A large‐scale exome array analysis of venous thromboembolism

Abstract

Although recent Genome‐Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome‐wide search for low‐frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta‐analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene‐based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene‐based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low‐frequency and rare variants associated with VTE risk.

Genetic risk factors for venous thromboembolism

“…The development of several so-called next generation sequencing (NGS) or High-Throughput Nucleotide Sequencing platforms is offering the possibility of generating fast, inexpensive and accurate genomic information, reviewed by Cunha et al [54]. A few such studies have been published [55][56][57][58][59][60][61][62][63][64]. These studies could be either agnostic [61][62][63][64], i.e.…”

“…A few such studies have been published [55][56][57][58][59][60][61][62][63][64]. These studies could be either agnostic [61][62][63][64], i.e. whole exome sequencing (WES) or whole genome sequencing (WGS), or using NGS for resequencing of targeted candidate genes [55][56][57][58][59][60].…”

An agnostic study of associations between ABO and RhD blood group and phenome-wide disease risk

“…Multiple subsequent studies have revealed associations with a range of diseases, with a prominent example being a decreased risk of thromboembolic events and increased risks of some hemorrhagic events in individuals with blood group O ( Franchini et al, 2012 ; Edgren et al, 2010 ; Vasan et al, 2016a ). The difference in thrombotic and hemorrhagic phenotypes has been attributed to variability in levels of Factor VIII and von Willebrand factor , where ABO status may explain as much as 30% of this variability ( Franchini et al, 2012 ; Orstavik et al, 1985 ; Germain et al, 2015 ; Lindström et al, 2019 ; O'Donnell et al, 2002 ) Other prominent examples include associations with risks of a number of infectious diseases, to the extent that the allele distribution of the blood group antigens has evolved to reflect some areas endemic to these infectious diseases ( Franchini and Bonfanti, 2015 ). This is in part true for infectious disease such as Plasmodium falciparum malaria, Helicobacter pylori , and Vibrio cholera , where ABO blood groups are involved in different aspects of pathogenesis, from microbe attachment and entry into cells to subsequent disease development and severity of disease ( Stowell and Stowell, 2019a ; Franchini and Bonfanti, 2015 ; Cserti and Dzik, 2007 ; Degarege et al, 2019 ).…”

Advances in Understanding Mechanisms of Thrombophilic Disorders

“…However, a metanalysis of large-scale exome array analyses of VTE failed to identify novel VTE genes. 63…”