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

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

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

Kaplan–Meier survival curves for 5a) CATHGEN and 5b) IMHC Caucasian control subjects by genotype for LSAMP SNP rs1462845.

<p><i>X</i>-axis displays the number of days from index catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan-Meier survival probability by genotype. G is the minor allele; AA, wild-type genotype (reference; black curve); AG, heterozygous genotype (blue curve); and GG, risk homozygous genotype (red curve). No significant differences were found in any statistical modeling (data not shown).</p

Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship

<div><p>Survival bias may unduly impact genetic association with complex diseases; gene-specific survival effects may further complicate such investigations. Coronary artery disease (CAD) is a complex phenotype for which little is understood about gene-specific survival effects; yet, such information can offer insight into refining genetic associations, improving replications, and can provide candidate genes for both mortality risk and improved survivorship in CAD. Building on our previous work, the purpose of this current study was to: evaluate <i>LSAMP</i> SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of our CAD cases; and, perform additional replication in an independent dataset. We examined two <i>LSAMP</i> SNPs—rs1462845 and rs6788787—using CAD case-only Cox proportional hazards regression for additive genetic effects, censored on time-to-all-cause mortality or last follow-up among Caucasian subjects from the Catheterization Genetics Study (CATHGEN; <i>n</i> = 2,224) and the Intermountain Heart Collaborative Study (IMHC; <i>n</i> = 3,008). Only after controlling for age, sex, body mass index, histories of smoking, type 2 diabetes, hyperlipidemia and hypertension (<i>HR</i> = 1.11, 95%<i>CI</i> = 1.01–1.22, <i>p</i> = 0.032), rs1462845 conferred significantly increased hazards of all-cause mortality among CAD cases. Even after controlling for multiple covariates, but in only the primary cohort, rs6788787 conferred significantly improved survival (<i>HR</i> = 0.80, 95% <i>CI</i> = 0.69–0.92, <i>p</i> = 0.002). Post-hoc analyses further stratifying by sex and disease severity revealed replicated effects for rs1462845: even after adjusting for aforementioned covariates and coronary interventional procedures, males with severe burden of CAD had significantly amplified hazards of death with the minor variant of rs1462845 in both cohorts (<i>HR</i> = 1.29, <i>95% CI</i> = 1.08–1.55, <i>p</i> = 0.00456; replication <i>HR</i> = 1.25, <i>95% CI</i> = 1.05–1.49, <i>p</i> = 0.013). Kaplan-Meier curves revealed unique cohort-specific genotype effects on survival. Additional analyses demonstrated that the homozygous risk genotype (‘A/A’) fully explained the increased hazard in both cohorts. None of the post-hoc analyses in control subjects were significant for any model. This suggests that genetic effects of rs1462845 on survival are unique to CAD presence. This represents formal, replicated evidence of genetic contribution of rs1462845 to increased risk for all-cause mortality; the contribution is unique to CAD case status and specific to males with severe burden of CAD.</p></div

Post-hoc Power Analyses.

<p>Post-hoc Power Analyses.</p

Kaplan–Meier survival curves for IMHC males with severe CAD by genotype for <i>LSAMP</i> SNP rs6788787.

<p><i>X</i>-axis displays the number of days from catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan–Meier survival probability by genotype. A is the minor allele; GG, wild-type genotype (reference; black curve); GA, heterozygous genotype; and AA, risk homozygous genotype (red curve). No significant differences were found in any statistical modeling (data not shown).</p

Hazards of Death in Caucasian Control Subjects.

<p>Hazards of Death in Caucasian Control Subjects.</p

Kaplan–Meier survival curves for CATHGEN males with severe CAD by genotype for <i>LSAMP</i> SNP rs1462845.

<p><i>X</i>-axis displays the number of days from index catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan-Meier survival probability by genotype. G is the minor allele; AA, wild-type genotype (reference; black curve); AG, heterozygous genotype (blue curve); and GG, risk homozygous genotype (red curve). Hazards of all-cause mortality were significant for each addition of the G risk allele (<i>HR</i> = 1.39, <i>95% CI</i> = 1.16–1.66, <i>p</i> = 0.0003, additive genetic model).</p

Kaplan–Meier survival curves for CATHGEN males with severe CAD by genotype for <i>LSAMP</i> SNP rs6788787.

<p><i>X</i>-axis displays the number of days from catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan–Meier survival probability by genotype. A is the minor allele; GG, wild-type genotype (reference; black curve); GA, heterozygous genotype; and AA, risk homozygous genotype (red curve). Only after controlling for covariates was this model significant for reduced hazards of death by genotype (<i>HR</i> = 0.71, <i>95% CI</i> = 0.54–0.93, <i>p</i> = 0.0148, additive genetic model).</p