Genome-Wide Association Study of Obstructive Sleep Apnea and Objective Sleep-related Traits Identifies Novel Risk Loci in Han Chinese Individuals.

Abstract

<b>Rationale:</b> Previous genetic studies of obstructive sleep apnea (OSA) have limitations in terms of precise case definition, integrated quantitative traits, and interpretation of genetic functions; thus, the heritability of OSA remains poorly explained. <b>Objectives:</b> To identify novel genetic variants associated with OSA and objective sleep-related traits and to explore their functional roles. <b>Methods:</b> A genome-wide association study was performed in 20,590 Han Chinese individuals (5,438 OSA and 15,152 control samples). Human samples and point mutation knockin mice were used for follow-up investigation of gene functions. <b>Measurements and Main Results:</b> Two characteristic study-wide significant loci (<i>P</i> < 2.63 × 10^-9) for OSA were identified: the <i>PACRG</i> intronic variant rs6455893 on 6q26 (odds ratio [OR] = 1.62; 95% confidence interval [CI], 1.39-1.89; <i>P</i> = 6.98 × 10^-10) and the missense variant rs3746804 (p.Pro267Leu) in the riboflavin transporter <i>SLC52A3</i> on 20p13 (OR = 0.83; 95% CI, 0.79-0.88; <i>P</i> = 7.57 × 10^-10). In addition, 18 genome-wide significant loci associated with quantitative OSA and objective sleep-related traits were identified, 5 of which exceeded the study-wide significance threshold. Rs3746804 was associated with elevated serum riboflavin concentrations, and the corresponding mutation in mice increased riboflavin concentrations, suggesting that this variant may facilitate riboflavin uptake and riboflavin-dependent physiological activity. <b>Conclusions:</b> We identified several novel genome-wide significant loci associated with OSA and objective sleep-related traits. Our findings provide insight into the genetic architecture of OSA and suggest that <i>SLC52A3</i> might be a therapeutic target, whereas riboflavin might be a therapeutic agent.