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Nature DOI:10.1038/nature16549

Schizophrenia risk from complex variation of complement component 4.

Publication TypeJournal Article
Year of Publication2016
AuthorsSekar, A, Bialas, AR, de Rivera, H, Davis, A, Hammond, TR, Kamitaki, N, Tooley, K, Presumey, J, Baum, M, Van Doren, V, Genovese, G, Rose, SA, Handsaker, RE, Daly, MJ, Carroll, MC, Stevens, B, McCarroll, SA
Corporate AuthorsSchizophrenia Working Group of the Psychiatric Genomics Consortium
Date Published2016 Feb 11
KeywordsAlleles, Amino Acid Sequence, Animals, Axons, Base Sequence, Brain, Complement C4, Complement Pathway, Classical, Dendrites, Gene Dosage, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Humans, Major Histocompatibility Complex, Mice, Models, Animal, Neuronal Plasticity, Polymorphism, Single Nucleotide, Risk Factors, RNA, Messenger, Schizophrenia, Synapses

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.


Alternate JournalNature
PubMed ID26814963
PubMed Central IDPMC4752392
Grant ListR01 MH077139 / MH / NIMH NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
T32 AI074549 / AI / NIAID NIH HHS / United States
R01 HG006855 / HG / NHGRI NIH HHS / United States
R01 MH042191 / MH / NIMH NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
G0901310 / / Medical Research Council / United Kingdom
U01 MH105641 / MH / NIMH NIH HHS / United States
PDA/02/06/016 / / Department of Health / United Kingdom
MR/L010305/1 / / Medical Research Council / United Kingdom
G0800509 / / Medical Research Council / United Kingdom