A Putatively Functional Polymorphism in the HTR2C Gene is Associated with Depressive Symptoms in White Females Reporting Significant Life Stress

Abstract

Psychosocial stress is well known to be positively associated with subsequent depressive symptoms. Cortisol response to stress may be one of a number of biological mechanisms that links psychological stress to depressive symptoms, although the precise causal pathway remains unclear. Activity of the x-linked serotonin 5-HTR2C receptor has also been shown to be associated with depression and with clinical response to antidepressant medications. We recently demonstrated that variation in a single nucleotide polymorphism on the HTR2C gene, rs6318 (Ser23Cys), is associated with different cortisol release and short-term changes in affect in response to a series of stress tasks in the laboratory. Based on this observation, we decided to examine whether rs6318 might moderate the association between psychosocial stress and subsequent depressive symptoms. In the present study we use cross-sectional data from a large population-based sample of young adult White men (N = 2,366) and White women (N = 2,712) in the United States to test this moderation hypothesis. Specifically, we hypothesized that the association between self-reported stressful life events and depressive symptoms would be stronger among homozygous Ser23 C females and hemizygous Ser23 C males than among Cys23 G carriers. In separate within-sex analyses a genotype-by-life stress interaction was observed for women (p = .022) but not for men (p = .471). Homozygous Ser23 C women who reported high levels of life stress had depressive symptom scores that were about 0.3 standard deviations higher than female Cys23 G carriers with similarly high stress levels. In contrast, no appreciable difference in depressive symptoms was observed between genotypes at lower levels of stress. Our findings support prior work that suggests a functional SNP on the HTR2C gene may confer an increased risk for depressive symptoms in White women with a history of significant life stress.

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

“…Additionally this finding was replicated in a sample ( N = 60) that included C/C (n=1) and G/G (n=15) females, although females were not tested separately (Brummett, Babyak, Kuhn, Siegler, & Williams, 2014). In a larger sample, the same group also found that the C-allele moderates the relationship between self-reported life stress and depression symptoms in C/C females, but not in C males (Brummett, Babyak, Williams, et al, 2014), consistent with prior work that implicated the C-allele in risk for both depression and bipolar disorder (Lerer et al, 2001). …”

“…Although we hypothesized that C-carriers would have greater evidence of dysfunctional affective functioning, and rs6318 has been shown to moderate the relationship between life stress and depression in C/C females (Brummett, Babyak, Williams, et al, 2014), we were surprised to find in the exploratory analysis that C-carriers had significantly higher rates of current subclinical depression symptoms. Historically, genetic main effects on depression in genome wide association studies have not reached significance (MDD Working Group of the GWAS Consortium, 2013) and studies examining the main effects of polymorphisms on depression have produced inconsistent results (for a review, see Lohoff, 2010).…”

“…Taken together, the 5-HT2 C receptor appears to play a key role in regulating cortisol and behavioral responses to stress. Furthermore, given reported effects of rs6318 on negative affect under stress and evidence for its functionality, the C-allele may contribute to risk for emotional disorders such as depression, either alone or in interaction with life stress (Brummett, Babyak, Williams, et al, 2014). …”

Pharmacogenomic incidental findings in 308 families: The NIH Undiagnosed Diseases Program experience

“…These medications were escitalopram, carbamazepine, morphine, and acetylsalicylic acid. First, a female adult (Patient 1) prescribed escitalopram had a PharmGKB category 3 association: rs6318 genotype CG, which has been associated with altered function of the X-linked serotonin 5-HTR2C receptor and various phenotypes ranging from altered cortisol response to stress 7 to increased risk for cardiovascular disease mortality and morbidity 8 . Second, a child (Patient 2) who had seizures refractory to carbamazepine had a PharmGKB category 2B association: rs1051740 genotype CT, which has been associated with a requirement for increased dosage of carbamazepine 9 .…”

Association study of three single-nucleotide polymorphisms in the cyclic adenosine monophosphate response element binding 1 gene and major depressive disorder

“…The blood samples were centrifuged (3,000 xg/min, 10 min) and the supernatant was extracted and stored at -70˚C. Total DNA from the supernatant pellet was isolated using the traditional phenolchloroform (Sangon Biotech Co., Ltd, Shanghai, China) method (12).…”