Genome-wide Association Studies: Findings at the Major Histocompatibility Complex Locus in Psychosis

The major histocompatibility complex (MHC) is one of the most intensively investigated, genetically diverse regions of the genome. In its extended form, it encodes more than 400 genes critical to immunity but is also involved in many other functions. In 2009, three simultaneously published genome-wide association studies (GWAS) reported the first compelling evidence for involvement of the MHC in schizophrenia susceptibility. In this review, we describe the structure and function of the MHC, discuss some of the challenges for genetic analysis of the region, and provide an update on findings from GWAS studies before describing potential approaches to interpreting the role of the locus in schizophrenia etiology. The GWAS literature supports involvement of the MHC locus in schizophrenia susceptibility. Current evidence suggests that the MHC plays a more significant role in schizophrenia susceptibility than in other psychiatric disorders. Because of the substantial diversity at the locus, there are differences in the implicated risk variants between ancestral groups, as there are for many other disorders. This is somewhat different than the pattern emerging at other loci. The association findings presently capture large genomic regions, with at least some evidence to suggest that multiple signals may be involved. Based on notable successes in other disorders, we suggest approaches to refining association signals at the locus. Finally, we discuss that these genetic data may be used to understand how the MHC contributes to the complex etiology of schizophrenia.