@article {6681, title = {Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 Apr 2}, pages = {532-42}, abstract = {

Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5~{\texttimes} 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67~{\texttimes} 10(-16)) and 1.21 (p = 2.75~{\texttimes} 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

}, keywords = {Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Membrane Glycoproteins, Membrane Transport Proteins, Odds Ratio, Tetraspanins, Venous Thromboembolism}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.01.019}, author = {Germain, Marine and Chasman, Daniel I and de Haan, Hugoline and Tang, Weihong and Lindstr{\"o}m, Sara and Weng, Lu-Chen and de Andrade, Mariza and de Visser, Marieke C H and Wiggins, Kerri L and Suchon, Pierre and Saut, No{\'e}mie and Smadja, David M and Le Gal, Gr{\'e}goire and van Hylckama Vlieg, Astrid and Di Narzo, Antonio and Hao, Ke and Nelson, Christopher P and Rocanin-Arjo, Ares and Folkersen, Lasse and Monajemi, Ramin and Rose, Lynda M and Brody, Jennifer A and Slagboom, Eline and A{\"\i}ssi, Dylan and Gagnon, France and Deleuze, Jean-Francois and Deloukas, Panos and Tzourio, Christophe and Dartigues, Jean-Fran{\c c}ois and Berr, Claudine and Taylor, Kent D and Civelek, Mete and Eriksson, Per and Psaty, Bruce M and Houwing-Duitermaat, Jeanine and Goodall, Alison H and Cambien, Francois and Kraft, Peter and Amouyel, Philippe and Samani, Nilesh J and Basu, Saonli and Ridker, Paul M and Rosendaal, Frits R and Kabrhel, Christopher and Folsom, Aaron R and Heit, John and Reitsma, Pieter H and Tr{\'e}gou{\"e}t, David-Alexandre and Smith, Nicholas L and Morange, Pierre-Emmanuel} } @article {7777, title = {Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study.}, journal = {Hum Genet}, volume = {136}, year = {2017}, month = {2017 07}, pages = {897-902}, abstract = {

Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P~<~0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95\% CI 1.02-1.12, P~=~0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR~=~1.59, 95\% CI 1.30-1.93 per standard deviation increase in BMI, P~=~5.8~{\texttimes}~10). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.

}, keywords = {Adult, Body Mass Index, Case-Control Studies, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Incidence, Logistic Models, Male, Mendelian Randomization Analysis, Obesity, Polymorphism, Single Nucleotide, Proportional Hazards Models, Venous Thromboembolism}, issn = {1432-1203}, doi = {10.1007/s00439-017-1811-x}, author = {Lindstr{\"o}m, Sara and Germain, Marine and Crous-Bou, Marta and Smith, Erin N and Morange, Pierre-Emmanuel and van Hylckama Vlieg, Astrid and de Haan, Hugoline G and Chasman, Daniel and Ridker, Paul and Brody, Jennifer and de Andrade, Mariza and Heit, John A and Tang, Weihong and DeVivo, Immaculata and Grodstein, Francine and Smith, Nicholas L and Tregouet, David and Kabrhel, Christopher} } @article {7816, title = {DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis.}, journal = {Blood}, year = {2018}, month = {2018 Jul 24}, abstract = {

Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95\% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95\% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

}, issn = {1528-0020}, doi = {10.1182/blood-2018-02-831347}, author = {Ward-Caviness, Cavin K and Huffman, Jennifer E and Evertt, Karl and Germain, Marine and van Dongen, Jenny and Hill, W David and Jhun, Min A and Brody, Jennifer A and Ghanbari, Mohsen and Du, Lei and Roetker, Nicholas S and de Vries, Paul S and Waldenberger, Melanie and Gieger, Christian and Wolf, Petra and Prokisch, Holger and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J and Levy, Daniel and Liu, Chunyu and Truong, Vinh and Wells, Philip S and Tr{\'e}gou{\"e}t, David-Alexandre and Tang, Weihong and Morrison, Alanna C and Boerwinkle, Eric and Wiggins, Kerri L and McKnight, Barbara and Guo, Xiuqing and Psaty, Bruce M and Sotoodenia, Nona and Boomsa, Dorret I and Willemsen, Gonneke and Ligthart, Lannie and Deary, Ian J and Zhao, Wei and Ware, Erin B and Kardia, Sharon L R and van Meurs, Joyce B J and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Eriksson, Per and Franco-Cereceda, Anders and Pankow, James S and Johnson, Andrew D and Gagnon, France and Morange, Pierre-Emmanuel and de Geus, Eco J C and Starr, John M and Smith, Jennifer A and Dehghan, Abbas and Bj{\"o}rck, Hanna M and Smith, Nicholas L and Peters, Annette} } @article {7924, title = {Genome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.}, journal = {Circulation}, year = {2018}, month = {2018 Nov 20}, abstract = {

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

RESULTS: We identified 13 novel genome-wide significant (p<=2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.034532}, author = {Sabater-Lleal, Maria and Huffman, Jennifer E and de Vries, Paul S and Marten, Jonathan and Mastrangelo, Michael A and Song, Ci and Pankratz, Nathan and Ward-Caviness, Cavin K and Yanek, Lisa R and Trompet, Stella and Delgado, Graciela E and Guo, Xiuqing and Bartz, Traci M and Martinez-Perez, Angel and Germain, Marine and de Haan, Hugoline G and Ozel, Ayse B and Polasek, Ozren and Smith, Albert V and Eicher, John D and Reiner, Alex P and Tang, Weihong and Davies, Neil M and Stott, David J and Rotter, Jerome I and Tofler, Geoffrey H and Boerwinkle, Eric and de Maat, Moniek P M and Kleber, Marcus E and Welsh, Paul and Brody, Jennifer A and Chen, Ming-Huei and Vaidya, Dhananjay and Soria, Jos{\'e} Manuel and Suchon, Pierre and van Hylckama Vlieg, Astrid and Desch, Karl C and Kolcic, Ivana and Joshi, Peter K and Launer, Lenore J and Harris, Tamara B and Campbell, Harry and Rudan, Igor and Becker, Diane M and Li, Jun Z and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and Franco, Oscar H and Cushman, Mary and Psaty, Bruce M and Morange, Pierre-Emmanuel and McKnight, Barbara and Chong, Michael R and Fernandez-Cadenas, Israel and Rosand, Jonathan and Lindgren, Arne and Gudnason, Vilmundur and Wilson, James F and Hayward, Caroline and Ginsburg, David and Fornage, Myriam and Rosendaal, Frits R and Souto, Juan Carlos and Becker, Lewis C and Jenny, Nancy S and M{\"a}rz, Winfried and Jukema, J Wouter and Dehghan, Abbas and Tr{\'e}gou{\"e}t, David-Alexandre and Morrison, Alanna C and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Strachan, David P and Lowenstein, Charles J and Smith, Nicholas L} } @article {8198, title = {Associations of autozygosity with a broad range of human phenotypes.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Oct 31}, pages = {4957}, abstract = {

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55\% decrease [95\% CI 44-66\%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12283-6}, author = {Clark, David W and Okada, Yukinori and Moore, Kristjan H S and Mason, Dan and Pirastu, Nicola and Gandin, Ilaria and Mattsson, Hannele and Barnes, Catriona L K and Lin, Kuang and Zhao, Jing Hua and Deelen, Patrick and Rohde, Rebecca and Schurmann, Claudia and Guo, Xiuqing and Giulianini, Franco and Zhang, Weihua and Medina-G{\'o}mez, Carolina and Karlsson, Robert and Bao, Yanchun and Bartz, Traci M and Baumbach, Clemens and Biino, Ginevra and Bixley, Matthew J and Brumat, Marco and Chai, Jin-Fang and Corre, Tanguy and Cousminer, Diana L and Dekker, Annelot M and Eccles, David A and van Eijk, Kristel R and Fuchsberger, Christian and Gao, He and Germain, Marine and Gordon, Scott D and de Haan, Hugoline G and Harris, Sarah E and Hofer, Edith and Huerta-Chagoya, Alicia and Igartua, Catherine and Jansen, Iris E and Jia, Yucheng and Kacprowski, Tim and Karlsson, Torgny and Kleber, Marcus E and Li, Shengchao Alfred and Li-Gao, Ruifang and Mahajan, Anubha and Matsuda, Koichi and Meidtner, Karina and Meng, Weihua and Montasser, May E and van der Most, Peter J and Munz, Matthias and Nutile, Teresa and Palviainen, Teemu and Prasad, Gauri and Prasad, Rashmi B and Priyanka, Tallapragada Divya Sri and Rizzi, Federica and Salvi, Erika and Sapkota, Bishwa R and Shriner, Daniel and Skotte, Line and Smart, Melissa C and Smith, Albert Vernon and van der Spek, Ashley and Spracklen, Cassandra N and Strawbridge, Rona J and Tajuddin, Salman M and Trompet, Stella and Turman, Constance and Verweij, Niek and Viberti, Clara and Wang, Lihua and Warren, Helen R and Wootton, Robyn E and Yanek, Lisa R and Yao, Jie and Yousri, Noha A and Zhao, Wei and Adeyemo, Adebowale A and Afaq, Saima and Aguilar-Salinas, Carlos Alberto and Akiyama, Masato and Albert, Matthew L and Allison, Matthew A and Alver, Maris and Aung, Tin and Azizi, Fereidoun and Bentley, Amy R and Boeing, Heiner and Boerwinkle, Eric and Borja, Judith B and de Borst, Gert J and Bottinger, Erwin P and Broer, Linda and Campbell, Harry and Chanock, Stephen and Chee, Miao-Li and Chen, Guanjie and Chen, Yii-der I and Chen, Zhengming and Chiu, Yen-Feng and Cocca, Massimiliano and Collins, Francis S and Concas, Maria Pina and Corley, Janie and Cugliari, Giovanni and van Dam, Rob M and Damulina, Anna and Daneshpour, Maryam S and Day, Felix R and Delgado, Graciela E and Dhana, Klodian and Doney, Alexander S F and D{\"o}rr, Marcus and Doumatey, Ayo P and Dzimiri, Nduna and Ebenesersd{\'o}ttir, S Sunna and Elliott, Joshua and Elliott, Paul and Ewert, Ralf and Felix, Janine F and Fischer, Krista and Freedman, Barry I and Girotto, Giorgia and Goel, Anuj and G{\"o}gele, Martin and Goodarzi, Mark O and Graff, Mariaelisa and Granot-Hershkovitz, Einat and Grodstein, Francine and Guarrera, Simonetta and Gudbjartsson, Daniel F and Guity, Kamran and Gunnarsson, Bjarni and Guo, Yu and Hagenaars, Saskia P and Haiman, Christopher A and Halevy, Avner and Harris, Tamara B and Hedayati, Mehdi and van Heel, David A and Hirata, Makoto and H{\"o}fer, Imo and Hsiung, Chao Agnes and Huang, Jinyan and Hung, Yi-Jen and Ikram, M Arfan and Jagadeesan, Anuradha and Jousilahti, Pekka and Kamatani, Yoichiro and Kanai, Masahiro and Kerrison, Nicola D and Kessler, Thorsten and Khaw, Kay-Tee and Khor, Chiea Chuen and de Kleijn, Dominique P V and Koh, Woon-Puay and Kolcic, Ivana and Kraft, Peter and Kr{\"a}mer, Bernhard K and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lawlor, Deborah A and Lee, I-Te and Lee, Wen-Jane and Lerch, Markus M and Li, Liming and Liu, Jianjun and Loh, Marie and London, Stephanie J and Loomis, Stephanie and Lu, Yingchang and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Manichaikul, Ani W and Manunta, Paolo and M{\'a}sson, G{\'\i}sli and Matoba, Nana and Mei, Xue W and Meisinger, Christa and Meitinger, Thomas and Mezzavilla, Massimo and Milani, Lili and Millwood, Iona Y and Momozawa, Yukihide and Moore, Amy and Morange, Pierre-Emmanuel and Moreno-Macias, Hortensia and Mori, Trevor A and Morrison, Alanna C and Muka, Taulant and Murakami, Yoshinori and Murray, Alison D and de Mutsert, Ren{\'e}e and Mychaleckyj, Josyf C and Nalls, Mike A and Nauck, Matthias and Neville, Matt J and Nolte, Ilja M and Ong, Ken K and Orozco, Lorena and Padmanabhan, Sandosh and P{\'a}lsson, Gunnar and Pankow, James S and Pattaro, Cristian and Pattie, Alison and Polasek, Ozren and Poulter, Neil and Pramstaller, Peter P and Quintana-Murci, Lluis and R{\"a}ikk{\"o}nen, Katri and Ralhan, Sarju and Rao, Dabeeru C and van Rheenen, Wouter and Rich, Stephen S and Ridker, Paul M and Rietveld, Cornelius A and Robino, Antonietta and van Rooij, Frank J A and Ruggiero, Daniela and Saba, Yasaman and Sabanayagam, Charumathi and Sabater-Lleal, Maria and Sala, Cinzia Felicita and Salomaa, Veikko and Sandow, Kevin and Schmidt, Helena and Scott, Laura J and Scott, William R and Sedaghati-Khayat, Bahareh and Sennblad, Bengt and van Setten, Jessica and Sever, Peter J and Sheu, Wayne H-H and Shi, Yuan and Shrestha, Smeeta and Shukla, Sharvari Rahul and Sigurdsson, Jon K and Sikka, Timo Tonis and Singh, Jai Rup and Smith, Blair H and Stan{\v c}{\'a}kov{\'a}, Alena and Stanton, Alice and Starr, John M and Stefansdottir, Lilja and Straker, Leon and Sulem, Patrick and Sveinbjornsson, Gardar and Swertz, Morris A and Taylor, Adele M and Taylor, Kent D and Terzikhan, Natalie and Tham, Yih-Chung and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tillander, Annika and Tracy, Russell P and Tusi{\'e}-Luna, Teresa and Tzoulaki, Ioanna and Vaccargiu, Simona and Vangipurapu, Jagadish and Veldink, Jan H and Vitart, Veronique and V{\"o}lker, Uwe and Vuoksimaa, Eero and Wakil, Salma M and Waldenberger, Melanie and Wander, Gurpreet S and Wang, Ya Xing and Wareham, Nicholas J and Wild, Sarah and Yajnik, Chittaranjan S and Yuan, Jian-Min and Zeng, Lingyao and Zhang, Liang and Zhou, Jie and Amin, Najaf and Asselbergs, Folkert W and Bakker, Stephan J L and Becker, Diane M and Lehne, Benjamin and Bennett, David A and van den Berg, Leonard H and Berndt, Sonja I and Bharadwaj, Dwaipayan and Bielak, Lawrence F and Bochud, Murielle and Boehnke, Mike and Bouchard, Claude and Bradfield, Jonathan P and Brody, Jennifer A and Campbell, Archie and Carmi, Shai and Caulfield, Mark J and Cesarini, David and Chambers, John C and Chandak, Giriraj Ratan and Cheng, Ching-Yu and Ciullo, Marina and Cornelis, Marilyn and Cusi, Daniele and Smith, George Davey and Deary, Ian J and Dorajoo, Rajkumar and van Duijn, Cornelia M and Ellinghaus, David and Erdmann, Jeanette and Eriksson, Johan G and Evangelou, Evangelos and Evans, Michele K and Faul, Jessica D and Feenstra, Bjarke and Feitosa, Mary and Foisy, Sylvain and Franke, Andre and Friedlander, Yechiel and Gasparini, Paolo and Gieger, Christian and Gonzalez, Clicerio and Goyette, Philippe and Grant, Struan F A and Griffiths, Lyn R and Groop, Leif and Gudnason, Vilmundur and Gyllensten, Ulf and Hakonarson, Hakon and Hamsten, Anders and van der Harst, Pim and Heng, Chew-Kiat and Hicks, Andrew A and Hochner, Hagit and Huikuri, Heikki and Hunt, Steven C and Jaddoe, Vincent W V and De Jager, Philip L and Johannesson, Magnus and Johansson, Asa and Jonas, Jost B and Jukema, J Wouter and Junttila, Juhani and Kaprio, Jaakko and Kardia, Sharon L R and Karpe, Fredrik and Kumari, Meena and Laakso, Markku and van der Laan, Sander W and Lahti, Jari and Laudes, Matthias and Lea, Rodney A and Lieb, Wolfgang and Lumley, Thomas and Martin, Nicholas G and M{\"a}rz, Winfried and Matullo, Giuseppe and McCarthy, Mark I and Medland, Sarah E and Merriman, Tony R and Metspalu, Andres and Meyer, Brian F and Mohlke, Karen L and Montgomery, Grant W and Mook-Kanamori, Dennis and Munroe, Patricia B and North, Kari E and Nyholt, Dale R and O{\textquoteright}Connell, Jeffery R and Ober, Carole and Oldehinkel, Albertine J and Palmas, Walter and Palmer, Colin and Pasterkamp, Gerard G and Patin, Etienne and Pennell, Craig E and Perusse, Louis and Peyser, Patricia A and Pirastu, Mario and Polderman, Tinca J C and Porteous, David J and Posthuma, Danielle and Psaty, Bruce M and Rioux, John D and Rivadeneira, Fernando and Rotimi, Charles and Rotter, Jerome I and Rudan, Igor and den Ruijter, Hester M and Sanghera, Dharambir K and Sattar, Naveed and Schmidt, Reinhold and Schulze, Matthias B and Schunkert, Heribert and Scott, Robert A and Shuldiner, Alan R and Sim, Xueling and Small, Neil and Smith, Jennifer A and Sotoodehnia, Nona and Tai, E-Shyong and Teumer, Alexander and Timpson, Nicholas J and Toniolo, Daniela and Tr{\'e}gou{\"e}t, David-Alexandre and Tuomi, Tiinamaija and Vollenweider, Peter and Wang, Carol A and Weir, David R and Whitfield, John B and Wijmenga, Cisca and Wong, Tien-Yin and Wright, John and Yang, Jingyun and Yu, Lei and Zemel, Babette S and Zonderman, Alan B and Perola, Markus and Magnusson, Patrik K E and Uitterlinden, Andr{\'e} G and Kooner, Jaspal S and Chasman, Daniel I and Loos, Ruth J F and Franceschini, Nora and Franke, Lude and Haley, Chris S and Hayward, Caroline and Walters, Robin G and Perry, John R B and Esko, T{\~o}nu and Helgason, Agnar and Stefansson, Kari and Joshi, Peter K and Kubo, Michiaki and Wilson, James F} } @article {8200, title = {Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.}, journal = {Blood}, volume = {134}, year = {2019}, month = {2019 Nov 07}, pages = {1645-1657}, abstract = {

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

}, issn = {1528-0020}, doi = {10.1182/blood.2019000435}, author = {Lindstr{\"o}m, Sara and Wang, Lu and Smith, Erin N and Gordon, William and van Hylckama Vlieg, Astrid and de Andrade, Mariza and Brody, Jennifer A and Pattee, Jack W and Haessler, Jeffrey and Brumpton, Ben M and Chasman, Daniel I and Suchon, Pierre and Chen, Ming-Huei and Turman, Constance and Germain, Marine and Wiggins, Kerri L and MacDonald, James and Braekkan, Sigrid K and Armasu, Sebastian M and Pankratz, Nathan and Jackson, Rebecca D and Nielsen, Jonas B and Giulianini, Franco and Puurunen, Marja K and Ibrahim, Manal and Heckbert, Susan R and Damrauer, Scott M and Natarajan, Pradeep and Klarin, Derek and de Vries, Paul S and Sabater-Lleal, Maria and Huffman, Jennifer E and Bammler, Theo K and Frazer, Kelly A and McCauley, Bryan M and Taylor, Kent and Pankow, James S and Reiner, Alexander P and Gabrielsen, Maiken E and Deleuze, Jean-Francois and O{\textquoteright}Donnell, Chris J and Kim, Jihye and McKnight, Barbara and Kraft, Peter and Hansen, John-Bjarne and Rosendaal, Frits R and Heit, John A and Psaty, Bruce M and Tang, Weihong and Kooperberg, Charles and Hveem, Kristian and Ridker, Paul M and Morange, Pierre-Emmanuel and Johnson, Andrew D and Kabrhel, Christopher and Tr{\'e}gou{\"e}t, David-Alexandre and Smith, Nicholas L} } @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 {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} }