The major histocompatibility complex (MHC / human leukocyte antigen / HLA) region is consistently most highly associated with SCZ, but it is a difficult region to dissect for causal variation because of its unusually high linkage disequilibrium and gene density (>200 DLPFC-expressed genes in chr6:25–36 Mb). Nevertheless, only five genes in this locus were ranked highly by Sherlock and passed evaluation for concordance of associations (Supplementary data file 2): C4A, HCG17, VARS2, HLA-DMB, and BRD2. Consistent with recent work identifying structural variation of the C4 genes as partly mediating the genetic MHC association, resulting in higher expression and perhaps driving pathological synapse loss in schizophrenia32, we found a strong correlation between the risk alleles for SCZ and up-regulation of expression of C4A (complement component 4A; Spearman’s ρ = 0.66, P < 10−16).
