Additive genetic risk from five serotonin system polymorphisms interacts with interpersonal stress to predict depression

Suzanne Vrshek-Schallhorn*, Catherine B. Stroud, Susan Mineka, Richard E. Zinbarg, Emma K. Adam, Eva E. Redei, Constance Hammen, Michelle G. Craske

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


Behavioral genetic research supports polygenic models of depression in which many genetic variations each contribute a small amount of risk, and prevailing diathesis-stress models suggest gene-environment interactions (GXE). Multilocus profile scores of additive risk offer an approach that is consistent with polygenic models of depression risk. In a first demonstration of this approach in a GXE predicting depression, we created an additive multilocus profile score from 5 serotonin system polymorphisms (1 each in the genes HTR1A, HTR2A, HTR2C, and 2 in TPH2). Analyses focused on 2 forms of interpersonal stress as environmental risk factors. Using 5 years of longitudinal diagnostic and life stress interviews from 387 emerging young adults in the Youth Emotion Project, survival analyses show that this multilocus profile score interacts with major interpersonal stressful life events to predict major depressive episode onsets (hazard ratio [HR] 1.815, p .007). Simultaneously, there was a significant protective effect of the profile score without a recent event (HR 0.83, p .030). The GXE effect with interpersonal chronic stress was not significant (HR 1.15, p .165). Finally, effect sizes for genetic factors examined ignoring stress suggested such an approach could lead to overlooking or misinterpreting genetic effects. Both the GE effect and the protective simple main effect were replicated in a sample of early adolescent girls (N 105). We discuss potential benefits of the multilocus genetic profile score approach and caveats for future research.

Original languageEnglish (US)
Pages (from-to)776-790
Number of pages15
JournalJournal of abnormal psychology
Issue number4
StatePublished - Nov 1 2015


  • Depression
  • Gene-environment interaction
  • Interpersonal
  • Serotonin
  • Stressful life events

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry


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