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Over-expression of <jats:italic>C4A<\/jats:italic> has been observed in SZ postmortem brain tissue, and the gene encoding for a protein inhibitor of C4A activity, CUB and Sushi multiple domains 1 (<jats:italic>CSMD1<\/jats:italic>) gene, has been implicated in SZ risk and cognitive ability. Herein, we examined <jats:italic>C4A<\/jats:italic> and <jats:italic>CSMD1<\/jats:italic> mRNA expression in peripheral blood from antipsychotic-naive individuals with first-episode psychosis (FEP; <jats:italic>n<\/jats:italic>\u2009=\u200973) and mentally healthy volunteers (<jats:italic>n<\/jats:italic>\u2009=\u200948). Imputed <jats:italic>C4<\/jats:italic> locus structural alleles and C4A serum protein levels were investigated. Associations with symptom severity and cognitive domains performance were explored. A significant decrease in <jats:italic>CSMD1<\/jats:italic> expression levels was noted among FEP patients compared to healthy volunteers, further indicating a positive correlation between <jats:italic>C4A<\/jats:italic> and <jats:italic>CSMD1<\/jats:italic> mRNA levels in healthy volunteers but not in FEP cases. In addition, <jats:italic>C4<\/jats:italic> copy number variants previously associated with SZ risk correlated with higher <jats:italic>C4A<\/jats:italic> mRNA levels in FEP cases, which confirms the regulatory effect of <jats:italic>C4<\/jats:italic> structural variants on gene expression. Evidence also emerged for markedly elevated C4A serum concentrations in FEP cases. Within the FEP patient group, higher <jats:italic>C4A<\/jats:italic> mRNA levels correlated with more severe general psychopathology symptoms and lower <jats:italic>CSMD1<\/jats:italic> mRNA levels predicted worse working memory performance. Overall, these findings suggest C4A complement pathway perturbations in individuals with FEP and corroborate the involvement of <jats:italic>CSMD1<\/jats:italic> in prefrontal-mediated cognitive functioning.<\/jats:p>","DOI":"10.1007\/s00406-022-01409-5","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T10:02:56Z","timestamp":1652090576000},"page":"1219-1228","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability"],"prefix":"10.1007","volume":"272","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0291-1399","authenticated-orcid":false,"given":"Alex","family":"Hatzimanolis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Foteli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pentagiotissa","family":"Stefanatou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeliki-Aikaterini","family":"Ntigrintaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Ralli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Kollias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrysoula","family":"Nikolaou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gazouli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikos C.","family":"Stefanis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,9]]},"reference":[{"key":"1409_CR1","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1093\/schbul\/sby024","volume":"44","author":"N Muller","year":"2018","unstructured":"Muller N (2018) Inflammation in schizophrenia: pathogenetic aspects and therapeutic considerations. 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