This is an important new study from the Irish Schizophrenia Genomics Consortium and the second wave of the Wellcome Trust Case-Control Consortium (WTCCC).
The study is notable, as it found genomewide significance for an association of schizophrenia with genetic variation in the major histocompatibility locus (MHC). Given concerns about stratification effects at this locus, it is notable that this association was significant in a sample from a single country with relatively homogeneous ancestry. Prior studies had combined data from multiple different countries, and these results provide an important consistency check.
In addition, the authors provide important suggestive evidence for a specific variant in a class 1 MHC locus (HLA-C gene, the "01:02" variant, p = 3e-4).
The use of 1000 Genomes Project data for imputation is notable for the improved signal pattern it appeared to afford.
View all comments by Patrick Sullivan
The newly reported HLA-C*01:02 as a risk factor of schizophrenia by Strange et al., 2012, in this GWAS (Irish Schizophrenia Genomics Consortium & the Wellcome Trust Case Control Consortium) is a significant contribution and has further strengthened MHC’s role in schizophrenia. Although multiple GWAS in various populations have implicated MHC as a major and best replicated risk loci of schizophrenia (as reviewed in Debnath et al., 2012), the findings remained inconclusive.
Strange et al. (2012), in this GWAS on 1,606 schizophrenia patients and 1,794 controls, found association of three SNPs (rs204999, rs2523722, and rs7746922) within the MHC region with schizophrenia, of which the most significant association was with rs204999. They also replicated this study by considering some selected SNPs in a large, independent set of 13,195 schizophrenia patients and 31,021 controls. In the combined samples (this GWAS and replication data), rs2523722 appeared as the most significantly associated MHC variant. Intriguingly, these findings are distinct from all other published GWAS data of schizophrenia. In addition, this new GWAS also reproduced the association of previously reported variants within MHC (rs3131296 and rs9272219), TCF4, ZNF804A, and VRK2. Furthermore, this study once again replicates and validates the association with two protective HLA alleles (HLA-B*08:01 and DRB1*03:01) previously identified by Stefansson et al. (2009). Taken together, data derived by Strange et al. implicate HLA-C*01:02 as a risk allele, and HLA-B*08:01 and DRB1*03:01 as protective alleles of schizophrenia.
However, to make this conclusion consistent, and considering the population stratification at the MHC locus, it is necessary to extend these findings to other major world populations. Furthermore, functional verification of these top variants is necessary to understand their precise neurobiological functions in schizophrenia. As the HLA-C locus is increasingly being implicated in pregnancy disorders as well as in viral infections, translational studies focusing on its role in prenatal infection and neurodevelopment will surely advance our understanding of the mechanism of HLA-C-mediated risk of schizophrenia.
Debnath M, Cannon DM, Venkatasubramanian G. Variation in the major histocompatibility complex [MHC] gene family in schizophrenia: Associations and functional implications. Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jul 17. Abstract
Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature 2009;460:744-747. AbstractView all comments by Monojit Debnath