Background Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. Results The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258). Conclusions The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

Although both genetic factors and features of the social environment are important predictors of posttraumatic stress disorder (PTSD), there are few data examining gene-social environment interactions in studies of PTSD. The authors examined whether features of the social environment (county-level crime rate and unemployment) modified the association between the serotonin protein gene (SLC6A4) promoter variant (5-HTTLPR) and risk of current PTSD in a sample of 590 participants from the 2004 Florida Hurricane Study. Interviews conducted in 2005 were used to obtain individual-level risk factor measures and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, PTSD diagnoses. DNA was extracted from salivary samples. County-level crime and unemployment rates were assessed from Federal Bureau of Investigation and US Census data, respectively. There was a significant interaction between 5-HTTLPR genotype and both crime rate (odds ratio = 2.68, 95% confidence interval: 1.09, 6.57) and unemployment rate (odds ratio = 3.67, 95% confidence interval: 1.42, 9.50) in logistic regression models predicting PTSD risk, after adjustment for individual-level determinants of PTSD. Stratified analyses indicated that the "s" allele of the 5-HTTLPR polymorphism was associated with decreased risk of PTSD in low-risk environments (low crime/unemployment rates) but increased risk of PTSD in high-risk environments. These results suggest that social environment modifies the effect of 5-HTTLPR genotype on PTSD risk.

Objective-The well-documented gender differences in the risk for depression may be explained by genetic factors, by different responses to social context, or by a combination of both. We sought to assess whether there were gender differences in the longitudinal associations between serotonin transporter promoter (5-HTTLPR) genotype and depressive symptoms in adolescents, and whether macrosocial context plays a role in explaining any observed differences.Methods-Using data from a nationally representative survey of adolescents, we applied multilevel mixed models to assess, separately for adolescent males and females (a) the relation between 5-HTTLPR genotype and depressive symptoms; and (b) the interaction of county-level deprivation and 5-HTTLPR genotype in models predicting depressive symptoms. All models adjusted for age and other covariates.Results-Among females (n=560), main effects models showed an association between the sl genotype and lowered risk of depressive symptoms (b=−0.18, p=0.03). Among males (n=524), interaction models showed an association between sl genotype and lowered risk of depressive symptoms in deprived counties only (b=−0.32, p=0.04).Conclusions-In adolescent females, the 5-HTTLPR sl genotype confers protection against depressive symptoms independent of county-level social context whereas in adolescent males, protection by the same genotype is conferred only within the context of county-level deprivation. Future work should aim to understand how genetic and macrosocial factors jointly shape risk for mental illness, and how these factors shape gender differences in mental illness.

Objective The well-documented gender differences in the risk for depression may be explained by genetic factors, by different responses to social context, or by a combination of both. We sought to assess whether there were gender differences in the longitudinal associations between serotonin transporter promoter (5-HTTLPR) genotype and depressive symptoms in adolescents, and whether macrosocial context plays a role in explaining any observed differences. Methods Using data from a nationally representative survey of adolescents, we applied multilevel mixed models to assess, separately for adolescent males and females (a) the relation between 5-HTTLPR genotype and depressive symptoms; and (b) the interaction of county-level deprivation and 5-HTTLPR genotype in models predicting depressive symptoms. All models adjusted for age and other covariates. Results Among females (n=560), main effects models showed an association between the sl genotype and lowered risk of depressive symptoms (b=−0.18, p=0.03). Among males (n=524), interaction models showed an association between sl genotype and lowered risk of depressive symptoms in deprived counties only (b=−0.32, p=0.04). Conclusions In adolescent females, the 5-HTTLPR sl genotype confers protection against depressive symptoms independent of county-level social context whereas in adolescent males, protection by the same genotype is conferred only within the context of county-level deprivation. Future work should aim to understand how genetic and macrosocial factors jointly shape risk for mental illness, and how these factors shape gender differences in mental illness.

Context Geoffrey Rose’s two principal approaches to public health intervention are (1) targeted strategies focusing on individuals at a personal increased risk of disease and (2) population-wide approaches focusing on the whole population. Beyond his discussion of the strengths and weaknesses of these approaches, there is no empiric work examining the conditions under which one of these approaches may be better than the other. Methods This article uses mathematical simulations to model the benefits and costs of the two approaches, varying the cut points for treatment, effect magnitudes, and costs of the interventions. These techniques then were applied to the specific example of an intervention on blood pressure to reduce cardiovascular disease. Findings In the general simulation (using an inverse logit risk curve), lower costs of intervention, treating people with risk factor values at or above where the slope on the risk curve is at its steepest (for targeted interventions), and interventions with larger effects on reducing the risk factor (for population-wide interventions) provided benefit/cost advantages. In the specific blood pressure intervention example, lower-cost population-wide interventions had better benefit/cost ratios, but some targeted treatments with lower cutoffs prevented more absolute cases of disease. Conclusions These simulations empirically evaluate some of Rose’s original arguments. They can be replicated for particular interventions being considered and may be useful in helping public health decision makers assess potential intervention strategies.