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- Title
Heterogeneity of linkage disequilibriumin human genes has implications for association studies of commondiseases.
- Authors
Tiret, Laurence; Poirier, Odette; Nicaud, Viviane; Barbaux, Sandrine; Herrmann, Stefan-Martin; Perret, Claire; Raoux, Ségolène; Francomme, Carole; Lebard, Géraud; Trégouët, David; Cambien, François
- Abstract
Linkage disequilibrium (LD) is the central conceptof genetic association studies. Although LD has been shown not tobe uniformly distributed across the genome, limited informationis available about the characteristics of LD within candidate genesat large. We screened coding and regulatory regions of 50 candidate genesfor cardiovascular diseases and identified 228 polymorphisms. Theoverall sequence diversity was 3.81 ± 0.31 × 10–4. IntragenicLD was generally very strong, with 40% of the 464 pairsof polymorphisms exhibiting a complete LD. However, if we consider ½D′½ = 0.7as an arbitrary limit for useful LD in association studies, 26% ofthe pairs fell below this threshold, half of which being in negativeLD, a situation where LD is even more difficult to detect. Non-synonymouscoding polymorphisms, which are more likely to have a functional role,were more represented among low-frequency alleles and were moreoften in complete negative LD with other polymorphisms. This impliesthat in many situations the power to detect the effect of a non-synonymous polymorphismby measuring a nearby marker might be low. Although intragenic LDwas partly a function of physical distance, gene-specific patternsof LD were observed, making it difficult to provide general guidelinesfor selecting the most useful polymorphisms in association studies.For all these reasons, association studies should concentrate onthe overall sequence variation of functionally important regionsof candidate genes and not only on a few polymorphisms. The variabilityof important intergenic regions identified by different approachesincluding comparative genomics will also have to be assessed.
- Publication
Human Molecular Genetics, 2002, Vol 11, Issue 4, p419
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/11.4.419