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COVID-19 outcomes were genetically correlated with 11 IDPs related to brain connectivity, cortical structures, and white matter. With respect to these, we also identified local genetic correlations within five loci mapping genes involved in inflammatory response, immune regulation, brain development, and neuropsychiatric disorders. We also identified 305 Bonferroni-significant gene ontologies (GO), highlighting the pleiotropy linking COVID-19 to brain structure and function through developmental processes (e.g., immune system development, leukocyte differentiation, and neurogenesis) and intracellular signaling (e.g., synaptic signaling and immune response regulation). Our drug-repurposing analysis uncovered 41 compounds, including approved drugs that could potentially influence both COVID-19 outcomes and brain-related disorders. For instance, chlorpromazine is an antipsychotic that appears to also have antiviral and immunomodulatory activity. Overall, the present findings contributed to dissecting the biological mechanisms shared between COVID-19 and brain structure and function, highlighting the systemic nature of their relationship.<\/jats:p>","DOI":"10.1101\/2025.11.03.25339411","type":"posted-content","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T21:25:18Z","timestamp":1762291518000},"source":"Crossref","is-referenced-by-count":0,"title":["Neuroimmune pleiotropy links COVID-19 outcomes to brain structural and functional imaging-derived phenotypes"],"prefix":"10.64898","author":[{"given":"Qianyu","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4729-9997","authenticated-orcid":false,"given":"Brenda","family":"Cabrera-Mendoza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0745-6046","authenticated-orcid":false,"given":"Renato","family":"Polimanti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025110601300638000_2025.11.03.25339411v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01576-9"},{"issue":"1","key":"2025110601300638000_2025.11.03.25339411v1.2","doi-asserted-by":"crossref","first-page":"19049","DOI":"10.1038\/s41598-024-69772-y","article-title":"Patients recovering from COVID-19 who presented with anosmia during their acute episode have behavioral, functional, and structural brain alterations","volume":"14","year":"2024","journal-title":"Scientific Reports"},{"key":"2025110601300638000_2025.11.03.25339411v1.3","doi-asserted-by":"crossref","first-page":"105792","DOI":"10.1016\/j.neubiorev.2024.105792","article-title":"COVID-19 is associated with changes in brain function and structure: A multimodal meta-analysis of neuroimaging studies","volume":"164","year":"2024","journal-title":"Neuroscience & Biobehavioral Reviews"},{"key":"2025110601300638000_2025.11.03.25339411v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-023-07236-3"},{"key":"2025110601300638000_2025.11.03.25339411v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04569-5 3"},{"key":"2025110601300638000_2025.11.03.25339411v1.6","doi-asserted-by":"crossref","unstructured":"Bendella Z , Widmann CN , Layer JP , Layer YL , Haase R , Sauer M et al. 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