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In our analyses, COVID-19 outcomes showed evidence of polygenic overlap with respect to 11 imaging-derived phenotypes (IDPs) related to brain structure (e.g. parahippocampal and entorhinal cortical thickness) and connectivity (e.g. Broca\u2019s area and dorsolateral prefrontal cortex). Among these, the genetic liability to COVID-19 hospitalization and SARS-CoV-2 infection was inversely related to the area of pars opercularis. We also identified local genetic correlations between COVID-19 outcomes and brain IDPs within five loci mapping genes involved in inflammatory response, immune regulation, brain development, and neuropsychiatric disorders (e.g. LAMP3, SOX2, and TSHZ2). Additionally, we uncovered colocalized variants linking COVID-19 outcomes to brain structural variation (rs13107325 with entorhinal mean thickness) and brain transcriptomic regulation of immune-related genes (e.g. IL6R in brain cortex and HLA-C in caudate basal ganglia). Our drug-repurposing analysis based on gene ontologies shared between COVID-19 outcomes and brain IDPs uncovered 41 compounds, including psychiatric medications that appear to also have antiviral and immunomodulatory activity. Overall, the present findings contributed to dissecting the biological mechanisms shared between COVID-19 and brain variation, highlighting the systemic nature of their relationship.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag372","type":"journal-article","created":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T11:37:52Z","timestamp":1791027472000},"source":"Crossref","is-referenced-by-count":0,"title":["COVID-19 pleiotropy with brain imaging-derived phenotypes highlights novel insights into the biology shared between immune function and brain variation"],"prefix":"10.1093","volume":"8","author":[{"given":"Qianyu","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"University of Connecticut , Storrs, CT 06269 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Ethics, Karolinska Institutet , Stockholm, S-171 77 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0877-5488","authenticated-orcid":false,"given":"Ziang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Veterans Affairs Connecticut Healthcare Center Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), , West Haven, CT 06516 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