The most strongly linked common genetic variation to schizophrenia was identified through GWAS and resides within the major histocompatibility complex (MHC) region (e.g., rs115329265 OR=1.21, p≈2.48e−31) (Schizophrenia Working Group of the Psychiatric Genomics, 2014). Seven years following the initial identification of this region for schizophrenia (International Schizophrenia et al., 2009), Sekar and colleagues (2016) distilled the MHC genetic signal, in part, to complex structural variation within the complement component 4 gene (C4) (Sekar et al., 2016). C4 is a component of the innate immune system’s non-specific defense against foreign pathogens, and cellular debris that has also been implicated in the pruning of synapses. These researchers also showed that C4 variation altered brain C4 expression proportional to schizophrenia risk and that C4 mediated synaptic pruning during postnatal development in mice. Collectively, these results suggest that the MHC genetic signal for schizophrenia may be partially attributable to variability in C4-related synaptic pruning, which ultimately may be leveraged for treatment and/or prevention.
