Meta-analytic evidence supports a gene-environment (G×E) interaction between life stress and the serotonin transporter polymorphism (5-HTTLPR) on depression, but few studies have examined factors that influence detection of this effect, despite years of inconsistent results. We propose that the candidate environment (akin to a candidate gene) is key. Theory and evidence implicate major stressful life events (SLEs)-particularly major interpersonal SLEs-as well as chronic family stress. Participants (N = 400) from the Youth Emotion Project (which began with 627 high school juniors oversampled for high neuroticism) completed up to five annual diagnostic and life stress interviews and provided DNA samples. A significant G×E effect for major SLEs and S-carrier genotype was accounted for significantly by major interpersonal SLEs but not significantly by major non-interpersonal SLEs. S-carrier genotype and chronic family stress also significantly interacted. Identifying such candidate environments may facilitate future G×E research in depression and psychopathology more broadly.

Meta-analytic evidence supports a gene-environment (G×E) interaction between life stress and the serotonin transporter polymorphism (5-HTTLPR) on depression, but few studies have examined factors that influence detection of this effect, despite years of inconsistent results. We propose that the "candidate environment" (akin to a candidate gene) is key. Theory and evidence implicate major stressful life events (SLEs)-particularly major interpersonal SLEs-as well as chronic family stress. Participants (N = 400) from the Youth Emotion Project (which began with 627 high school juniors oversampled for high neuroticism) completed up to five annual diagnostic and life stress interviews and provided DNA samples. A significant G×E effect for major SLEs and S-carrier genotype was accounted for significantly by major interpersonal SLEs but not significantly by major non-interpersonal SLEs. S-carrier genotype and chronic family stress also significantly interacted. Identifying such candidate environments may facilitate future G×E research in depression and psychopathology more broadly.

Genetically diverse inbred strains are frequently used in quantitative trait mapping to identify sequence variants underlying trait variation. Poor locus resolution and high genetic complexity impede variant discovery. As a solution, we explore reduced complexity crosses (RCCs) between phenotypically divergent, yet genetically similar, rodent substrains. RCCs accelerate functional variant discovery via decreasing the number of segregating variants by orders of magnitude. The simplified genetic architecture of RCCs often permit immediate identification of causal variants or rapid fine-mapping of broad loci to smaller intervals. Whole-genome sequences of substrains make RCCs possible by supporting the development of array- and targeted sequencing-based genotyping platforms, coupled with rapid genome editing for variant validation. In summary, RCCs enhance discovery-based genetics of complex traits.