A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC

Abstract

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and play an essential role in self/nonself immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune disease1. Yet identification of causal variants is problematic due to linkage disequilibrium (LD) that extends across multiple HLA and non-HLA genes in the MHC2,3. We therefore set out to characterize the LD patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common single nucleotide polymorphisms (SNPs) and deletion/insertion polymorphisms (DIPs) across four population samples. The analysis provides informative tag SNPs that capture some of the variation in the MHC region and that could be used in initial Corresponding author: John D. Rioux, Montreal Heart Institute, 5000 Rue Bélanger, Montréal, Québec, Canada, H1T 1C8, E-mail: rioux@broad.mit.edu. 16 These authors contributed equally All data will be available at the following sites: http://www.broad.mit.edu/mpg/idrg/projects/hla/ http://www.sanger.ac.uk/HGP/Chr6/ http://www.glovar.org COMPETING FINANCIAL INTEREST STATEMENTThe authors declare that they have no competing financial interests. Numerous studies have demonstrated association between HLA alleles and disease susceptibility (a partial list is provided in Table 1 and Supplementary Table 1), but the interpretation of these results is confounded by the strong correlation between alleles at neighboring HLA and non-HLA genes. Major efforts have therefore been directed at cataloguing the gene and variation content of the entire MHC4-6. In addition, previous studies in European-derived populations have examined the distribution of LD across the region and have suggested that SNPs could help dissect causal variation within the MHC2,3,7-10. Here, we have created a resource to guide future association studies by genotyping genetic variants across the extended MHC region of 7.5 Mb at a higher density and in more DNA samples than previously reported. In 361 individuals of African (YRI), European (CEU), Chinese (CHB), and Japanese (JPT) ancestry, the inferred haplotype structure across the region shows that LD is systematically higher in CEU, CHB and JPT samples than in the YRI sample (Fig. 1). Alleles across the different classical HLA loci demonstrate strong correlation (Supplementary Table 2). These high levels of LD among SNPs and DIPs and among HLA alleles suggest that SNPs outside the HLA genes are informative about HLA types (Fig. 2a), and that a few, well chosen SNPs may capture common classical HLA variation at several loci. Europe PMC Funders GroupWe examined the association between HLA types and single SNPs across the entire region. Fig. 2b shows the results for HLA-C (see Supplementary Fig. 1 for the other HLA genes). In the four populations studied, 34-44% of the HLA alleles present are strongly associa...

Genome‐wide association studies of multiple sclerosis

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Associations of killer cell immunoglobulin-like receptor genes with complications of rheumatoid arthritis

“…[25][26][27][28][29] Therefore, gene-disease associations in Caucasians and Chinese may be different, as has already been described in several other diseases. …”

HLA-DPB1 and NFKBIL1 may confer the susceptibility to chronic thromboembolic pulmonary hypertension in the absence of deep vein thrombosis

“…As there was tight LD among the alleles of HLA and non-HLA genes in the HLA region, which extended over several mega-bases (Mb) in some haplotypes, 11,28 we have evaluated LD among these diseaseassociated alleles in the controls, DVT-negative patients and DVTpositive patients (Table 3). It was found that DPB1*0202 was not in LD with the other disease-associated alleles in both controls and Owing to the strong LD, it was difficult to determine whether IKBLp*03 or B*5201 (or both of them) was primarily associated with the disease.…”

“…19 On the other hand, earlier HLA studies in Caucasoid populations showed that some HLA alleles were associated with pulmonary arterial hypertension, but the results were not consistent with each other, [14][15][16][17][18] implying that the observed associations with HLA were specific to the investigated ethnic groups because the complexity of HLA region depends on the nature of ethnic groups. 11 It is also possible that these reports might be false-positive findings owing to the type I error in the statistical analyses, because none of the earlier studies was concerned about multiple testing. However, the possibility remains that the association with HLA might be confined to a specific category of CTEPH, because the etiology and pathogenesis of CTEPH were heterogeneous.…”

“…[7][8][9] It is well known that HLA genes are highly polymorphic and their allelic distributions are different among different ethnic groups; diseases can be associated with different HLA alleles among different ethnic groups, and there is a possibility that the different HLA alleles may contribute to the difference in pathogenesis based on ethnicity. 9,10 Recently, de Bakker et al 11 reported a high-resolution single nucleotide polymorphism (SNP) mapping of the HLA region, which showed the ethnicityspecific complexity of HLA haplotypes.…”