Human Molecular Genetics Advance Access originally published online on January 20, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 6 577-588
DOI: 10.1093/hmg/ddh060
The impact of SNP density on fine-scale patterns of linkage disequilibrium
1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, 2Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK and 3University of Southampton, Southampton, UK
Received September 26, 2003; Revised December 23, 2003; Accepted January 13, 2004
Linkage disequilibrium (LD) is a measure of the degree of association between alleles in a population. The detection of disease-causing variants by association with neighbouring single nucleotide polymorphisms (SNPs) depends on the existence of strong LD between them. Previous studies have indicated that the extent of LD is highly variable in different chromosome regions and different populations, demonstrating the importance of genome-wide accurate measurement of LD at high resolution throughout the human genome. A uniform feature of these studies has been the inability to detect LD in regions of low marker density. To investigate the dependence of LD patterns on marker selection we performed a high-resolution study in African-American, Asian and UK Caucasian populations. We selected over 5000 SNPs with an average spacing of 
1 SNP per 2 kb after validating ca 12 000 SNPs derived from a dense SNP collection (1 SNP per 0.3 kb on average). Applications of different statistical methods of LD assessment highlight similar areas of high and low LD. However, at high resolution, features such as overall sequence coverage in LD blocks and block boundaries vary substantially with respect to marker density. Model-based linkage disequilibrium unit (LDU) maps appear robust to marker density and consistently influenced by marker allele frequency. The results suggest that very dense marker sets will be required to yield stable views of fine-scale LD in the human genome.
* To whom correspondence should be addressed. Tel: +44 1223834244; Fax: +44 1223494919; Email: panos{at}sanger.ac.uk
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