Abstract
The HLA region on chromosome 6 is gene-rich and under selective pressure because of the high proportion of immunity-related genes. Linkage disequilibrium (LD) patterns and allele frequencies in this region are highly differentiated across broad geographical populations, making it a region of interest for population genetics and immunity-related disease studies. We examined LD in this important region of the genome in six European populations using 166 putatively neutral SNPs and the classical HLA-A, -B and -C gene alleles. We found that the pattern of association between classic HLA gene alleles and SNPs implied that most of the SNPs predated the origin of classic HLA gene alleles. The SNPs most strongly associated with HLA gene alleles were in some cases highly predictive of the HLA allele carrier status (misclassification rates ranged from <1 to 27%) in independent populations using five or fewer SNPs, a much smaller number than tagSNP panels previously proposed and often with similar accuracy, showing that our approach may be a viable solution to designing new HLA prediction panels. To describe the LD within this region, we developed a new haplotype clustering method/software based on r2, which may be more appropriate for use within regions of strong LD. Haplotype blocks created using this proposed method, as well as classic HLA gene alleles and SNPs, were predictive of a northern versus southern European population membership (misclassification error rates ranged from 0 to 23%, depending on which independent population was used for prediction), indicating that this region may be a rich source of ancestry informative markers.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Miretti MM, Walsh EC, Ke X et al: A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am J Hum Genet 2005; 76: 634–646.
Shen R, Fan JB, Campbell D et al: High-throughput SNP genotyping on universal bead arrays. Mutat Res 2005; 573: 70–82.
Tonks S, Marsh S, Bunce M, Bodmer JG : Molecular typing for HLA class I using ARMS-PCR: further development following the 12th International Histocompatibility Workshop. Tissue Antigens 1999; 53: 175–183.
Bartlett S, Straub J, Tonks S, Wells RS, Bodmer JG, Bodmer WF : Alkaline-mediated differential interaction (AMDI): a simple automatable single-nucleotide polymorphism assay. Proc Natl Acad Sci USA 2001; 98: 2694–2697.
Barrett JC, Fry B, Maller J, Daly MJ : Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Gabriel SB, Schaffner SF, Nguyen H et al: The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.
Weir BS, Cockerham CC : Estimating F-statistics for the analysis of population structure. Evolution 1984; 38: 1358–1370.
Guillot G, Mortier F, Estoup A : Geneland: a program for landscape genetics. Mol Ecol Notes 2005; 5: 1261–1280.
Stephens M, Smith N, Donnelly P : A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.
Stephens M, Donnelly P : A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D : Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.
Karatzoglou A, Smola A, Hornik K, Zeileis A : kernlab-An S4 Package for Kernel Methods in R. J Stat Soft 2004; 11: 1–20.
Pritchard JK, Stephens M, Donnelly P : Inference of population structure using multilocus genotype data. Genetics 2000; 155: 945–959.
Falush D, Stephens M, Pritchard JK : Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 2003; 164: 1567–1587.
Corander J, Waldman P, Silanpää MJ : Bayesian analysis of genetic differentiation between populations. Genetics 2003; 163: 367–374.
Corander J, Marttinen P, Siren J, Tang J : Enhanced Bayesian modeling in BAPS software for learning genetic structures of populations. BMC Bioinformatics 2008; 9: 539.
Bodmer JG : The HLA system: The HLA-DR antigens and HLA haplotypes in 2 populations. in Eriksson E (ed): Population Structure and Genetic Disorders. Acad Press: London, 1980, pp 211–238.
Cavalli-Sforza LL, Menozzi P, Piazza A : The History and Geography of Human Genes. Princeton: Princeton University Press, 1994.
de Bakker PI, McVean G, Sabeti PC et al: A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 2006; 38: 1166–1172.
Leslie S, Donnelly P, McVean G : A statistical method for predicting classical HLA alleles from SNP data. Am J Hum Genet 2008; 82: 48–56.
Acknowledgements
The project was funded by the European Union (Linkage Disequilibrium in European Populations, 2001–2005, CT-2001–00916), the Wellcome Trust (support for KKN) and by Cancer Research UK (support for CB and ST). DNA samples were provided by project partners: Prof Howard Cann (Fondation Jean Dausset-CEPH, Paris, France), Prof Laurent Excoffier (Computational and Molecular Population Genetics Lab, Zoological Institute, University of Bern, Switzerland), Prof Antti Sajantila (Department of Forensic Medicine, Laboratory of Forensic Biology, University of Helsinki, Finland), Prof Alberto Piazza (Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, Italy), Prof Silvana Santachiara (Department of Genetics and Microbiology, University of Pavia, Italy) and Prof Jaume Bertranpetit (Biologia Evolutiva, CEXs, Universitat Pompeu Fabra, Barcelona, Spain).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on European Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Evseeva, I., Nicodemus, K., Bonilla, C. et al. Linkage disequilibrium and age of HLA region SNPs in relation to classic HLA gene alleles within Europe. Eur J Hum Genet 18, 924–932 (2010). https://doi.org/10.1038/ejhg.2010.32
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2010.32
Keywords
This article is cited by
-
Benchmarking the HLA typing performance of Polysolver and Optitype in 50 Danish parental trios
BMC Bioinformatics (2018)
-
High-accuracy imputation for HLA class I and II genes based on high-resolution SNP data of population-specific references
The Pharmacogenomics Journal (2015)
-
Fine-scale human genetic structure in Western France
European Journal of Human Genetics (2015)
-
Predicting HLA genotypes using unphased and flanking single-nucleotide polymorphisms in Han Chinese population
BMC Genomics (2014)
-
HIBAG—HLA genotype imputation with attribute bagging
The Pharmacogenomics Journal (2014)
