@article {9194, title = {Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.}, journal = {Circulation}, volume = {146}, year = {2022}, month = {2022 Oct 18}, pages = {1225-1242}, abstract = {

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.

METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.

RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1\% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.

CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

}, keywords = {Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Thrombosis, Venous Thromboembolism}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.122.059675}, author = {Thibord, Florian and Klarin, Derek and Brody, Jennifer A and Chen, Ming-Huei and Levin, Michael G and Chasman, Daniel I and Goode, Ellen L and Hveem, Kristian and Teder-Laving, Maris and Martinez-Perez, Angel and A{\"\i}ssi, Dylan and Daian-Bacq, Delphine and Ito, Kaoru and Natarajan, Pradeep and Lutsey, Pamela L and Nadkarni, Girish N and de Vries, Paul S and Cuellar-Partida, Gabriel and Wolford, Brooke N and Pattee, Jack W and Kooperberg, Charles and Braekkan, Sigrid K and Li-Gao, Ruifang and Saut, No{\'e}mie and Sept, Corriene and Germain, Marine and Judy, Renae L and Wiggins, Kerri L and Ko, Darae and O{\textquoteright}Donnell, Christopher J and Taylor, Kent D and Giulianini, Franco and de Andrade, Mariza and N{\o}st, Therese H and Boland, Anne and Empana, Jean-Philippe and Koyama, Satoshi and Gilliland, Thomas and Do, Ron and Huffman, Jennifer E and Wang, Xin and Zhou, Wei and Manuel Soria, Jose and Carlos Souto, Juan and Pankratz, Nathan and Haessler, Jeffery and Hindberg, Kristian and Rosendaal, Frits R and Turman, Constance and Olaso, Robert and Kember, Rachel L and Bartz, Traci M and Lynch, Julie A and Heckbert, Susan R and Armasu, Sebastian M and Brumpton, Ben and Smadja, David M and Jouven, Xavier and Komuro, Issei and Clapham, Katharine R and Loos, Ruth J F and Willer, Cristen J and Sabater-Lleal, Maria and Pankow, James S and Reiner, Alexander P and Morelli, Vania M and Ridker, Paul M and Vlieg, Astrid van Hylckama and Deleuze, Jean-Francois and Kraft, Peter and Rader, Daniel J and Min Lee, Kyung and Psaty, Bruce M and Heidi Skogholt, Anne and Emmerich, Joseph and Suchon, Pierre and Rich, Stephen S and Vy, Ha My T and Tang, Weihong and Jackson, Rebecca D and Hansen, John-Bjarne and Morange, Pierre-Emmanuel and Kabrhel, Christopher and Tr{\'e}gou{\"e}t, David-Alexandre and Damrauer, Scott M and Johnson, Andrew D and Smith, Nicholas L} } @article {9914, title = {Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases.}, journal = {Nat Genet}, volume = {57}, year = {2025}, month = {2025 Mar}, pages = {539-547}, abstract = {

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.

}, keywords = {Atrial Fibrillation, Chromatin, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-024-02072-3}, author = {Roselli, Carolina and Surakka, Ida and Olesen, Morten S and Sveinbjornsson, Gardar and Marston, Nicholas A and Choi, Seung Hoan and Holm, Hilma and Chaffin, Mark and Gudbjartsson, Daniel and Hill, Matthew C and Aegisdottir, Hildur and Albert, Christine M and Alonso, Alvaro and Anderson, Christopher D and Arking, Dan E and Arnar, David O and Barnard, John and Benjamin, Emelia J and Braunwald, Eugene and Brumpton, Ben and Campbell, Archie and Chami, Nathalie and Chasman, Daniel I and Cho, Kelly and Choi, Eue-Keun and Christophersen, Ingrid E and Chung, Mina K and Conen, David and Crijns, Harry J and Cutler, Michael J and Czuba, Tomasz and Damrauer, Scott M and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton and Duong, ThuyVy and Erikstrup, Christian and Esko, T{\~o}nu and Fatkin, Diane and Faul, Jessica D and Ferreira, Manuel and Freitag, Daniel F and Ganesh, Santhi K and Gaziano, J Michael and Geelhoed, Bastiaan and Ghouse, Jonas and Gieger, Christian and Giulianini, Franco and Graham, Sarah E and Gudnason, Vilmundur and Guo, Xiuqing and Haggerty, Christopher and Hayward, Caroline and Heckbert, Susan R and Hveem, Kristian and Ito, Kaoru and Johnson, Renee and Jukema, J Wouter and Jurgens, Sean J and K{\"a}{\"a}b, Stefan and Kane, John P and Kany, Shinwan and Kardia, Sharon L R and Kavousi, Maryam and Khurshid, Shaan and Kamanu, Frederick K and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Komuro, Issei and Krieger, Jose E and Launer, Lenore J and Li, Dadong and Lin, Honghuang and Lin, Henry J and Loos, Ruth J F and Lotta, Luca and Lubitz, Steven A and Lunetta, Kathryn L and Macfarlane, Peter W and Magnusson, Patrik K E and Malik, Rainer and Mantineo, Helene and Marcus, Gregory M and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Melloni, Giorgio E M and Meyre, Pascal B and Miyazawa, Kazuo and Mohanty, Sanghamitra and Monfort, Laia M and M{\"u}ller-Nurasyid, Martina and Nafissi, Navid A and Natale, Andrea and Nazarian, Saman and Ostrowski, Sisse R and Pak, Hui-Nam and Pang, Shichao and Pedersen, Ole B and Pedersen, Nancy L and Pereira, Alexandre C and Pirruccello, James P and Preuss, Michael and Psaty, Bruce M and Pullinger, Clive R and Rader, Daniel J and R{\"a}m{\"o}, Joel T and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rotter, Jerome I and Sabatine, Marc S and Schunkert, Heribert and Shah, Svati H and Shim, Jaemin and Shoemaker, M Benjamin and Simonson, Bridget and Sinner, Moritz F and Smit, Roelof A J and Smith, Jennifer A and Smith, Nicholas L and Smith, J Gustav and Soliman, Elsayed Z and S{\o}rensen, Erik and Sotoodehnia, Nona and Strbian, Daniel and Stricker, Bruno H and Teder-Laving, Maris and Sun, Yan V and Th{\'e}riault, S{\'e}bastien and Thorolfsdottir, Rosa B and Thorsteinsdottir, Unnur and Tveit, Arnljot and van der Harst, Pim and van Meurs, Joyce and Wang, Biqi and Weiss, Stefan and Wells, Quinn S and Weng, Lu-Chen and Wilson, Peter W and Xiao, Ling and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Zhao, Wei and Zhou, Xiang and Z{\"o}llner, Sebastian and Ruff, Christian T and Bundgaard, Henning and Willer, Cristen and Stefansson, Kari and Ellinor, Patrick T} }