European Journal of Human Genetics (2010) 18, 924–932; doi:10.1038/ejhg.2010.32; published online 31 March 2010

Linkage disequilibrium and age of HLA region SNPs in relation to classic HLA gene alleles within Europe

Irina Evseeva1,4, Kristin K Nicodemus1,2,4, Carolina Bonilla1, Susan Tonks1 and Walter F Bodmer1,3

  1. 1Department of Clinical Pharmacology, Old Road Campus Research Building, University of Oxford, Oxford, UK
  2. 2Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  3. 3Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK

Correspondence: Dr WF Bodmer, Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. Tel: +44 (0)1865 222 422; Fax: +44 (0)1865 222 431; E-mail:

4These authors contributed equally to this work

Received 21 October 2009; Revised 2 February 2010; Accepted 11 February 2010; Published online 31 March 2010.



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.


HLA; population genetics; Europe; LD; haplotype