Linkage disequilibrium patterns and tagSNP transferability among European populations.

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.

[1]  P. Deloukas,et al.  The impact of SNP density on fine-scale patterns of linkage disequilibrium. , 2004, Human molecular genetics.

[2]  P. Donnelly,et al.  The effects of human population structure on large genetic association studies , 2004, Nature Genetics.

[3]  C. Carlson,et al.  Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. , 2004, American journal of human genetics.

[4]  Juliet M Chapman,et al.  Detecting Disease Associations due to Linkage Disequilibrium Using Haplotype Tags: A Class of Tests and the Determinants of Statistical Power , 2003, Human Heredity.

[5]  E Ukkonen,et al.  Minimum description length block finder, a method to identify haplotype blocks and to compare the strength of block boundaries. , 2003, American journal of human genetics.

[6]  G. Abecasis,et al.  Using haplotype blocks to map human complex trait loci. , 2003, Trends in genetics : TIG.

[7]  Kun Zhang,et al.  HaploBlockFinder: Haplotype Block Analyses , 2003, Bioinform..

[8]  John S. Witte,et al.  Haplotype Tagging Single Nucleotide Polymorphisms and Association Studies , 2003, Human Heredity.

[9]  Russell Schwartz,et al.  Robustness of Inference of Haplotype Block Structure , 2003, J. Comput. Biol..

[10]  A. Andrés,et al.  Spatial patterns of cystic fibrosis mutation spectra in European populations , 2003, European Journal of Human Genetics.

[11]  Masatoshi Nei,et al.  Genetic Distance between Populations , 1972, The American Naturalist.

[12]  H. Cann,et al.  Centre d'etude du polymorphisme humain (CEPH): collaborative genetic mapping of the human genome. , 1990, Genomics.

[13]  B. J. Carey,et al.  Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots , 2003, Nature Genetics.

[14]  M. Feldman,et al.  Genetic Structure of Human Populations , 2002, Science.

[15]  J. Todd,et al.  The usefulness of different density SNP maps for disease association studies of common variants. , 2003, Human Molecular Genetics.

[16]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[17]  J. Chan,et al.  Ethnic differences in the linkage disequilibrium and distribution of single-nucleotide polymorphisms in 35 candidate genes for cardiovascular diseases. , 2004, Genomics.

[18]  Sergey Nejentsev,et al.  Comparative high-resolution analysis of linkage disequilibrium and tag single nucleotide polymorphisms between populations in the vitamin D receptor gene. , 2004, Human molecular genetics.

[19]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[20]  J. Wall,et al.  Haplotype blocks and linkage disequilibrium in the human genome , 2003, Nature Reviews Genetics.

[21]  R R Sokal,et al.  Zones of sharp genetic change in Europe are also linguistic boundaries. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Hoggart,et al.  Design and analysis of admixture mapping studies. , 2004, American journal of human genetics.

[23]  Nicholas W Wood,et al.  Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: implications for linkage-disequilibrium gene mapping. , 2003, American journal of human genetics.

[24]  J. Hampe,et al.  Patterns of linkage disequilibrium in the MHC region on human chromosome 6p , 2004, Human Genetics.

[25]  D. F. Roberts,et al.  The History and Geography of Human Genes , 1996 .