Schizophrenia risk from complex variation of complement component 4

Sekar, Aswin; Bialas, Allison R.; Genovese, Giulio; Rose, Samuel A.; Handsaker, Robert E.; Schizophrenia Working Group of the Psychiatric Genomics Consortium,; Daly, Mark J.; Carroll, Michael C.; Stevens, Beth; McCarroll, Steven A.; Tooney, Paul A.; Henskens, Frans A.; de Rivera, Heather; Michie, Patricia; Schall, Ulrich; Loughland, Carmel; Cairns, Murray J.; Kelly, Brian J.; Scott, Rodney; Davis, Avery; Hammond, Timothy R.; Kamitaki, Nolan; Tooley, Katherine; Presumey, Jessy; Baum, Matthew; Van Doren, Vanessa

Title: Schizophrenia risk from complex variation of complement component 4
Creator: Sekar, Aswin; Bialas, Allison R.; Genovese, Giulio; Rose, Samuel A.; Handsaker, Robert E.; Schizophrenia Working Group of the Psychiatric Genomics Consortium,; Daly, Mark J.; Carroll, Michael C.; Stevens, Beth; McCarroll, Steven A.; Tooney, Paul A.; Henskens, Frans A.; de Rivera, Heather; Michie, Patricia; Schall, Ulrich; Loughland, Carmel; Cairns, Murray J.; Kelly, Brian J.; Scott, Rodney; Davis, Avery; Hammond, Timothy R.; Kamitaki, Nolan; Tooley, Katherine; Presumey, Jessy; Baum, Matthew; Van Doren, Vanessa
Relation: Nature Vol. 530, Issue 7589, p. 177-183
Publisher Link: http://dx.doi.org/10.1038/nature16549
Publisher: Nature Publishing Group
Resource Type: journal article
Date: 2016
Description: 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.
Subject: genetics; synaptic development; haplotypes; structural variation
Identifier: http://hdl.handle.net/1959.13/1347504
Identifier: uon:30050
Identifier: ISSN:0028-0836
Language: eng
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