Schizophrenia: From genetics to physiology at last.

Abstract

The identification of a set of genetic variations that are strongly associated with the risk of developing schizophrenia provides insights into the neurobiology of this destructive disease. See Article p.177 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.