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Schizophrenia risk from complex variation of complement component 4

Sekar, Aswin and Bialas, Allison R. and de Rivera, Heather and Davis, Avery and Hammond, Timothy R. and Kamitaki, Nolan and Tooley, Katherine and Presumey, Jessy and Baum, Matthew and Van Doren, Vanessa and Genovese, Giulio and Rose, Samuel A. and Handsaker, Robert E. and Daly, Mark J. and Carroll, Michael C. and Stevens, Beth and McCarroll, Steven A. and Knight, Jo and , Schizophrenia Working Group of the Psychiatric Genomics Consortium (2016) Schizophrenia risk from complex variation of complement component 4. Nature, 530 (7589). pp. 177-183. ISSN 0028-0836

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    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.

    Item Type: Article
    Journal or Publication Title: Nature
    Uncontrolled Keywords: Alleles ; Amino Acid Sequence ; Animals ; Axons ; Base Sequence ; Brain ; Complement C4 ; Complement Pathway, Classical ; Dendrites ; Gene Dosage ; Gene Expression Regulation ; Genetic Predisposition to Disease ; Genetic Variation ; Haplotypes ; Humans ; Major Histocompatibility Complex ; Mice ; Models, Animal ; Neuronal Plasticity ; Polymorphism, Single Nucleotide ; RNA, Messenger ; Risk Factors ; Schizophrenia ; Synapses
    Subjects:
    Departments: Faculty of Health and Medicine > Medicine
    ID Code: 80067
    Deposited By: ep_importer_pure
    Deposited On: 22 Jul 2016 08:58
    Refereed?: Yes
    Published?: Published
    Last Modified: 18 Dec 2017 07:52
    Identification Number:
    URI: http://eprints.lancs.ac.uk/id/eprint/80067

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