Delineation of Two Genetic Pathways to Major Depression

Background: We sought to identify two sets of familial/genetic risk factors for major depression (MD): 1) high familial loading for MID, which we predicted would be most prominent in cases of MD with an early age at onset (AAO), and 2) high familial loading for vascular disease (VD), which should be strongest in MD cases with a late AAO. Methods: We examined 4785 twin pairs from the Swedish Twin Registry, assessed at a mean age of 54.0 (SD = 7.4), where both members of the pair were evaluated by interview and at least one member reported a lifetime history of modified DSM-IV MD. Risk for VD was assessed from hospital discharge information and death certificates. Results: Using Cox proportional hazard models and controlling for zygosity, age, and sex, early AAO in depressed twins predicted risk for MD in their cotwins, whereas late AAO predicted cotwin risk for VD. Using piecewise regression, the hazard ratio (HR) relating AAO per decade to risk for MD in cotwin was much stronger for AAO from 13-23 years (HR = .62) than for AAO 24-65 years (HR = 0.94). The HR relating AAO of MD in twin and risk for VD in cotwin was twice as strong for AAO from 47-65 years (HR = 1.17) as for AAO 13-46 years (1.08). Conclusions: From a familial/genetic perspective, MD is etiologically heterogeneous. Early and late onset MD are indexed, respectively, by the risk for MD and VD in relatives.