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 and Steven A. McCarroll ()
Additional contact information
Aswin Sekar: Harvard Medical School
Allison R. Bialas: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School
Heather de Rivera: Harvard Medical School
Avery Davis: Harvard Medical School
Timothy R. Hammond: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School
Nolan Kamitaki: Harvard Medical School
Katherine Tooley: Harvard Medical School
Jessy Presumey: Program in Cellular and Molecular Medicine, Boston Children’s Hospital
Matthew Baum: Harvard Medical School
Vanessa Van Doren: Harvard Medical School
Giulio Genovese: Harvard Medical School
Samuel A. Rose: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Robert E. Handsaker: Harvard Medical School
Mark J. Daly: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Michael C. Carroll: Program in Cellular and Molecular Medicine, Boston Children’s Hospital
Beth Stevens: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Steven A. McCarroll: Harvard Medical School

Nature, 2016, vol. 530, issue 7589, 177-183

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature16549

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