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PLoS By Category | Recent PLoS Articles
Hematology

Caution in Interpreting Results from Imputation Analysis When Linkage Disequilibrium Extends over a Large Distance: A Case Study on Venous Thrombosis
Published: Monday, June 04, 2012
Author: Marine Germain et al.

by Marine Germain, Noémie Saut, Tiphaine Oudot-Mellakh, Luc Letenneur, Anne-Marie Dupuy, Marion Bertrand, Marie-Christine Alessi, Jean-Charles Lambert, Diana Zelenika, Joseph Emmerich, Laurence Tiret, Francois Cambien, Mark Lathrop, Philippe Amouyel, Pierre-Emmanuel Morange, David-Alexandre Trégouët

By applying an imputation strategy based on the 1000 Genomes project to two genome-wide association studies (GWAS), we detected a susceptibility locus for venous thrombosis on chromosome 11p11.2 that was missed by previous GWAS analyses that had been conducted on the same datasets. A comprehensive linkage disequilibrium and haplotype analysis of the whole locus where twelve SNPs exhibited association p-values lower than 2.23 10-11 and the use of independent case-control samples demonstrated that the culprit variant was a rare variant located ~1 Mb away from the original hits, not tagged by current genome-wide genotyping arrays and even not well imputed in the original GWAS samples. This variant was in fact the rs1799963, also known as the FII G20210A prothrombin mutation. This work may be of major interest not only for its scientific impact but also for its methodological findings.
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