Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the Major Histocompatibility Complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to recognize. We show here that schizophrenia’s association with the MHC locus arises in substantial part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles promoted widely varying levels of C4A and C4B expression and associated with schizophrenia in proportion to their tendency to promote greater expression of C4A in the brain. Human C4 protein localized at neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals affected with schizophrenia.

The mammalian brain is composed of diverse, specialized cell populations. To systematically ascertain and learn from these cellular specializations, we used Drop-seq to profile RNA expression in 690,000 individual cells sampled from 9 regions of the adult mouse brain. We identified 565 transcriptionally distinct groups of cells using computational approaches developed to distinguish biological from technical signals. Cross-region analysis of these 565 cell populations revealed features of brain organization, including a gene-expression module for synthesizing axonal and presynaptic components, patterns in the co-deployment of voltage-gated ion channels, functional distinctions among the cells of the vasculature and specialization of glutamatergic neurons across cortical regions. Systematic neuronal classifications for two complex basal ganglia nuclei and the striatum revealed a rare population of spiny projection neurons. This adult mouse brain cell atlas, accessible through interactive online software (DropViz), serves as a reference for development, disease, and evolution.

Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjögren’s syndrome affect nine times more women than men 1 , whereas schizophrenia affects men more frequently and severely 2 . All three illnesses have their strongest common genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen ( HLA ) genes at that locus 3 – 6 . Here we show that the complement component 4 ( C4 ) genes, which are also in the MHC locus and were recently found to increase risk for schizophrenia 7 , generate 7-fold variation in risk for lupus (95% CI: 5.88–8.61; p < 10 −117 in total) and 16-fold variation in risk for Sjögren’s syndrome (95% CI: 8.59–30.89; p < 10 −23 in total) among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduced risk for lupus and Sjögren’s syndrome. In all three illnesses, C4 alleles acted more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for lupus, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (vs. 6-fold, 15-fold, and 1.26-fold among women respectively). At a protein level, both C4 and its effector C3 were present at greater levels in men than women in cerebrospinal fluid ( p < 10 −5 for both C4 and C3) and plasma 8 , 9 among adults ages 20–50, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s, and men’s greater vulnerability in schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.