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The neurotropic herpesvirus, human cytomegalovirus (HCMV), is a major cause of white matter pathology in immunosuppressed populations but its relationship with FA has never been tested in MDD despite the presence of inflammation and weakened antiviral immunity in a subset of depressed patients. We tested the relationship between FA and HCMV infection in two independent samples consisting of 176 individuals with MDD and 44 healthy controls (HC) (Discovery sample) and 88 participants with MDD and 48 HCs (Replication sample). Equal numbers of HCMV positive (HCMV+) and HCMV negative (HCMV\u2212) groups within each sample were balanced on ten different clinical\/demographic variables using propensity score matching. Anti-HCMV IgG antibodies were measured using a solid-phase ELISA. In the Discovery sample, significantly lower FA was observed in the right inferior fronto-occipital fasciculus (IFOF) in HCMV+ participants with MDD compared to HCMV\u2212 participants with MDD (cluster size 1316\u2009mm<jats:sup>3<\/jats:sup>;<jats:italic>p<\/jats:italic><jats:sub>FWE<\/jats:sub>\u2009&lt;\u20090.05,<jats:italic>d<\/jats:italic>\u2009=\u2009\u22120.58). This association was confirmed in the replication sample by extracting the mean FA from this exact cluster and applying the identical statistical model (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05,<jats:italic>d<\/jats:italic>\u2009=\u2009\u22120.45). There was no significant effect of diagnosis or interaction between diagnosis and HCMV in either sample. The effect of chronic HCMV infection on white matter integrity may\u2014in at-risk individuals\u2014contribute to the psychopathology of depression. These findings may provide a novel target of intervention for a subgroup of patients with MDD.<\/jats:p>","DOI":"10.1038\/s41386-021-00971-1","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T21:20:07Z","timestamp":1611696007000},"page":"928-938","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Replicable association between human cytomegalovirus infection and reduced white matter fractional anisotropy in major depressive disorder"],"prefix":"10.1038","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5262-6676","authenticated-orcid":false,"given":"Haixia","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Bergamino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6269-0735","authenticated-orcid":false,"given":"Bart N.","family":"Ford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayus","family":"Kuplicki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-Cheng","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerzy","family":"Bodurka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiping","family":"Burrows","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Tulsa 1000 Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Aupperle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerzy","family":"Bodurka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Feinstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahib S.","family":"Khalsa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin P.","family":"Paulus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Savitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa A.","family":"Victor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W.","family":"Hunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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