Regulatory variation at serotonin receptor 1F (HTR1F) modulates arousals and risk for sleep apnea

BackgroundSleep apnea is a common sleep disorder affecting at least ten percent of the population. It is caused by lack of breathing during sleep, typically mediated by obstruction of airways or less frequently by misdirected central signals for breathing. The primary risk factor is a high body mass index (BMI), causing airway obstruction. However, understanding risk factors for sleep apnea in non-obese (BMI < 30) individuals requires further exploration. AimOur goal was to elucidate genetic risk factors for sleep apnea in non-obese individuals. MethodsWe performed genome-wide association testing in individuals with BMI < 30 in FinnGen including 20,413 cases with sleep apnea diagnosis (ICD-10 G47.3 or ICD-9 3472) and 443,463 disease free controls. We replicated our analysis in Estonian Biobank. ResultsWe identified a significant association within the Serotonin receptor 1F (HTR1F) locus (rs1818163, beta = 0.059, se = 0.010, P < 1.58e-8), and replicated the association in Estonian Biobank (beta =0.042, se = 0.021, P = 0.046). The association signal co-localized with HTR1F expression across multiple tissues (posterior probability > 0.8), and single cell sequencing implicated HTR1F expression particularly in neurons. Analysis of eQTL data further supported a possible regulatory role in neurons (beta = -0.03, P = 1.2e-4). Finally, objectively measured sleep-activity data showed association with number awakenings during night (P = 5.6e-8). ConclusionsThe findings indicate association of HTR1F in sleep apnea particularly in the patient population within the non-obese BMI range and provide insight into the growing evidence of serotonin signaling as a factor modulating liability to sleep apnea.