Nonsynonymous HTR2C polymorphism predicts cortisol response to psychosocial stress I: Effects in males and females

Abstract

Background Genetic influences on stress reactivity may provide insight into depression risk mechanisms. The C-allele of rs6318, a putatively functional polymorphism located within the HTR2C gene, has been reported to predict greater cortisol and negative affective reactivity to lab-induced stress. However, the potential moderating effect of sex has not been examined despite X-linkage of HTR2C. We hypothesized that sex moderates the effect of rs6318 on cortisol and affective reactivity to lab-induced stress, with males showing stronger effects. Methods Non-depressed young adults (N = 112; 39 female) screened via clinical interview provided a DNA sample and completed either a negative evaluative Trier Social Stress Test, or a non-evaluative control protocol. Salivary cortisol and self-reported affect were assessed at four timepoints. Results Contrary to hypotheses, C-carriers showed blunted rather than exaggerated cortisol responses to lab-induced stress in multilevel models (b = 0.467, p < 0.001), which persisted when covarying subclinical depression symptoms. This effect was not moderated by sex (b = 0.174, p = 0.421), and remained significant when examining females (b = 0.362, p = 0.013) and males (b = 0.537, p < 0.001) separately. C-carriers also exhibited marginally greater reactivity in negative self-focused affect in response to stress than non-carriers when covarying subclinical depression symptoms (b = −0.360, p = 0.067), and exhibited higher levels of subclinical depression symptoms than non-carriers (F = 6.463, p = 0.012). Conclusions Results support a role for the rs6318 C-allele in dysregulated stress responding, and suggest that the C-allele may contribute to risk for depression.

Cortisol awakening response and additive serotonergic genetic risk interactively predict depression in two samples: The 2019 Donald F. Klein Early Career Investigator Award Paper

“…Genotypes were coded for the number of risk alleles (0–2), except for (a) 5‐HTTLPR which was coded 0 or 1 representing S‐carriers, consistent with prior work in this sample (Vrshek‐Schallhorn et al, ) and Goodyer's report (2009); and (b) HTR2C 's rs6318 , which is X‐linked. This SNP was coded as 0/1 because males have one copy; prior work indicates that its influence over cortisol reactivity to laboratory‐based stress did not vary by sex when coded this way (Avery & Vrshek‐Schallhorn, ). Risk alleles were summed, permitting one missing genotype per person via prorating risk alleles; scores were centered for analyses.…”

The Trier Social Stress Test: Principles and practice

“…Consistent with this pattern of findings, rs6318 moderated TSST response: homozygous females and hemizygous males had greater cortisol reactivity ( Way et al., 2016 ). Furthermore, carriers of the C-allele of rs6318 showed blunted cortisol response to the TSST, and this effect was not moderated by sex ( Avery and Vrshek-Schallhorn, 2016 ). The serotonergic system has been implicated in other physiological responses to the TSST besides HPA axis activity; participants carrying the short-short allele for the 5HT transporter gene-linked polymorphic region (5-HTTLPR) had increased immune activation (IL-1beta) in response to the TSST ( Yamakawa et al., 2015 ).…”

Sex differences modulating serotonergic polymorphisms implicated in the mechanistic pathways of risk for depression and related disorders:

“…However, inheritance patterns in family studies have raised the possibility of sex-linked genes playing a role in depression: maternal grandfather longevity was associated with mental health in a male group, though maternal mental health was not associated, suggestive of an x-linked recessive genetic basis (Vaillant et al, 2005). There are several X-linked genes that have been associated with depression endophenotypes, including HTR2C, though its interactions with sex remain unclear (Avery and Vrshek-Schallhorn, 2016). …”