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

<div><p>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 <i>HTR2C</i> 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 <i>HTR2C</i> gene may confer an increased risk for depressive symptoms in White women with a history of significant life stress.</p></div

Genotype distribution of <i>APOE</i> rs769450, rs405509 and rs439401 for controls and obese participants in absolute numbers and percentages at survey S-46 (n = 1,186) and S-49 (n = 385).

<p>*The minor alleles are shown in bold-faced letters.</p><p>**SNP position based on the Human Genome Build.</p><p>SNPs = single nucleotide polymorphisms, MAF = Minor allele frequency.</p><p>S-46 and S-49 denote the separate surveys in which participants were examined at the mean age of 46 and 49 years, respectively.</p

Descriptive Statistics by rs6318: Men.

<p><i>a</i><b>b</b><i>c</i> represent the lower quartile <i>a</i>, the median <b><i>b</i></b>, and the upper quartile <i>c</i> for continuous variables.</p><p><i>N</i> is the number of non–missing values.</p><p>Numbers after percents are frequencies.</p><p>Kruskal-Wallis test for continuous variable; Pearson chi-square test used for frequencies.</p><p>Descriptive Statistics by rs6318: Men.</p

Study population characteristic given as mean±SD by stress status at survey 46 (S-46) and survey 49 (S-49).

<p>P-value for trend was >0.05 for all variables, except for age at S-46.</p

Interaction between the stress index and rs6318 genotypes predicting depressive symptom scores among White women (Panel A) and White men (Panel B).

<p>Estimates are adjusted for antidepressant use and age. Shaded gray areas represent 95% confidence bands generated using the Huber-White estimator. Tick marks represent case density. The sample was comprised of 86 C/C, 738 G/C, and 1,888 G/G women, and 360 C/- and 2,006 G/- men. The interaction term was statistically significant for women (p = .022), but not for men (p = .471).</p

Metabolic traits and OGTT-derived indices in relation to <i>APOE rs439401</i> at survey 46 (S-46) and survey 49 (S-49). OR (95% confidence intervals) in stressed individuals homozygous for the minor T-allele.

<p>BMI = body mass index, BIGTT-AIR = OGTT-derived index of acute insulin response, BP = blood pressure, BIGTT-S_I = OGTT-derived index of insulin sensitivity, IS = insulin sensitivity.</p><p>*: Per two-unit increment of BMI,</p><p>**: Per five cm increment of waist circumference.</p

The seven items in construct of stress in order of increasing prevalence.

<p>The seven items in construct of stress in order of increasing prevalence.</p

Cox regression models predicting death or non-fatal myocardial infarction (N = 6,126, N events = 1,769).

<p> Note: The model including adjustment covariates included all predictors simultaneously.</p

Clinical Characteristics by sex and <i>5HTR2C</i> rs6318 Ser23 C and Cys23 G allele.

<p>^a p-value derived from unadjusted linear model;^b p-value derived from age-adjusted logistic regression model;^c p-value derived from age-adjusted linear model;^d p-value was derived from age-adjusted ordinal logistic regression model with number of diseased vessels modeled as an ordinal variable ranging from 0 to 3. Note. </p

Kaplan-Meier curves illustrating the risk of death or myocardial infarction for each rs6318 genotype in Women (panel a) and Men (panel b).

<p>Using pre-specified contrasts in a Cox regression model adjusted for covariates, differences were statistically significant when comparing: male Ser23 C hemizygotes and female Ser23 C homozygotes to all Cys23 G carriers (p  = .005); male Ser23 C hemizygotes to male Cys23 G hemizygotes (p  = .022), and female Ser23 C homozygotes to female Cys23 G carriers (p  = .024).</p