1.1. Genetic Loci Related to Major Histocompatibility (MHC) Region
Multiple genome-wide association (GWAS) studies have reported significant MHC single-nucleotide polymorphisms (SNPs) associated with schizophrenia, bipolar disorder, cognition, or hippocampal volume [12,13,14,15,16,17,18]. Finding highly associated SNPs within this region is a first step towards locating causative gene(s). Currently, these associations with schizophrenia do not necessarily imply immunity as the causative mechanism underlying the association, as the linkage disequilibrium is complicated across different populations. This highly replicated region encompasses hundreds of genes, some that are non-immune, in long-range linkage disequilibrium (LD), with extensive allelic heterogeneity. The GWAS studies to date have not found the gene(s) responsible or causative variants in the MHC locus, although the HLA-B and HLA-DRB1 loci were protective, and the HLA-C increased risk for schizophrenia [12]. One recent study of the C4 gene in the MHC locus showed an association with increased brain expression and risk of schizophrenia [19]. Thus, additional evidence of gene expression in the MHC locus needs to be pursued to directly examine some of the immune genes from persons with psychiatric disorders.