Genetic associations between serotonin receptor 1F (HTR1F) regulatory variation and sleep apnoea in non-obese individuals: insights from GWAS and eQTL analyses.

BACKGROUND

Sleep apnoea is a common sleep disorder affecting at least 10% 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, causing airway obstruction. However, understanding risk factors for sleep apnoea in non-obese (body mass index <30 kg·m-2) individuals requires further exploration. Our goal was to elucidate genetic risk factors for sleep apnoea in non-obese individuals.

METHODS

We performed genome-wide association testing in non-obese individuals in FinnGen, including 20 413 participants with a sleep apnoea diagnosis (International Classification of Diseases (ICD)-9 3472 or ICD-10 G47.3) and 443 463 disease-free controls. We replicated our analysis in the Estonian Biobank.

RESULTS

We identified a significant association within the serotonin receptor 1F (HTR1F) locus (rs1818163, β=0.059, se=0.010, p=1.58×10- 8), and replicated the association in the Estonian Biobank (β=0.042, se=0.020, p=0.034). The association signal colocalised with HTR1F expression across multiple tissues (posterior probability >0.8), and single-cell sequencing implicated HTR1F expression, particularly in neurons. Analysis of expression quantitative trait locus data further supported a possible regulatory role in neurons (β= -0.03, p=1.2×10-4). Finally, phenome-wide association study analysis of rs1818163 showed an association with objectively measured sleep-activity data, specifically with the number of awakenings during the night (p=5.6×10-8).

CONCLUSIONS

The findings indicate that HTR1F is associated with sleep apnoea, particularly in the non-obese patient population, and provide insight into the growing evidence of serotonin signalling as a factor modulating liability to sleep apnoea.