Archival Report| Volume 72, ISSUE 8, P620-628, October 15, 2012

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Genome-Wide Association Study Implicates HLA-C*01:02 as a Risk Factor at the Major Histocompatibility Complex Locus in Schizophrenia

  • Irish Schizophrenia Genomics Consortium and the Wellcome Trust Case Control Consortium 2


      We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia.


      The discovery scan included 1606 patients and 1794 controls from Ireland, using 6,212,339 directly genotyped or imputed single nucleotide polymorphisms (SNPs). A subset of this sample (270 cases and 860 controls) was subsequently included in the Psychiatric GWAS Consortium-schizophrenia GWAS meta-analysis.


      One hundred eight SNPs were taken forward for replication in an independent sample of 13,195 cases and 31,021 control subjects. The most significant associations in discovery, corrected for genomic inflation, were (rs204999, p combined = 1.34 × 10−9 and in combined samples (rs2523722 p combined = 2.88 × 10−16) mapped to the major histocompatibility complex (MHC) region. We imputed classical human leukocyte antigen (HLA) alleles at the locus; the most significant finding was with HLA-C*01:02. This association was distinct from the top SNP signal. The HLA alleles DRB1*03:01 and B*08:01 were protective, replicating a previous study.


      This study provides further support for involvement of MHC class I molecules in schizophrenia. We found evidence of association with previously reported risk alleles at the TCF4, VRK2, and ZNF804A loci.

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      Linked Article

      • The Genes in the Major Histocompatibility Complex as Risk Factors for Schizophrenia: De Omnibus Dubitandum
        Biological PsychiatryVol. 72Issue 8
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          The major histocompatibility complex (MHC) is an approximately 4 megabase region located on the short arm of chromosome 6 (6p21); it is also known as the human leukocyte antigen (HLA) superlocus. MHC encodes the classical and transplantation HLA genes and many other genes with essential roles for immune function and cellular processes including genes that are important for nervous system development and function. Although the MHC represents only a very small part (about .1%) of the human genome its properties can easily be described as extreme and intricate: most complex, most gene dense, most polymorphic, second largest contiguous sequence, containing the most disease associations, and most difficult to analyze.
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