title: Schizophrenia risk from complex variation of complement component 4.
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.
authors.affiliation: 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.
authors.forename: Aswin
authors.initials: A
authors.lastname: Sekar
authors.affiliation: 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.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Bialas
authors.affiliation: 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.
authors.forename: Heather
authors.initials: H
authors.lastname: de Rivera
authors.affiliation: 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.
authors.forename: Avery
authors.initials: A
authors.lastname: Davis
authors.affiliation: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hammond
authors.affiliation: 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.
authors.forename: Nolan
authors.initials: N
authors.lastname: Kamitaki
authors.affiliation: 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.
authors.forename: Katherine
authors.initials: K
authors.lastname: Tooley
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Jessy
authors.initials: J
authors.lastname: Presumey
authors.affiliation: 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.
authors.forename: Matthew
authors.initials: M
authors.lastname: Baum
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Van Doren
authors.affiliation: 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.
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Rose
authors.affiliation: 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.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Handsaker
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Stevens
authors.affiliation: 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.
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000378:metabolism; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003181:Complement C4 / Q000737:chemistry / Q000235:genetics*; D003171:Complement Pathway, Classical; D003712:Dendrites / Q000378:metabolism; D018628:Gene Dosage / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D051379:Mice; D023421:Models, Animal; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D013569:Synapses / Q000378:metabolism
chemical_list: D003181:Complement C4; D012333:RNA, Messenger
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