Title: Schizophrenia risk from complex variation of complement component 4
year: 2016
Journal: Nature
Volume: 530
Issue: 7589
Pages: 177-83
Epubdate: 28/01/2016
date: 01/02/2011
Alternate Journal: Nature
ISSN: 0028-0836
Legal note: PMC4752392
PMCID: NIHMS746506
Article Number: 26814963
Keywords: Alleles Amino Acid Sequence Animals Axons/metabolism Base Sequence Brain/metabolism/pathology Complement C4/chemistry/*genetics Complement Pathway, Classical Dendrites/metabolism Gene Dosage/genetics Gene Expression Regulation/genetics Genetic Predisposition to Disease/*genetics Genetic Variation/*genetics Haplotypes/genetics Humans Major Histocompatibility Complex/genetics Mice Models, Animal Neuronal Plasticity/genetics/physiology Polymorphism, Single Nucleotide/genetics RNA, Messenger/analysis/genetics Risk Factors Schizophrenia/*genetics/pathology Synapses/metabolism
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.
Notes: 1476-4687 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 Schizophrenia Working Group of the Psychiatric Genomics Consortium Daly, Mark J Carroll, Michael C Stevens, Beth McCarroll, Steven A R01 MH077139/MH/NIMH NIH HHS/United States T32 GM007753/GM/NIGMS NIH HHS/United States T32 AI074549/AI/NIAID NIH HHS/United States R01 HG006855/HG/NHGRI NIH HHS/United States U01 MH105641/MH/NIMH NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nature. 2016 Feb 11;530(7589):177-83. doi: 10.1038/nature16549. Epub 2016 Jan 27.
URL: http://ovidsp.tx.ovid.com/ovftpdfs/FPDDNCGCBBEDDE00/fs047/ovft/live/gv024/00006056/00006056-201602110-00043.pdf
URI: https://open-access.imh.com.sg/handle/123456789/5020
Authors Address: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. MD-PhD Program, Harvard Medical School, Boston, Massachusetts 02115, USA. Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Database Provider: NLM
language: eng
Appears in Collections:2016

Files in This Item:
File Description SizeFormat 
Schizophrenia risk from complex variation of complement component 4.pdf5.92 MBAdobe PDFThumbnail
View/Open



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.