A NEWLY identified genetic association suggests that serotonin signalling may play a key role in sleep apnoea risk among non-obese individuals, offering insight into the pathophysiology of this common yet heterogeneous condition.
Obstructive sleep apnoea, primarily linked to elevated BMI and airway collapse, affects over 10% of the general population. However, many patients present without obesity, raising questions about underlying non-mechanical mechanisms. In this genome-wide association study, researchers from the FinnGen consortium analysed genetic data from 20,413 Finnish individuals with diagnosed sleep apnoea (BMI <30) and 443,463 controls. They sought to pinpoint heritable risk factors distinct from obesity. Findings were subsequently validated using data from the Estonian Biobank.
The study identified a significant association between sleep apnoea and a variant in the HTR1F gene locus (rs1818163), which encodes a serotonin receptor. In the FinnGen cohort, the variant was associated with sleep apnoea at genome-wide significance (β=0.059, SE=0.010, p<1.58×10-8), and the result replicated in the Estonian Biobank (β=0.042, SE=0.020, p=0.034). Further integrative analyses showed strong co-localisation of this variant with HTR1F gene expression in neural tissues (posterior probability >0.8), particularly in neurons. Expression quantitative trait loci data also supported its regulatory effect in neuronal cells (β=-0.03, p=1.2×10-4). Complementing this, a phenome-wide association study (PheWAS) linked the same variant to increased night-time awakenings (p=5.6×10⁻⁸), a common feature of disrupted sleep.
These findings suggest that HTR1F may influence sleep apnoea risk through neural pathways independent of body weight, highlighting serotonin receptor function as a potential target for future mechanistic and therapeutic research.
A better understanding of neurogenetic contributions to sleep apnoea could help identify at-risk individuals outside the traditional high-BMI population and refine personalised treatment approaches.
Reference
Strausz S et al. Genetic associations between Serotonin Receptor 1F (HTR1F) regulatory variation and sleep apnea in non-obese individuals: insights from GWAS and eQTL analyses. Eur Respir J. 2025; DOI: 10.1183/13993003.01778-2024.
