A study published in Nature (2016) reveals that schizophrenia risk is linked to complex variations in the complement component 4 (C4) gene within the Major Histocompatibility Complex (MHC) locus. The research identifies multiple structurally diverse C4 alleles that influence C4A and C4B expression levels in the brain, with higher expression of C4A correlating with increased schizophrenia risk. C4 proteins are localized at neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediates synapse elimination during postnatal development, suggesting excessive complement activity may contribute to schizophrenia pathogenesis. The study also shows that C4A expression levels are elevated in brain tissues of schizophrenia patients. C4 is expressed by neurons and secreted, and it promotes synapse elimination during brain development. The findings suggest that C4 may work with other components of the classical complement cascade to promote synaptic pruning, which could explain the reduced synapse numbers in schizophrenia patients. The study highlights the complex genetic architecture of schizophrenia and the potential role of C4 in its pathogenesis.A study published in Nature (2016) reveals that schizophrenia risk is linked to complex variations in the complement component 4 (C4) gene within the Major Histocompatibility Complex (MHC) locus. The research identifies multiple structurally diverse C4 alleles that influence C4A and C4B expression levels in the brain, with higher expression of C4A correlating with increased schizophrenia risk. C4 proteins are localized at neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediates synapse elimination during postnatal development, suggesting excessive complement activity may contribute to schizophrenia pathogenesis. The study also shows that C4A expression levels are elevated in brain tissues of schizophrenia patients. C4 is expressed by neurons and secreted, and it promotes synapse elimination during brain development. The findings suggest that C4 may work with other components of the classical complement cascade to promote synaptic pruning, which could explain the reduced synapse numbers in schizophrenia patients. The study highlights the complex genetic architecture of schizophrenia and the potential role of C4 in its pathogenesis.