Search for schizophrenia susceptibility variants at the HLA-DRB1 locus among a British population

Abstract

Schizophrenia is a complex mental disorder with unknown aetiology. Both candidate gene and genome-wide association (GWA) studies suggest that the human leukocyte antigen (HLA) system may play a part in development of the illness, but the causal HLA variant(s) remain(s) unclear. Previous studies showed that the DRB1*0101 and DRB1*13 alleles might be associated with a high risk of schizophrenia. Therefore, the present study was undertaken to test their association with the disease by genotyping seven DRB1-tagging single nucleotide polymorphisms (SNPs) in a British population. The results showed that, of the previously reported variants that were associated with schizophrenia, the DRB1*1303 allele was the only one marginally associated with a protective effect on the illness in our sample set (χ² = 4.138, P = 0.042, odds ratio (OR) = 0.42, 95 % confidence interval (CI) 0.27-0.66). Interestingly, a significant association was found for rs424232 (χ² = 9.404, P = 0.002, OR = 0.69, 95 % CI 0.54-0.88), which is a tag SNP for the DRB1*1303 allele and located near to the NOTCH4 gene that is a schizophrenia susceptibility locus confirmed by GWA studies. Analysis with the Haploview program demonstrated that rs424232 was in complete linkage disequilibrium with rs3130297 and rs3131296 present in the NOTCH4 locus. While we have failed to confirm association of the candidate alleles in the DRB1 gene with a high risk of schizophrenia, the present work suggests that the association signal detected in the HLA class II locus may extend a relatively long distance, and more work is needed in order to identify the true causal variants within this region or nearby.

HLA Class I Alleles Are Associated with Peptide-Binding Repertoires of Different Size, Affinity, and Immunogenicity

“…It is noteworthy that similar variation in repertoire size was recently noted in the case of the class I molecules expressed by the rhesus macaque ( Macaca mulatta (55)). Therefore, it is reasonable to speculate that similar allele-related variation in repertoire size will be broadly observed.…”

Development and validation of a broad scheme for prediction of HLA class II restricted T cell epitopes

“…The extensive polymorphism of HLA class II molecules in the general population does represent a formidable obstacle to epitope identification approaches. However, it has been recognized that the majority of molecules expressed in the general population can be reconciled to a manageable number by focusing on those most frequently expressed (McKinney et al, 2013). At the same time, extensive similarities exist within the peptides bound by different allelic variants, and even across different loci (Greenbaum et al, 2011).…”

Association of theNOTCH4Gene Polymorphism rs204993 with Schizophrenia in the Chinese Han Population

“…Schizophrenia (SCZ) is a chronic, severe psychotic mental disorder characterized by both positive (e.g., delusions, hallucinations, and thought disorders) and negative symptoms (e.g., social withdrawal, apathy, and cognitive impairment) [ 1 ]. As a serious neurological disability, SCZ affects approximately 1% of the general population worldwide and is regarded as a major public health problem, ranking ninth in terms of global disease burden [ 2 ]. Based on evidence from family-based, twin and adoption studies, which have implicated numerous genes in the etiology of SCZ, the disorder is currently understood as a polygenic neurodevelopment disorder caused by the interplay between environmental factors and genetics [ 3 ].…”