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

  • Aiden Corvin
    Correspondence
    Address correspondence to Aiden Corvin, M.D., Ph.D., Trinity College Dublin, Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Dublin 2, Ireland
    Affiliations
    Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
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  • Derek W. Morris
    Affiliations
    Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
    Search for articles by this author
Published:November 06, 2013DOI:https://doi.org/10.1016/j.biopsych.2013.09.018
      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.

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      Linked Article

      • Is There a Flame in the Brain in Psychosis?
        Biological PsychiatryVol. 75Issue 4
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          For many decades, it was believed that the brain was immunologically privileged, hence it was surprising when Shatz and colleagues (1) reported in 2000 that a number of immune proteins (cytokines and major histocompatibility complex [MHC] proteins) were not just present in the brain but were localized at functional synapses. Subsequent work has shown that these molecules play a major role in brain development as well as in mature synaptic function and plasticity (2,3).
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