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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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined platelet mtDNA heteroplasmy for associations with depressive symptoms among 137 participants over age 70 from the community\u2010based Health, Aging and Body Composition Study. Depressive symptoms were assessed using the 10\u2010point version of the Center for Epidemiologic Studies Depression Scale (CES\u2010D 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 5 candidate complex I mtDNA mutations examined for effects on depressive symptoms, increased heteroplasmy at m.13514A&gt;G, <jats:italic>ND5<\/jats:italic>, was significantly associated with higher CES\u2010D score (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.01). A statistically significant interaction between m.13514A\u00a0&gt;\u00a0G heteroplasmy and sex was detected (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.04); in sex\u2010stratified analyses, the impact of m.13514A&gt;G heteroplasmy was stronger in male (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.003) than in female (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.98) participants. Men in highest tertile of mtDNA heteroplasmy exhibited significantly higher (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.0001) mean\u00a0\u00b1\u00a0SE CES\u2010D 10 scores, 5.37\u00a0\u00b1\u00a00.58, when compared with those in the middle, 2.13\u00a0\u00b1\u00a00.52, and lowest tertiles, 2.47\u00a0\u00b1\u00a00.58. No associations between the 4 other candidate sites and depressive symptoms were observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Increased mtDNA heteroplasmy at m.13514A&gt;G is associated with depressive symptoms in older men. Heteroplasmy may represent a novel biological risk factor for depression.<\/jats:p><\/jats:sec>","DOI":"10.1002\/gps.4928","type":"journal-article","created":{"date-parts":[[2018,7,9]],"date-time":"2018-07-09T04:29:12Z","timestamp":1531110552000},"page":"1319-1326","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mitochondrial <scp>DNA m.13514G&gt;A<\/scp> heteroplasmy is associated with depressive symptoms in the elderly"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5520-812X","authenticated-orcid":false,"given":"Gregory J.","family":"Tranah","sequence":"first","affiliation":[{"name":"California Pacific Medical Center Research Institute, San Francisco  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne E.","family":"Maglione","sequence":"additional","affiliation":[{"name":"University of California, San Diego Department of Psychiatry  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