Mitochondrial DNA m.13514G>A heteroplasmy is associated with depressive symptoms in the elderly

Objectives Mitochondrial DNA (mtDNA) heteroplasmy is a mixture of normal and mutated mtDNA molecules in a cell. High levels of heteroplasmy at several mtDNA sites in complex I lead to inherited neurological neurologic diseases and brain magnetic resonance imaging (MRI) abnormalities. Here, we test the hypothesis that mtDNA heteroplasmy at these complex I sites is associated with depressive symptoms in the elderly. Methods We examined platelet mtDNA heteroplasmy for associations with depressive symptoms among 137 participants over age 70 from the community‐based Health, Aging and Body Composition Study. Depressive symptoms were assessed using the 10‐point version of the Center for Epidemiologic Studies Depression Scale (CES‐D 10). Complete mtDNA sequencing was performed and heteroplasmy derived for 5 mtDNA sites associated with neurologic mitochondrial diseases and tested for associations with depressive symptoms. Results Of 5 candidate complex I mtDNA mutations examined for effects on depressive symptoms, increased heteroplasmy at m.13514A>G, ND5 , was significantly associated with higher CES‐D score ( P = .01). A statistically significant interaction between m.13514A > G heteroplasmy and sex was detected ( P = .04); in sex‐stratified analyses, the impact of m.13514A>G heteroplasmy was stronger in male ( P = .003) than in female ( P = .98) participants. Men in highest tertile of mtDNA heteroplasmy exhibited significantly higher ( P = .0001) mean ± SE CES‐D 10 scores, 5.37 ± 0.58, when compared with those in the middle, 2.13 ± 0.52, and lowest tertiles, 2.47 ± 0.58. No associations between the 4 other candidate sites and depressive symptoms were observed. Conclusions Increased mtDNA heteroplasmy at m.13514A>G is associated with depressive symptoms in older men. Heteroplasmy may represent a novel biological risk factor for depression.