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 recognize. We show here that schizophrenia’s association with the MHC locus arises in substantial part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles promoted widely varying levels of C4A and C4B expression and associated with schizophrenia in proportion to their tendency to promote greater expression of C4A in the brain. Human C4 protein localized at 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 affected with schizophrenia.

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…Given their role in immune surveillance and debris clearance, it is perhaps unsurprising that microglial activation in particular has been implicated in neurodegenerative diseases beyond Alzheimer's disease, including multiple sclerosis and Parkinson's disease (Chung et al, 2015b;Heneka et al, 2015;Hong et al, 2016). As evidence accumulates positioning glia as critical for synapse maturity and elimination, many have speculated that glia and immune signaling are associated with many neuropsychiatric disorders, from stress-related conditions such as depression (Hodes et al, 2015;Miller and Raison, 2015), to neurodevelopmental disorders such as autism and schizophrenia (Gupta et al, 2014;Sekar et al, 2016;Werling et al, 2016). Here, we propose that microglia and astrocytes have an important yet largely unexplored role in the development and maintenance of drug addiction.…”

Joint Effects of Exposure to Prenatal Infection and Peripubertal Psychological Trauma in Schizophrenia

“…Schizophrenia and infectious diseases have been associated with genetic markers in the human leukocyte antigens and the complement system, 46,47 and previous studies have indicated interaction between family history of psychosis and exposure to infection. 19,30,34 We therefore explored the pattern of results for individuals with and without a family history of psychiatric disorders to investigate whether they could be explained by genetic vulnerability in these individuals, and found no support for this alternative hypothesis.…”

10 Years of GWAS Discovery: Biology, Function, and Translation

“…Notably, the last 5 years have witnessed some clever laboratory experiments that have followed up on GWAS association, and these have led to the discovery of the target gene, for example, the targets of the associations between FTO (MIM: 610966) and obesity (MIM: 601665) 64 and between the major histocompatibility complex (MHC) and schizophrenia. 65 Performing similar or new laboratory experiments for many loci could be possible but would be time consuming and expensive.…”

“…The position of the association signal within the MHC region led to investigation of common structural haplotypes of complement factor 4 genes C4A (MIM: 120810) and C4B (MIM: 120820), combinations of which correlated well with schizophrenia risk and increased C4 expression and showed differential brain expression between case and control individuals. 65 Several other complement proteins play a role in synapse elimination, and decreased numbers of synapses have long been suggested as a primary abnormality in schizophrenia. Observations that, in mice, a complement gene that shares features with human C4A and C4B is expressed in neurons and promoted synapse elimination in a developmental brain circuit strongly implicate this gene and its protein.…”