Caution in interpreting results from imputation analysis when linkage disequilibrium extends over a large distance: a case study on venous thrombosis.
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.
INSERM UMR_S 937, ICAN Institute, Université Pierre et Marie Curie, Paris, France.
Marine
M
Germain
Noémie
N
Saut
Tiphaine
T
Oudot-Mellakh
Luc
L
Letenneur
Anne-Marie
AM
Dupuy
Marion
M
Bertrand
Marie-Christine
MC
Alessi
Jean-Charles
JC
Lambert
Diana
D
Zelenika
Joseph
J
Emmerich
Laurence
L
Tiret
Francois
F
Cambien
Mark
M
Lathrop
Philippe
P
Amouyel
Pierre-Emmanuel
PE
Morange
David-Alexandre
DA
Trégouët
D016022:Case-Control Studies; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D013223:Statistics as Topic; D020246:Venous Thrombosis / Q000235:genetics*