Journal Article

Schizophrenia risk from complex variation of complement component 4

Davis, Avery, Van Doren, Vanessa, Kamitaki, Nolan, Bialas, Allison R., Tooley, Katherine, Daly, Mark J., de Rivera, Heather, Genovese, Giulio, Hammond, Timothy R., Presumey, Jessy, Baum, Matthew, Handsaker, Robert E., McCarroll, Steven A., Carroll, Michael C., Stevens, Beth, Sekar, Aswin, Rose, Samuel A.

2016

Overview

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. WebSchizophrenia is associated with genetic variation at the major histocompatibility complex locus; this study reveals that alleles at this locus associate with schizophrenia in proportion to their tendency to generate greater expression of complement component 4 ( C4A ) genes and that C4 promotes the elimination of synpases. The genetics of schizophrenia The strongest genetic association found in schizophrenia is its association to genetic markers across the major histocompatibility complex (MHC) locus, first described in three Nature papers in 2009. The association signal at the MHC is extremely complex. Here Steven McCarroll and colleagues report a dissection of the MHC association to schizophrenia. They find a strong contribution from many structurally diverse alleles of the complement component 4 ( C4 ) genes. The linkage was higher for C4 alleles that promoted greater expression of C4A , measured in the brain tissues of adult post-mortem donors with or without schizophrenia. The authors suggest that C4 may work with other components of the classical complement cascade to promote synaptic pruning, and demonstrate that C4 mediates synaptic refinement in a mouse model.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208 / 631/208/457/649/2157 / 631/208/728 / 631/378/2571/2577 / Alleles / Amino Acid Sequence / Analysis / Animals / Antigens / Axons - metabolism / Base Sequence / Binding sites / Brain / Brain - metabolism / Brain - pathology / Chromosomes / Complement (Immunology) / Complement C4 - chemistry / Complement C4 - genetics / Complement Pathway, Classical / Dendrites - metabolism / Development and progression / Gene Dosage - genetics / Gene expression / Gene Expression Regulation - genetics / Genes / Genetic aspects / Genetic Predisposition to Disease - genetics / Genetic Variation - genetics / Genomes / Haplotypes / Haplotypes - genetics / Health aspects / Humanities and Social Sciences / Humans / Major Histocompatibility Complex - genetics / Mental disorders / Mice / Models, Animal / multidisciplinary / Neuronal Plasticity - genetics / Neuronal Plasticity - physiology / Polymorphism, Single Nucleotide - genetics / Proteins / Risk Factors / RNA, Messenger - analysis / RNA, Messenger - genetics / Schizophrenia / Schizophrenia - genetics / Schizophrenia - pathology / Science / Synapses - metabolism