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

Area of Science:

• Behavioral genetics
• Psychiatric genetics
• Molecular psychiatry

Background:

• Depression is influenced by multiple genes (polygenic models) and gene-environment interactions (GxE).
• Existing research often examines single genetic variations, potentially overlooking cumulative genetic risk.
• Multilocus profile scores offer a way to aggregate small genetic risks consistent with polygenic models.

Purpose of the Study:

• To demonstrate the utility of a multilocus genetic profile score in predicting depression onset.
• To investigate gene-environment interactions between a serotonin system genetic profile score and interpersonal stress.
• To assess the protective effects of the genetic profile score in the absence of stress.

Main Methods:

• Constructed an additive multilocus profile score from 5 serotonin system polymorphisms (HTR1A, HTR2A, HTR2C, TPH2).
• Utilized longitudinal data (5 years) from 387 young adults (Youth Emotion Project) including diagnostic interviews and life stress interviews.
• Employed survival analyses to examine interactions between the genetic profile score and interpersonal stress (major stressful life events, chronic stress).

Main Results:

• The multilocus profile score significantly interacted with major interpersonal stressful life events to predict major depressive episode onsets (HR = 1.815, p = .007).
• A significant protective effect of the genetic profile score was observed in the absence of recent stressful life events (HR = 0.83, p = .030).
• No significant GxE effect was found for interpersonal chronic stress (HR = 1.15, p = .165).
• The findings were replicated in a separate sample of 105 early adolescent girls.

Conclusions:

• Multilocus genetic profile scores are valuable for capturing polygenic risk and detecting gene-environment interactions in depression.
• Examining genetic factors in isolation may obscure important GxE effects and protective genetic influences.
• This approach offers a more nuanced understanding of the genetic architecture of depression and its interplay with environmental factors.