Multiple dimensions of stress vs. genetic effects on depression

Many psychiatric disorders including depression involve complex interactions of genetics and environmental stressors. Environmental influence is challenging to measure objectively and account for in genetic studies because the necessary large population samples in these studies involve individuals with varying cultures and life experiences, clouding genetic findings. In a unique population with relative sociocultural homogeneity and a narrower range of types of stress experiences, we quantitatively assessed multiple stress dimensions and measured their potential influence in biasing the heritability estimate of depression. We quantified depressive symptoms, major lifetime stressors, current perceived stress, and a culturally specific community stress measure in individuals with depression-related diagnoses and community controls in Old Order Amish and Mennonite populations. Results showed that lifetime stressors measured by lifetime stressor inventory (R²= 0.06, p = 2 × 10^-5) and current stress measured by Perceived Stress Scale (R²= 0.13, p < 1 × 10^-6) were both associated with current depressive symptoms quantified by Beck Depression Inventory in community controls, but current stress was the only measure associated with current depressive symptoms in individuals with a depression diagnosis, and to a greater degree (R² = 0.41, p < 1 × 10^-6). A novel, culturally specific community stress measure demonstrated internal reliability and was associated with current stress but was not significantly related to depression. Heritability (h²) for depression diagnosis (0.46 ± 0.14) and quantitative depression severity as measured by Beck Depression Inventory (0.45 ± 0.12) were significant, but h² for depression diagnosis decreased to 0.25 ± 0.14 once stressors were accounted for in the model. This quantifies and demonstrates the importance of accounting for environmental influence in reducing phenotypic heterogeneity of depression and improving the power and replicability of genetic association findings that can be better translated to patient groups.