Linkage Disequilibrium Patterns and tagSNP Transferability among European Populations

Abstract

The pattern of linkage disequilibrium (LD) is critical for association studies, in which disease-causing variants are identified by allelic association with adjacent markers. The aim of this study is to compare the LD patterns in several distinct European populations. We analyzed four genomic regions (in total, 749 kb) containing candidate genes for complex traits. Individuals were genotyped for markers that are evenly distributed at an average spacing of approximately 2-4 kb in eight population-based samples from ongoing epidemiological studies across Europe. The Centre d'Etude du Polymorphisme Humain (CEPH) trios of the HapMap project were included and were used as a reference population. In general, we observed a conservation of the LD patterns across European samples. Nevertheless, shifts in the positions of the boundaries of high-LD regions can be demonstrated between populations, when assessed by a novel procedure based on bootstrapping. Transferability of LD information among populations was also tested. In two of the analyzed gene regions, sets of tagging single-nucleotide polymorphisms (tagSNPs) selected from the HapMap CEPH trios performed surprisingly well in all local European samples. However, significant variation in the other two gene regions predicts a restricted applicability of CEPH-derived tagging markers. Simulations based on our data set show the extent to which further gain in tagSNP efficiency and transferability can be achieved by increased SNP density.

Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB1*03 and DRB1*04 haplotypes

“…The same observation was made by Stenzel et al studying LD across the MHC, 35 and even though ethnicity is a parameter influencing LD, maps seem to be transferable among European populations. 36 In contrast to the population similarities, we observed significant variations in LD pattern and haplotype blocks after grouping the data set, according to alleles carried at some HLA loci (i.e. DQB1, DQA1, DRB1, and in some instances MIB).…”

Haplotype tagging efficiency in worldwide populations in CTLA4 gene

“…26,27 Moreover, tag-SNPs identified in one population may not be applicable to other populations 28 even if they seem to be quite general for Europeans. 29 Furthermore, Crawford et al, 30 after analyzing the sequence diversity in 100 human genes, concluded that the amount of LD and the haplotype structure should be empirically analyzed in order to assess which and how many SNPs must be typed in a specific gene to detect an association with a disease-causing SNP in a case-control study.…”

Population differences in the International Multi‐Centre ADHD Gene Project

“…Additionally, the Israeli sample requires more tags than the other populations, after correcting for sample size, indicating that the CEPH sample defined tag set used to define the marker selection did not capture all the variation in the Israeli population. In general, most investigations into LD differences find that Northern Europeans can be grouped together for the purposes of generating and applying tag SNPs [Mueller et al, 2005;Gonzalez-Neira et al, 2006;de Bakker et al, 2006]. Southern Europeans and Israelis tend to form a different population cluster [Bauchet et al, 2007].…”

“…A key component of such work is tag selection from the LD information of the Centre d'Etude du Polymorphisme Humain (CEPH) sample. Mueller et al densely genotyped four gene regions (PLAU, SNCA, LMNA, and FKBP5) at a frequency of one SNP per $2-4 kb in strictly European populations to gauge populations differences [Mueller et al, 2005]. In general, mild allele frequency differences were detected.…”