Genetic variants associated with craniofacial features are related to obstructive sleep apnea risk and severity in two multinational cohorts

초록

Introduction: Obstructive sleep apnea (OSA) is a genetically complex disease, involving many genes that interact with various environmental and intermediate pathogenic traits. Specific pathways related to OSA include those involved with obesity, craniofacial features, and ventilatory control. In this study, we examined whether variants within candidate genes previously associated with variability in craniofacial features influenced OSA risk and severity within two multinational cohorts. Methods: A total of 2,099 individuals with genetic data, in-laboratory or home-based polysomnography, and photography-based craniofacial data from either the Korean Genomic Epidemiology Study(KoGES; n=1292) or the Sleep Apnea Global Interdisciplinary Consortium (SAGIC; n=807) were included. A total of 11,262 single nucleotide variants within 30 candidate genes associated with craniofacial features in prior publications and validated (p < 0.05) in genome-wide meta-analysis using craniofacial measurements from digital photographs in the current datasets were included in genetic association analyses. Primary outcomes included the apnea-hypopnea index (AHI) and OSA case/control status (case-definition: AHI ≥ 10). Genetic association analyses were performed by linear (AHI) or logistic (OSA status) regression, with adjustment for age, sex, 5 ancestry/population-informative principal components, and body mass index. Results:Variants within calcium voltage-gated channel auxiliary subunit alpha2delta 3(CACNA2D3) and parkin RBR E3 ubiquitin protein ligase(PRKN) were associated with AHI (rs61446413 within CACNA2D3: Gallele, β[SE] = 0.16 (0.04), p = 1.14 x 10 ^–5; rs6934514 within PRKN: A allele, β[SE]= 0.10 (0.03), p = 2.14 x 10 ^–3) and with OSA status(rs6786051 within CACNA2D3: C allele, odds ratio [OR] [SE] = 0.73(0.10), p = 1.93 x 10 ^–3; rs9458572 within PRKN: T allele, OR[SE] = 0.64 (0.14), p = 1.17 x 10^–3) in meta-analysis. Moreover, rs1649166 within fibroblast growth factor receptor 2(FGFR2) was associated with OSA risk (T allele, OR [SE] = 1.42 (0.08), p = 1.31 x 10 ^–5). Conclusions: We showed that certain variants within genes previously reported to be related to craniofacial features and associated with craniofacial traits in the current datasets are also associated with OSA risk and severity in two multinational cohorts. This study provides more information about the important role of genetic pathways related to craniofacial features in the development of obstructive sleep apnea.