Accepted author manuscript, 47.3 MB, multipart/x-zip
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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Schizophrenia risk from complex variation of complement component 4
AU - Sekar, Aswin
AU - Bialas, Allison R.
AU - de Rivera, Heather
AU - Davis, Avery
AU - Hammond, Timothy R.
AU - Kamitaki, Nolan
AU - Tooley, Katherine
AU - Presumey, Jessy
AU - Baum, Matthew
AU - Van Doren, Vanessa
AU - Genovese, Giulio
AU - Rose, Samuel A.
AU - Handsaker, Robert E.
AU - Daly, Mark J.
AU - Carroll, Michael C.
AU - Stevens, Beth
AU - McCarroll, Steven A.
AU - Knight, Jo
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium
PY - 2016/2/11
Y1 - 2016/2/11
N2 - 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.
AB - 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.
KW - Alleles
KW - Amino Acid Sequence
KW - Animals
KW - Axons
KW - Base Sequence
KW - Brain
KW - Complement C4
KW - Complement Pathway, Classical
KW - Dendrites
KW - Gene Dosage
KW - Gene Expression Regulation
KW - Genetic Predisposition to Disease
KW - Genetic Variation
KW - Haplotypes
KW - Humans
KW - Major Histocompatibility Complex
KW - Mice
KW - Models, Animal
KW - Neuronal Plasticity
KW - Polymorphism, Single Nucleotide
KW - RNA, Messenger
KW - Risk Factors
KW - Schizophrenia
KW - Synapses
U2 - 10.1038/nature16549
DO - 10.1038/nature16549
M3 - Journal article
C2 - 26814963
VL - 530
SP - 177
EP - 183
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7589
ER -