{"doi":"10.1038/s41398-021-01583-5","title":"Increased activation product of complement 4 protein in plasma of individuals with schizophrenia","abstract":"Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood-brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean = 654 ± 16 ng/mL, 557 ± 94 respectively, p = 0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.","journal":"Translational Psychiatry","year":2021,"id":173762,"datarank":0.48283137373023016,"base_score":3.2188758248682006,"endowment":3.2188758248682006,"self_citation_contribution":0.48283137373023016,"citation_network_contribution":0.0,"self_endowment_contribution":0.48283137373023016,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9441,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":712490,"name":"Joanna Liliental","orcid":null,"position":1,"is_corresponding":false},{"id":431859,"name":"Lauren Anker","orcid":"0000-0002-6153-217X","position":2,"is_corresponding":false},{"id":711866,"name":"Omer Linkovski","orcid":"0000-0001-7765-4414","position":3,"is_corresponding":false},{"id":545436,"name":"Collin Culbertson","orcid":"0000-0002-9814-6811","position":4,"is_corresponding":false},{"id":344307,"name":"Jacob Hall","orcid":"0000-0002-9740-8955","position":5,"is_corresponding":false},{"id":21460,"name":"Reenal Pattni","orcid":"0000-0003-4490-731X","position":6,"is_corresponding":false},{"id":29320,"name":"Chiara Sabatti","orcid":"0000-0001-5829-9058","position":7,"is_corresponding":false},{"id":711867,"name":"Douglas L. Noordsy","orcid":"0000-0002-9538-5016","position":8,"is_corresponding":false},{"id":21406,"name":"Joachim Hallmayer","orcid":"0000-0002-8520-4939","position":9,"is_corresponding":false},{"id":350837,"name":"Elizabeth Mellins","orcid":"0000-0003-2577-139X","position":10,"is_corresponding":false},{"id":661813,"name":"Jacob S. Ballon","orcid":"0000-0002-6157-4847","position":11,"is_corresponding":false},{"id":431862,"name":"Ruth O’Hara","orcid":"0000-0001-6583-4995","position":12,"is_corresponding":false},{"id":5362,"name":"Douglas F. Levinson","orcid":"0000-0001-8223-1301","position":13,"is_corresponding":false},{"id":20014,"name":"Alexander E. Urban","orcid":"0000-0001-9772-933X","position":14,"is_corresponding":false},{"id":711865,"name":"Agnieszka Kalinowski","orcid":"0000-0002-7678-4337","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:46:49.903770Z","pmid":"34552056","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}