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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 are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases1. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC2,3. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.

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Figure 1: The relationship between recombination rates and haplotype structure spanning the 7.5-Mb extended MHC region (the region from the SLC17A2 gene at the telomeric end to the DAXX gene at the centromeric end of chromosome 6).
Figure 2: Allelic association between SNPs across the 7.5-Mb extended MHC region and HLA types at each gene for the combined population data using the 5,754 SNPs that were typed in all populations and are polymorphic across the combined population samples (see Methods for details).
Figure 3: The evolutionary history of HLA-C.
Figure 4: The genetic distance over which the long-range haplotype associated with each allele for each SNP on chromosome 6 extends (before decaying to an EHH22 of 0.8) in each of the four populations (see Methods for details).

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Acknowledgements

The authors thank J. Oksenberg, P. De Jager and N. Walker for discussions and their critical reading of the manuscript. The authors are also grateful to B. Fry for technical assistance with the selection analysis. This project has been funded in whole or in part with federal funds from the US National Cancer Institute, National Institutes of Health (NIH), under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The Wellcome Trust supported the work of M.M., P.W., M.D., J.M., S.B., J.T., J.A.T. and P.D. The Juvenile Diabetes Research Foundation supported J.A.T. P.C.S. is funded by the Damon Runyon Cancer Fellowship. The International MS Genetics Consortium supported the work of D.H., S.G., M.P.V., and J.D.R. This work was also supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases (Autoimmunity Prevention Center grant U19 AI050864) to J.D.R.

Author information

Authors and Affiliations

Authors

Contributions

The study was designed by J.A.T., S.G., S.B., P.D. and J.D.R. Genotyping was performed by multiple groups (P.W., M.D., J.M., A.R., L.G., J.H., M.P.-V., S.S.M.). M.C. performed the HLA typing. A.J.M., C.W. and T.V. provided samples and genotype data for the cross-validation experiments. P.I.W.d.B., G.M., P.C.S., M.M., J.M., X.K., E.C.W. and T.G. performed analyses. The manuscript was written by P.I.W.d.B., G.M., P.C.S. and J.D.R., with contributions from J.A.T., D.A.H., M.J.D., M.C. and J.T. The genotyping, analysis and manuscript writing efforts of this international collaborative group were coordinated by J.D.R.

Corresponding author

Correspondence to John D Rioux.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Allelic association between SNPs across the 7.5-Mb extended MHC region and HLA types at each gene for the combined population data (using the 5,754 SNPs that were typed in all populations and are polymorphic across the combined population samples). (PDF 2374 kb)

Supplementary Fig. 2

A region of the MHC, including BAK1 and HLA-DPA1, contains one of the top 20 candidates for selection based on the long-range haplotype test in the YRI. (PDF 313 kb)

Supplementary Table 1

Partial summary of established HLA associations and associations of contemporary interest. (PDF 16 kb)

Supplementary Table 2

Correlations between alleles at the six classical HLA loci typed in the study. (PDF 4 kb)

Supplementary Table 3

List of tags for HLA alleles. (PDF 70 kb)

Supplementary Table 4

Cross-panel performance of HLA tags. (PDF 65 kb)

Supplementary Table 5

List of top-ranking SNPs and haplotypes with evidence for recent positive selection using EHH-based methods. (PDF 74 kb)

Supplementary Methods (PDF 30 kb)

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de Bakker, P., McVean, G., Sabeti, P. et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 38, 1166–1172 (2006). https://doi.org/10.1038/ng1885

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