Abstract

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.

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Acknowledgements

The authors would like to remember the late T. Stanley with appreciation and express their gratitude for his support. We thank S. Hyman, E. Lander, C. Bargmann, and C. Patil for conversations about the project and comments on drafts of the manuscript; M. Webster for expert advice on immunohistochemistry; B. Browning for expert advice on imputation; the Stanley Medical Research Institute Brain Collection and the NHGRI Gene and Tissue Expression (GTEx) Project for access to RNA and tissue samples; C. Emba for assistance with experiments; and C. Usher for contributions to manuscript figures. This work was supported by R01 HG 006855 (to S.A.M.), by the Stanley Center for Psychiatric Research (to S.A.M. and B.S.), by U01 MH105641 (to S.A.M.), by R01 MH077139 (to the PGC), and by T32 GM007753 (to A.S. and M.B.).

Author information

Affiliations

  1. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Aswin Sekar
    • , Heather de Rivera
    • , Avery Davis
    • , Nolan Kamitaki
    • , Katherine Tooley
    • , Matthew Baum
    • , Vanessa Van Doren
    • , Giulio Genovese
    • , Robert E. Handsaker
    •  & Steven A. McCarroll
  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Aswin Sekar
    • , Heather de Rivera
    • , Avery Davis
    • , Nolan Kamitaki
    • , Katherine Tooley
    • , Matthew Baum
    • , Giulio Genovese
    • , Samuel A. Rose
    • , Robert E. Handsaker
    • , Mark J. Daly
    • , Beth Stevens
    •  & Steven A. McCarroll
  3. MD-PhD Program, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Aswin Sekar
    •  & Matthew Baum
  4. Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Allison R. Bialas
    • , Timothy R. Hammond
    • , Matthew Baum
    •  & Beth Stevens
  5. Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, Massachusetts 02115, USA

    • Allison R. Bialas
    • , Jessy Presumey
    •  & Michael C. Carroll
  6. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Mark J. Daly

Consortia

  1. Schizophrenia Working Group of the Psychiatric Genomics Consortium

    Lists of participants and their affiliations appear in the Supplementary Information.

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Contributions

S.A.M. and A.S. conceived the genetic studies. A.S. performed the laboratory experiments and computational analyses to understand the molecular and population genetics of the C4 locus (Figs 1 and 2). A.S., K.T., N.K., and V.V.D. analysed C4 expression variation in human brain (Figs 3 and 5b, d). G.G., R.E.H., and S.A.R. contributed to genetic analyses. A.S. and A.D. did the imputation and association analysis (Figs 4 and 5a, c). M.J.D. provided advice on the association analyses. Investigators in the Schizophrenia Working Group of the Psychiatric Genomics Consortium collected and phenotyped cohorts and contributed genotype data for analysis. B.S. and M.C.C. contributed expertise and reagents for experiments described in Fig. 6 and 7. H.d.R and T.R.H. performed the C4 immunocytochemistry and immunohistochemistry experiments respectively, with advice from A.R.B. (Fig. 6). A.R.B. and J.P. analysed the role of C4 in synaptic refinement in the mouse visual system (Fig. 7). M.B. analysed C4 expression in mice. S.A.M and A.S. wrote the manuscript with contributions from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Steven A. McCarroll.

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    Supplementary Information

    This file contains Supplementary Methods, Supplementary Tables 1-3, a full list of the collaborators from the PGC Schizophrenia Working Group and additional references. This file was replaced on 11 April 2016 to update affiliation 210.

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https://doi.org/10.1038/nature16549

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