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The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research, and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis1) with qualifying unpublished data were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction, and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalizable, but must be of modest effect size and only observable in limited situations.

This study tested the hypothesis that a personality disposition defined by a strong sense of coherence is associated with a reduced risk of mortality. The authors prospectively examined, for < or =6 years, the relation between a strong sense of coherence and mortality due to all causes, cardiovascular disease, and cancer among 20,579 participants aged 41-80 years from the European Prospective Investigation into Cancer (EPIC)-Norfolk Study in the United Kingdom. Data were collected in 1996-2002. Participants were recruited by post from general practice age-sex registers and subsequently completed a postal assessment of their sense of coherence. During follow-up, 1,024 deaths were recorded. A strong sense of coherence was associated with a 30% reduction in mortality from all causes (rate ratio=0.69, p<0.0001), cardiovascular disease (rate ratio=0.70, p=0.001), and cancer (rate ratio=0.74, p=0.003), independent of age, sex, and prevalent chronic disease. These associations were consistent by sex, except that no association was observed for cancer mortality in women. The association for all-cause mortality remained after adjustment for cigarette smoking history, social class, body mass index, systolic blood pressure, cholesterol, hostility, and neuroticism (rate ratio=0.76, p=0.002). Results suggest that a strong sense of coherence may confer some resilience to the risk of chronic disease.

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