This study investigates the genetic association between schizophrenia and the Major Histocompatibility Complex (MHC) locus, focusing on the complement component 4 (C4) genes. The authors found that the association between schizophrenia and the MHC locus is largely explained by structurally diverse alleles of the C4 genes, which affect the expression of C4A and C4B proteins in the brain. These alleles are associated with schizophrenia risk in proportion to their tendency to promote greater expression of C4A. Human C4 protein is localized at neuronal synapses, and its expression is influenced by C4-HERV sequences. The study also demonstrates that C4 plays a role in synaptic pruning during the development of neuronal circuits, suggesting a potential mechanism for the observed synapse loss in schizophrenia. The findings highlight the importance of C4 in the pathogenesis of schizophrenia and provide insights into the genetic and molecular mechanisms underlying this complex disorder.This study investigates the genetic association between schizophrenia and the Major Histocompatibility Complex (MHC) locus, focusing on the complement component 4 (C4) genes. The authors found that the association between schizophrenia and the MHC locus is largely explained by structurally diverse alleles of the C4 genes, which affect the expression of C4A and C4B proteins in the brain. These alleles are associated with schizophrenia risk in proportion to their tendency to promote greater expression of C4A. Human C4 protein is localized at neuronal synapses, and its expression is influenced by C4-HERV sequences. The study also demonstrates that C4 plays a role in synaptic pruning during the development of neuronal circuits, suggesting a potential mechanism for the observed synapse loss in schizophrenia. The findings highlight the importance of C4 in the pathogenesis of schizophrenia and provide insights into the genetic and molecular mechanisms underlying this complex disorder.