Abstract Chronic opioid use is associated with an increased risk of sleep-disordered breathing (SDB), likely through mechanisms involving respiratory depression and central apnea. However, only a subset of chronic opioid users develops SDB, suggesting a possible genetic predisposition. The OPRM1 gene, encoding the μ-opioid receptor, has been implicated in variable opioid response and may influence susceptibility to SDB.Using data from the All of Us Research Program (a large, nationally representative, and ancestrally diverse U.S. cohort) we examined associations between OPRM1 variants and SDB among chronic opioid users. Participants aged ≥18 years with documented opioid use for ≥180 days were included (n = 64,865 after quality control). Chronic opioid exposure was determined by medication records, and SDB was identified using SNOMED codes for sleep apnea. Genomic data from All of Us version 8 (GRCh38) were filtered to include OPRM1 variants with allele frequency 0.01, Hardy–Weinberg equilibrium p 1 × 1016, and a minimum allele count threshold.Among 64,865 participants, 16,279 had SDB (25.1%) and 48,586 did not. The mean age was higher in the SDB group (65.8 vs. 61.6 years, p 0.01). Males had significantly greater odds of SDB compared with females (OR 1.40, 95% CI 1.35–1.45, p 0.01). Compared to European ancestry, African (OR 0.91, 95% CI 0.87–0.95), Admixed American (OR 0.52, 0.49–0.55), East Asian (OR 0.47, 0.39–0.56), Middle Eastern (OR 0.56, 0.41–0.76), and South Asian (OR 0.55, 0.44–0.70) participants had lower odds of SDB (all p 0.01). Ethnicity was not significantly associated with SDB (Hispanic OR 0.98, 0.92–1.05, p = 0.57).Several OPRM1 loci demonstrated significant variant-specific associations. Variants at Chr6:154093428 (AG) and Chr6:154093438 (CT) were associated with lower odds of SDB (OR 0.91 and 0.92, both p 0.001). Similarly, Chr6:154094299 (GT) and Chr6:154094300 (CT) showed protective effects (OR 0.93, p 0.001; OR 0.87, p = 0.02, respectively). Additional variants including Chr6:154090209 (GA) (OR 0.88, p 0.001) and Chr6:154110430 (GA) (OR 0.94, p 0.001) also demonstrated modest but significant associations. Other variants such as Chr6:154093240, Chr6:154107684, and Chr6:154118730 did not show significant associations.In one of the largest and most diverse genomic cohorts to date, we identified multiple OPRM1 variants associated with reduced odds of SDB in individuals with chronic opioid use. These findings suggest potential genetic modifiers of opioid-related respiratory vulnerability. The All of Us dataset provides unique power to investigate ancestry-specific genetic effects and supports further exploration of pharmacogenomic pathways in opioid-related sleep and respiratory outcomes. This abstract is funded by: None
Tavakoli et al. (Fri,) studied this question.