Schizophrenia risk from complex variation of complement component 4

Sekar, Aswin, Bialas, Allison R., de Rivera, Heather, Davis, Avery, Hammond, Timothy R., Kamitaki, Nolan, Tooley, Katherine, Presumey, Jessy, Baum, Matthew, Van Doren, Vanessa, Genovese, Giulio, Rose, Samuel A., Handsaker, Robert E., Daly, Mark J., Carroll, Michael C., Stevens, Beth, McCarroll, Steven A., Schizophrenia Working Group of the Psychiatric Genomics Consortium and Mowry, Bryan (2016) Schizophrenia risk from complex variation of complement component 4. Nature, 530 7589: 177-183. doi:10.1038/nature16549


Author Sekar, Aswin
Bialas, Allison R.
de Rivera, Heather
Davis, Avery
Hammond, Timothy R.
Kamitaki, Nolan
Tooley, Katherine
Presumey, Jessy
Baum, Matthew
Van Doren, Vanessa
Genovese, Giulio
Rose, Samuel A.
Handsaker, Robert E.
Daly, Mark J.
Carroll, Michael C.
Stevens, Beth
McCarroll, Steven A.
Schizophrenia Working Group of the Psychiatric Genomics Consortium
Mowry, Bryan
Title Schizophrenia risk from complex variation of complement component 4
Journal name Nature   Check publisher's open access policy
ISSN 1476-4687
0028-0836
Publication date 2016-02-01
Year available 2016
Sub-type Article (original research)
DOI 10.1038/nature16549
Open Access Status Not yet assessed
Volume 530
Issue 7589
Start page 177
End page 183
Total pages 7
Place of publication LONDON
Publisher Nature Publishing Group
Language eng
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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 HG 006855
U01 MH105641
R01 MH077139
T32 GM007753
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
 
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