQCB1, PI4K2B, CORO1A).
- These genetic loci are associated with cardiovascular risk, insulin resistance, and thiamine deficiency.
Conclusions:
- The identified genetic signals provide insights into biological pathways relevant to the excessively sleepy subtype of sleep apnea.
- These findings may help elucidate the distinct genetic architecture of sleep apnea with EDS.
- Understanding these genetic links could inform targeted interventions for sleep apnea patients with EDS.
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