Elsevier

Biological Psychiatry

Volume 72, Issue 8, 15 October 2012, Pages 620-628
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2012.05.035Get rights and content

Background

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

Methods

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.

Results

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.

Conclusions

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.

Section snippets

Discovery Sample Cases

The case sample of 1908 individuals was recruited through community mental services and inpatient units in the Republic of Ireland and Northern Ireland following similar research protocols and with local ethics approval. All participants were interviewed using a structured clinical interview (Structured Clinical Interview for DSM-IV [14]; Schedule for Affective Disorders and Schizophrenia [Lifetime Version] [15]; or Schedule for Clinical Assessment in Neuropsychiatry [16]). Diagnosis of a major

Results

The top association in this GWAS was in the MHC region (rs204999, p = 2.77 × 10−8) (Figures 1 and 2). This SNP is 63 kilobase upstream from, and in weak linkage disequilibrium (1000 Genomes CEU data R2 = .23) with, the signal reported by Stefansson et al. (12) (rs3131296). After accounting for rs204999, rs3131296 does not add any further signal in our dataset (p = .816). The MHC was the only region in the discovery GWAS with SNPs that had p < 10−7. Association analysis was also carried out on

Discussion

We report a schizophrenia GWAS in a sample of 1606 cases and 1794 control subjects. We found strong support for association at three SNPs in the MHC, including the lead SNP in the discovery data rs204999. Multiple SNPs in the MHC region have been identified in previous schizophrenia GWAS (3, 6, 12). Conditional analysis of the associated SNPs suggests that in this data the signal is being driven by association with rs204999, although there is evidence of association with other SNPs at the

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    Address correspondence to Aiden Corvin, M.D., Ph.D., Trinity Centre for Health Sciences, Department of Psychiatry, St. James's Hospital, Dublin 8, Ireland; E-mail: [email protected].

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