Serotonin receptor 1A promoter polymorphism, <italic>rs</italic>6295, modulates human anxiety levels via altering parasympathetic nervous activity.

Objective: The G‐allele of the ‐1019C/G (<italic>rs</italic>6295) promoter polymorphism of the serotonin receptor 1A (<italic>HTR1A</italic>) gene has been implicated in anxiety; however, the underlying neurophysiological processes are still not fully understood. Recent evidence indicates that low parasympathetic (vagal) tone is predictive of anxiety. We thus conducted a structural equation model (SEM) to examine whether the <italic>HTR1A rs</italic>6295 variant can affect anxiety by altering parasympathetic nervous activity. Method: A sample of 1141 drug‐free healthy Han Chinese was recruited for <italic>HTR1A</italic> genotyping. Autonomic nervous function was assessed by short‐term spectral analysis of heart rate variability (HRV). Anxiety and stress levels were evaluated by the Beck Anxiety Inventory (BAI) and the Perceived Stress Scale (PSS) respectively. Results: The number of the <italic>HTR1A</italic> G allele was inversely correlated with high‐frequency power (HF), a parasympathetic index of HRV. The HF index was negatively associated with BAI scores. Furthermore, the good‐fitting SEM, adjusting for confounding variables (e.g., age and PSS levels), revealed a significant pathway linking <italic>rs</italic>6295 variant to BAI scores via HF index modulation. Conclusion: These results are the first to show that <italic>HTR1A</italic> ‐1019C/G polymorphism influences anxiety levels by modulating parasympathetic tone, providing a neurophysiological insight into the role of <italic>HTR1A</italic> in human anxiety. [ABSTRACT FROM AUTHOR]