Schizophrenia genetics complements its mechanistic understanding

Abstract

Refinement of genetic variants within the major histocompatibility complex reveals three distinct genetic influences on schizophrenia risk and sheds light on the disease’s neurobiology.

Figure 1

Careful refinement of the schizophrenia GWAS locus in the MHC revealed that structural alleles of the C4 locus increase schizophrenia risk. These structural alleles increase C4A RNA levels in human brain, which predict a subsequent increase in C3, increasing synaptic pruning. A mouse knockout of C4 demonstrated that C3 levels decreased and synaptic pruning in the visual system was disrupted, which may be consistent with the model whereby an increase in human C4A expression results in increased synaptic pruning in schizophrenia. Points of potential convergence of other influences that may increase risk for this complex condition, such as environment and other genetic influences, are also indicated. Marina Corral Spence/Nature Publishing Group