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Quantitative susceptibility mapping (QSM) MRI has recently linked altered subcortical magnetic susceptibility (\u03c7) to schizophrenia. Since \u03c7 is increased by iron and decreased by myelin, abnormal levels of either could underlie these QSM differences. In white matter tracts, magnetic susceptibility anisotropy (\u03b4\u03c7) serves as a myelin-specific marker that is insensitive to iron content. To clarify the origin of case-control \u03c7 differences, we employed QSM in 85 individuals with schizophrenia, from first-episode mental health teams, and 86 healthy controls. A subset also underwent diffusion tensor imaging (DTI) to calculate subcortical tissue mean diffusivity, which inversely correlates with myelin concentration and fractional anisotropy. White matter \u03b4\u03c7 was calculated by combining QSM and DTI. Schizophrenia was associated with lower subcortical \u03c7 (d\u2009=\u2009\u22120.36, p\u2009=\u20090.023). This was significant in the caudate nucleus (d\u2009=\u2009\u22120.37, p\u2009=\u20090.037), putamen (d\u2009=\u2009\u22120.36, p\u2009=\u20090.037), globus pallidus (d\u2009=\u2009\u22120.57, p\u2009=\u20090.001), and SN-VTA (as previously reported). Additionally, schizophrenia was linked to higher subcortical mean diffusivity (d\u2009=\u20090.44, p\u2009=\u20090.018), and lower white matter \u03b4\u03c7 (d\u2009=\u2009\u22120.37, p\u2009=\u20090.047). These findings suggest that both subcortical iron and brain myelin levels are lower in schizophrenia. By comparing our voxelwise \u03c7 maps with postmortem gene expression data, we reveal that regions with lower subcortical \u03c7 in schizophrenia are enriched for oligodendrocyte-related genes (p\u2009&lt;\u20090.001). As oligodendrocytes are both the most iron-rich brain cells and essential for myelin synthesis, our results implicate oligodendrocyte dysfunction in schizophrenia pathophysiology.<\/jats:p>","DOI":"10.1038\/s41380-025-03195-7","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T15:10:20Z","timestamp":1757085020000},"page":"941-952","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The role of low subcortical iron, white matter myelin, and oligodendrocytes in schizophrenia: a quantitative susceptibility mapping and diffusion tensor imaging study"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1624-490X","authenticated-orcid":false,"given":"Luke J.","family":"Vano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"McCutcheon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Sedlacik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Rutigliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0194-0806","authenticated-orcid":false,"given":"Stephen J.","family":"Kaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1026-4626","authenticated-orcid":false,"given":"Valeria","family":"Finelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Lobo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6049-4418","authenticated-orcid":false,"given":"Alaine","family":"Berry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5118-7977","authenticated-orcid":false,"given":"Ben","family":"Statton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Fazlollahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian P.","family":"Everall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2928-1972","authenticated-orcid":false,"given":"Oliver D.","family":"Howes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,5]]},"reference":[{"key":"3195_CR1","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1001\/jamapsychiatry.2019.3360","volume":"77","author":"RA McCutcheon","year":"2020","unstructured":"McCutcheon RA, Reis Marques T, Howes OD. 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Dr. McCutcheon has received speaker\/consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and co-directs a company that designs digital resources to support treatment of mental illness. Dr. Rutigliano is supported by the EU Horizon 2020 Research and Innovation Program under Marie Sk\u0142odowska-Curie grant agreement 101026235 and by Guarantors of Brain with a Post-Doctoral Clinical Fellowship, and has been a consultant for Sumitomo Pharma. Dr. Howes has received investigator-initiated research funding from and\/or participated in advisory\/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neurocrine, Ontrack\/Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris\/Mylan. He was previously a part-time employee of Lundbeck A\/v. Dr Howes has a patent for the use of dopaminergic imaging. All other authors report no biomedical financial interests or potential conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The Office for Research Ethics Northern Ireland approved data collection for people with schizophrenia as part of a clinical study (19\/NI\/0098; NCT04038957), and the London Dulwich Research Ethics Committee approved data collection for healthy controls (21\/LO\/0312). This paper only presents baseline data. Written informed consent was obtained from all participants, and recruitment and study procedures were approved by the institutional review boards at each participating site.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"One participant provided potentially identifiable images and gave written informed consent for their publication in this article.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}