Novel gene variants and risk of venous thromboembolism

Family and twin studies indicate that genetic factors account for 60% of the venous thromboembolism risk.

Currently, known genetic variants, including common variants identified by genome-wide association studies (GWAS), explain 20-30% of the venous thromboembolism events. Previously implicated loci include protein coding variants in genes with common alleles of moderate effect (e.g. ABO and F5), and genes with multiple private mutations (e.g. PROC and PROS1) with high impact on venous thromboembolism risk.  Thus, there remains an unmet need for the genome-wide identification of common and rare coding variants that are associated with risk of venous thromboembolism.

Targeted sequencing of the human exome (all coding sequences) is a promising approach for maximizing the efficiency of second-generation sequencing technologies for population-based studies.

Whole exome sequencing has recently been completed on DNA isolated from samples in the Tromsø study (discovery cohort) at the Division of Genome Information Sciences, UCSD, La Jolla, CA, USA. This sequencing cohort is composed of 465 randomly selected venous thromboembolism patients and 455 population-based controls.

Exome sequencing was performed to an average depth of ~100X on target to identify high quality genotypes at both common and rare variants. Using the 1000 Genomes Project EUR population as a reference, we imputed high quality genotypes at 4.3M SNPs and 300K indels throughout the genome.

To identify novel gene and genetic loci associated with venous thromboembolism risk these variants will be tested for association with venous thromboembolism using single site and rare variant collapsing tests. Specific findings will be replicated in a large case-control study. 

Novel sites will be comprehensively characterized in epidemiological and functional studies. Studies will also be conducted to investigate how novel gene variants interact with anthropometric measures and life-style factors.

Responsible: John-Bjarne Hansen