A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis

Nicolas Greliche,Anne-Marie Dupuis,Marion Bertrand,Mark Lathrop,Jean-Charles Lambert,Marine Germain,William Cohen,Pierre-Emmanuel Morange,Luc Letenneur,Philippe Amouyel,David-Alexandre Trégouët

doi:10.1186/1471-2350-14-36

Abstract

BackgroundVenous Thrombosis (VT) is a common multifactorial disease with an estimated heritability between 35% and 60%. Known genetic polymorphisms identified so far only explain ~5% of the genetic variance of the disease. This study was aimed to investigate whether pair-wise interactions between common single nucleotide polymorphisms (SNPs) could exist and modulate the risk of VT.MethodsA genome-wide SNP x SNP interaction analysis on VT risk was conducted in a French case–control study and the most significant findings were tested for replication in a second independent French case–control sample. The results obtained in the two studies totaling 1,953 cases and 2,338 healthy subjects were combined into a meta-analysis.ResultsThe smallest observed p-value for interaction was p = 6.00 10-11 but it did not pass the Bonferroni significance threshold of 1.69 10-12 correcting for the number of investigated interactions that was 2.96 1010. Among the 37 suggestive pair-wise interactions with p-value less than 10-8, one was further shown to involve two SNPs, rs9804128 (IGFS21 locus) and rs4784379 (IRX3 locus) that demonstrated significant interactive effects (p = 4.83 10-5) on the variability of plasma Factor VIII levels, a quantitative biomarker of VT risk, in a sample of 1,091 VT patients.ConclusionThis study, the first genome-wide SNP interaction analysis conducted so far on VT risk, suggests that common SNPs are unlikely exerting strong interactive effects on the risk of disease.

Highlights

Venous Thrombosis (VT) is a common multifactorial disease with an estimated heritability between 35% and 60%
This work was based on two French Genome Wide Association Studies (GWAS) on VT, the Early-Onset Venous Thrombosis (EOVT) and the Marseille Thrombosis Association (MARTHA) studies
We first applied a pairwise tagging approach to discard redundant single nucleotide polymorphisms (SNPs) using a r2 threshold of 0.90, that led to the final selection of 243,189 SNPs from the EOVT study

Summary

Introduction

Venous Thrombosis (VT) is a common multifactorial disease with an estimated heritability between 35% and 60%. Known genetic polymorphisms identified so far only explain ~5% of the genetic variance of the disease. Venous Thrombosis (VT) is a common complex disease affecting ~0.2% of individuals a year. The recent Genome Wide Association Studies (GWAS) strategy brought great hopes to identify novel susceptibility loci to human diseases and some true successes were obtained in the field of VT genetics. None of the identified risk alleles demonstrated genetic effects stronger than those of the established VT-associated genes known before the GWAS era, ABO, F2, F5 and FGG [5]. Alternative strategies are needed to identify the army sources that could contribute to the unexplained heritability and these include gene-gene and geneenvironment interactions, deep sequencing, transcriptomic analyses and epigenomics [7,8,9,10]

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