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Caution in interpreting results from imputation analysis when linkage disequilibrium extends over a large distance: a case study on venous thrombosis.

Germain M, Saut N, Oudot-Mellakh T, Letenneur L, Dupuy AM, Bertrand M, Alessi MC, Lambert JC, Zelenika D, Emmerich J, Tiret L, Cambien F, Lathrop M, Amouyel P, Morange PE, Trégouët DA - PLoS ONE (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: INSERM UMR_S 937, ICAN Institute, Université Pierre et Marie Curie, Paris, France.

ABSTRACT
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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Related in: MedlinePlus

Case-control samples available in this work.(1) These individuals were typed with the Illumina Sentrix HumanHap300 beadchip containing 317,319 SNPs among which 291,872 satisfied the quality control (QC) criteria (Trégouët et al. (2009) Blood 113: 5298–5303). (2) These individuals were typed with the Illumina 610-Quad and Illumina 660W-Quad beadchips. Among the 551,141 SNPs common to both assays, 491,258 SNPs satisfied the QC criteria (Germain et al (2011) Plos One 6: e25581). (a) 812 VT patients of the MARTHA study were part of the GWAS(2) VT sample. (b) The FV Leiden and FII G20210A mutations were genotyped in the GWAS patients as part of the study design where patients homozygous for these mutations were excluded.
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pone-0038538-g001: Case-control samples available in this work.(1) These individuals were typed with the Illumina Sentrix HumanHap300 beadchip containing 317,319 SNPs among which 291,872 satisfied the quality control (QC) criteria (Trégouët et al. (2009) Blood 113: 5298–5303). (2) These individuals were typed with the Illumina 610-Quad and Illumina 660W-Quad beadchips. Among the 551,141 SNPs common to both assays, 491,258 SNPs satisfied the QC criteria (Germain et al (2011) Plos One 6: e25581). (a) 812 VT patients of the MARTHA study were part of the GWAS(2) VT sample. (b) The FV Leiden and FII G20210A mutations were genotyped in the GWAS patients as part of the study design where patients homozygous for these mutations were excluded.

Mentions: Therefore, in this work, we re-analyzed these two GWAS on VT based now on the 1000G 2010-08 release containing 11,572,501 autosomal SNPs, and validated novel results in two additional case-control samples. A brief summary of the available samples used in this work is shown in Figure 1.


Caution in interpreting results from imputation analysis when linkage disequilibrium extends over a large distance: a case study on venous thrombosis.

Germain M, Saut N, Oudot-Mellakh T, Letenneur L, Dupuy AM, Bertrand M, Alessi MC, Lambert JC, Zelenika D, Emmerich J, Tiret L, Cambien F, Lathrop M, Amouyel P, Morange PE, Trégouët DA - PLoS ONE (2012)

Case-control samples available in this work.(1) These individuals were typed with the Illumina Sentrix HumanHap300 beadchip containing 317,319 SNPs among which 291,872 satisfied the quality control (QC) criteria (Trégouët et al. (2009) Blood 113: 5298–5303). (2) These individuals were typed with the Illumina 610-Quad and Illumina 660W-Quad beadchips. Among the 551,141 SNPs common to both assays, 491,258 SNPs satisfied the QC criteria (Germain et al (2011) Plos One 6: e25581). (a) 812 VT patients of the MARTHA study were part of the GWAS(2) VT sample. (b) The FV Leiden and FII G20210A mutations were genotyped in the GWAS patients as part of the study design where patients homozygous for these mutations were excluded.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366937&req=5

pone-0038538-g001: Case-control samples available in this work.(1) These individuals were typed with the Illumina Sentrix HumanHap300 beadchip containing 317,319 SNPs among which 291,872 satisfied the quality control (QC) criteria (Trégouët et al. (2009) Blood 113: 5298–5303). (2) These individuals were typed with the Illumina 610-Quad and Illumina 660W-Quad beadchips. Among the 551,141 SNPs common to both assays, 491,258 SNPs satisfied the QC criteria (Germain et al (2011) Plos One 6: e25581). (a) 812 VT patients of the MARTHA study were part of the GWAS(2) VT sample. (b) The FV Leiden and FII G20210A mutations were genotyped in the GWAS patients as part of the study design where patients homozygous for these mutations were excluded.
Mentions: Therefore, in this work, we re-analyzed these two GWAS on VT based now on the 1000G 2010-08 release containing 11,572,501 autosomal SNPs, and validated novel results in two additional case-control samples. A brief summary of the available samples used in this work is shown in Figure 1.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: INSERM UMR_S 937, ICAN Institute, Université Pierre et Marie Curie, Paris, France.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus