Network signature of complement component 4 variation in the human brain identifies convergent molecular risk for schizophrenia

Genome-wide association studies have successfully identified hundreds of genomic regions associated with schizophrenia (SCZ). Subsequent fine-mapping of the strongest association signal, which lies in the major histocompatibility complex (MHC) locus, found that risk for SCZ is partially mediated by complex structural variation of the complement component 4 (C4) genes and resulting increased expression of C4A. Although C4A is believed to partake in synaptic pruning, its precise function in the human brain--and its relation to other SCZ risk factors--remains difficult to examine, due to lack of an appropriate experimental system and lack of evolutionary conservation in model organisms. Here we perform a large-scale functional genomic investigation of the human frontal cortex to characterize the systems-level architecture of C4A co-expression and how this network is remodeled with increased C4A copy number. We identify a putative transcriptomic signature of synaptic pruning as well as spatiotemporal and sex differences in C4A co-expression with largest effects observed in frontal cortical brain regions of middle-aged males. We also find that negative, but not positive, co-expression partners of C4A exhibit substantial enrichment for SNP-heritability in SCZ. In line with this finding, there is limited evidence that the complement system is a core SCZ-relevant pathway in comparison to synaptic components. Overall, our results highlight human brain-specific function of C4A and strong and specific convergence of polygenic effects in SCZ pathophysiology.