@article {7979, title = {A large-scale exome array analysis of venous thromboembolism.}, journal = {Genet Epidemiol}, year = {2019}, month = {2019 Jan 19}, 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.

}, issn = {1098-2272}, doi = {10.1002/gepi.22187}, author = {Lindstr{\"o}m, Sara and Brody, Jennifer A and Turman, Constance and Germain, Marine and Bartz, Traci M and Smith, Erin N and Chen, Ming-Huei and Puurunen, Marja and Chasman, Daniel and Hassler, Jeffrey and Pankratz, Nathan and Basu, Saonli and Guan, Weihua and Gyorgy, Beata and Ibrahim, Manal and Empana, Jean-Philippe and Olaso, Robert and Jackson, Rebecca and Braekkan, Sigrid K and McKnight, Barbara and Deleuze, Jean-Francois and O{\textquoteright}Donnell, Cristopher J and Jouven, Xavier and Frazer, Kelly A and Psaty, Bruce M and Wiggins, Kerri L and Taylor, Kent and Reiner, Alexander P and Heckbert, Susan R and Kooperberg, Charles and Ridker, Paul and Hansen, John-Bjarne and Tang, Weihong and Johnson, Andrew D and Morange, Pierre-Emmanuel and Tr{\'e}gou{\"e}t, David A and Kraft, Peter and Smith, Nicholas L and Kabrhel, Christopher} } @article {8791, title = {FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.}, journal = {J Thromb Haemost}, year = {2021}, month = {2021 Apr 20}, abstract = {

BACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.

OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.

METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n~=~15~603), tPA (n~=~6876,) and D-dimer (n~=~19~306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.

RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P~<~5~{\texttimes}~10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P~<~1~{\texttimes}~10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.

CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.

}, issn = {1538-7836}, doi = {10.1111/jth.15345}, author = {Thibord, Florian and Song, Ci and Pattee, Jack and Rodriguez, Benjamin A T and Chen, Ming-Huei and O{\textquoteright}Donnell, Christopher J and Kleber, Marcus E and Delgado, Graciela E and Guo, Xiuqing and Yao, Jie and Taylor, Kent D and Ozel, Ayse Bilge and Brody, Jennifer A and McKnight, Barbara and Gyorgy, Beata and Simonsick, Eleanor and Leonard, Hampton L and Carrasquilla, Germ{\'a}n D and Guindo-Martinez, Marta and Silveira, Angela and Temprano-Sagrera, Gerard and Yanek, Lisa R and Becker, Diane M and Mathias, Rasika A and Becker, Lewis C and Raffield, Laura M and Kilpel{\"a}inen, Tuomas O and Grarup, Niels and Pedersen, Oluf and Hansen, Torben and Linneberg, Allan and Hamsten, Anders and Watkins, Hugh and Sabater-Lleal, Maria and Nalls, Mike A and Tr{\'e}gou{\"e}t, David-Alexandre and Morange, Pierre-Emmanuel and Psaty, Bruce M and Tracy, Russel P and Smith, Nicholas L and Desch, Karl C and Cushman, Mary and Rotter, Jerome I and de Vries, Paul S and Pankratz, Nathan D and Folsom, Aaron R and Morrison, Alanna C and M{\"a}rz, Winfried and Tang, Weihong and Johnson, Andrew D} }