Genetic associations between Serotonin Receptor 1F (HTR1F) regulatory variation and sleep apnea in non-obese individuals: Insights from GWAS and eQTL analyses

Background Sleep 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. Aim Our goal was to elucidate genetic risk factors for sleep apnea in non-obese individuals. Methods We 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. Results We 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 =0.020, p=0.034). 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, PheWAS analysis of rs1818163 showed an association with objectively measured sleep-activity data, specifically with the number of awakenings during the night (p=5.6e-8). Conclusions The 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.