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Original Article |

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

Kenneth S. Kendler, MD; Steven H. Aggen, PhD; Michael C. Neale, PhD
JAMA Psychiatry. 2013;70(6):599-607. doi:10.1001/jamapsychiatry.2013.751.
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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.

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Figure. Parameter estimates for genetic and environmental factors from the best-fit multivariate twin model applied to the 9 DSM-IV criteria for major depression. A, Parameter estimates for genetic factors from the best-fit multivariate twin model applied to the 9 DSM-IV criteria for major depression. Three genetic common factors were identified as well as genetic factors unique to each criterion. Factor loadings from the common factors of 0.31 or more are bold. A1 through A3 refer to the first through third common genetic factors. A1 through A9 refer to the criteria-specific genetic influences for criteria 1 through 9, respectively. Squares are observed variables and circles/ovals indicate latent variables. B, Parameter estimates for environmental factors from the best-fit multivariate twin model applied to the 9 DSM-IV criteria for major depression. One common and 3 individual-specific environmental common factors were identified as well as individual-specific environmental factors unique to each criterion. Factor loadings from the common factors of 0.31 or more are bold. C1 and E1 through E3 refer, respectively, to the single common shared environmental and the first through third common individual-specific environmental factors. E1 through E9 refer to the criteria-specific individual-specific environmental influences for criteria 1 through 9, respectively. Squares are observed variables and circles/ovals indicate latent variables.

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