Schizophrenia risk from complex variation of complement component 4

Aswin Sekar, Allison R Bialas, Heather de Rivera, Avery Davis, Timothy R Hammond, Nolan Kamitaki, Katherine Tooley, Jessy Presumey, Matthew Baum, Vanessa Van Doren, Giulio Genovese, Samuel A Rose, Robert E Handsaker, Mark J Daly, Michael C Carroll, Beth Stevens, Steven A McCarroll, Schizophrenia Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to journalArticlepeer-review

1639 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)177-83
Number of pages7
Early online date27 Jan 2016
Publication statusPublished - 11 Feb 2016


  • Alleles
  • 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
  • RNA, Messenger
  • Risk Factors
  • Schizophrenia
  • Synapses


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