Serotonin 2A receptor (5-HT2A) gene promoter variant interacts with chronic perceived stress to modulate resting parasympathetic activity in humans

Decreased resting vagal (parasympathetic) tone is implicated in the development of stress-related disorders, including anxiety and depression. Chronic stress elevates the expression of serotonin 2A receptors (5-HT2A), while activation of 5-HT2A leads to inhibition of parasympathetic synaptic transmission. The T allele of the promoter variant, rs6311 (C > T), of the 5-HT2A gene has been shown to increase the 5-HT2A expression in vitro and to be associated with anxiety and depressive disorders. We thus hypothesized that the 5-HT2A functional polymorphism may influence resting vagal activity among persons with chronically high levels of perceived stress. A total of 1138 well-defined healthy, medication-free Han Chinese were included for 5-HT2A genotyping. The Perceived Stress Scale (PSS) was used to measure the level of perceived stress during the last month and participants were divided into low and high PSS groups. Resting-state heart rate variability (HRV) was used to assess autonomic function. No significant between-genotype difference was found in any HRV variable in the low PSS group (n = 610). However, in the high PSS group (n = 528), high frequency power and root mean square of successive heartbeat interval differences (both HRV indices of parasympathetic activity) were significantly reduced in T/T genotype carriers compared to C/C homozygotes. Our findings are the first to show that individuals homozygous for the high-expressing 5-HT2A (T) allele exhibit diminished resting vagal tone-an index of stress vulnerability-when experiencing chronically elevated levels of perceived stress. The present results may advance our understanding of the genetic mechanism underlying individual differences in susceptibility to stress.