Genetics of venous thrombosis: insights from a new genome wide association study

Abstract

Background: Venous Thrombosis (VT) is a common multifactorial disease associated with a major public health burden. Genetics factors are known to contribute to the susceptibility of the disease but how many genes are involved and their contribution to VT risk still remain obscure. We aimed to identify genetic variants associated with VT risk.

Methodology/principal findings: We conducted a genome-wide association study (GWAS) based on 551,141 SNPs genotyped in 1,542 cases and 1,110 controls. Twelve SNPs reached the genome-wide significance level of 2.0×10(-8) and encompassed four known VT-associated loci, ABO, F5, F11 and FGG. By means of haplotype analyses, we also provided novel arguments in favor of a role of HIVEP1, PROCR and STAB2, three loci recently hypothesized to participate in the susceptibility to VT. However, no novel VT-associated loci came out of our GWAS. Using a recently proposed statistical methodology, we also showed that common variants could explain about 35% of the genetic variance underlying VT susceptibility among which 3% could be attributable to the main identified VT loci. This analysis additionally suggested that the common variants left to be identified are not uniformly distributed across the genome and that chromosome 20, itself, could contribute to ∼7% of the total genetic variance.

Conclusions/significance: This study might also provide a valuable source of information to expand our understanding of biological mechanisms regulating quantitative biomarkers for VT.

Figure 1. Known candidate loci for VT.

Figure 2. Main outlines of the adopted sequential GWAS strategy.

Figure 3. Quantile-Quantile plot representation of the GWAS results obtained from 491,258 studied SNPs.

Q-Q plot derived from all SNP p-values is illustrated by + . The exclusion of 878 SNPs located within ±500 kb of the ABO, F5, FGG and FXI loci, the four main well-established VT-associated loci, lead to the Q-Q plot symbolized by ○ with its 95% confidence interval in shaded area.

Figure 4. Manhattan plot of the association results from the combined analysis of two imputed GWAS data sets for 2,475,305 SNPs.

Figure 5. Regional association plots at the four genome-wide significant loci using imputed SNPs.

Four genome-wide significant loci were F5 (top left), FGG (top right), F11 (bottom left) and ABO (bottom right). These plots were drawn from the SNAP software .

Figure 6. Distribution of VT genetic variance across chromosomes.

In light grey is shown the relative contribution of specific loci.