Evidence for Multiple Genetic Factors Underlying DSM-IV Criteria for Major Depression

Importance: We do not know whether the clinical criteria for major depression (MD) reflect a single or multiple dimensions of genetic risk. Objective: To determine the structure of genetic and environmental risk factors for the 9 DSM-IV symptomatic MD criteria. Design: Population-based twin registry. Setting: Virginia. Participants: Seven thousand five hundred members of adult twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Main Outcome Measure: Symptoms of lifetime MD as assessed at personal interview. Results: The best-fit twin model was multidimensional, requiring 3 genetic, 1 common environmental and 3 unique environmental common factors, and criterion-specific unique environmental factors. The first genetic factor was characterized by high loadings on cognitive and psychomotor depressive symptoms. The second and third genetic factors had strong loadings for mood and neurovegetative depressive symptoms, respectively. Genetic factor scores derived from these 3 factors differentially predicted patterns of comorbidity, other historical/clinical features of MD, and demographic variables. These results suggested that the first genetic factor reflected a general liability to internalizing disorders, while the third genetic factor was more specific for melancholic MD. The 3 unique environmental common factors reflected, respectively, global depressive, core mood, and cognitive depressive symptoms. Conclusions and Relevance: The DSM-IV syndrome of MD does not reflect a single dimension of genetic liability. Rather, these criteria reflect 3 underlying dimensions that index genetic risk for cognitive/psychomotor, mood, and neurovegetative symptoms. While in need of replication, these results, validated by predictions using estimated genetic factor scores, have implications for gene-finding efforts for MD.