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33 results on '"Hopewell, Jemma C."'

1. Proteomic profiling identifies novel independent relationships between inflammatory proteins and myocardial infarction

Author

Valdes-Marquez, Elsa, Clarke, Robert, Hill, Michael, Watkins, Hugh, and Hopewell, Jemma C

Abstract

The PROCARDIS study conducted a hypothesis-free proteomic study using a panel of 92 inflammatory proteins in cases with early onset myocardial infarction (MI) and healthy controls and identified 15 proteins that were significantly associated with MI, including five proteins that independently contributed to risk of MI.The study used state-of-the-art analytical methods including conventional statistical analysis and machine learning approaches to characterize the proteomic associations with MI. It also integrated bioinformatic and genomic data to consider the biological relevance of the proteins independently associated with MI.The findings provide novel insights into the ‘inflammatory basis’ of MI and provide support for prioritizing a wider array of inflammatory proteins for further study than have been previously considered in order to discover if therapeutic modification could be used for treatment and prevention of MI.

Published
2023
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2. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

Author

Aragam, Krishna G., Jiang, Tao, Goel, Anuj, Kanoni, Stavroula, Wolford, Brooke N., Atri, Deepak S., Weeks, Elle M., Wang, Minxian, Hindy, George, Zhou, Wei, Grace, Christopher, Roselli, Carolina, Marston, Nicholas A., Kamanu, Frederick K., Surakka, Ida, Venegas, Loreto Muñoz, Sherliker, Paul, Koyama, Satoshi, Ishigaki, Kazuyoshi, Åsvold, Bjørn O., Brown, Michael R., Brumpton, Ben, de Vries, Paul S., Giannakopoulou, Olga, Giardoglou, Panagiota, Gudbjartsson, Daniel F., Güldener, Ulrich, Haider, Syed M. Ijlal, Helgadottir, Anna, Ibrahim, Maysson, Kastrati, Adnan, Kessler, Thorsten, Kyriakou, Theodosios, Konopka, Tomasz, Li, Ling, Ma, Lijiang, Meitinger, Thomas, Mucha, Sören, Munz, Matthias, Murgia, Federico, Nielsen, Jonas B., Nöthen, Markus M., Pang, Shichao, Reinberger, Tobias, Schnitzler, Gavin, Smedley, Damian, Thorleifsson, Gudmar, von Scheidt, Moritz, Ulirsch, Jacob C., Arnar, David O., Burtt, Noël P., Costanzo, Maria C., Flannick, Jason, Ito, Kaoru, Jang, Dong-Keun, Kamatani, Yoichiro, Khera, Amit V., Komuro, Issei, Kullo, Iftikhar J., Lotta, Luca A., Nelson, Christopher P., Roberts, Robert, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Webb, Thomas R., Baras, Aris, Björkegren, Johan L. M., Boerwinkle, Eric, Dedoussis, George, Holm, Hilma, Hveem, Kristian, Melander, Olle, Morrison, Alanna C., Orho-Melander, Marju, Rallidis, Loukianos S., Ruusalepp, Arno, Sabatine, Marc S., Stefansson, Kari, Zalloua, Pierre, Ellinor, Patrick T., Farrall, Martin, Danesh, John, Ruff, Christian T., Finucane, Hilary K., Hopewell, Jemma C., Clarke, Robert, Gupta, Rajat M., Erdmann, Jeanette, Samani, Nilesh J., Schunkert, Heribert, Watkins, Hugh, Willer, Cristen J., Deloukas, Panos, Kathiresan, Sekar, and Butterworth, Adam S.

Abstract

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

Published
2022
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3. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jürgenson, Tuuli, Namba, Shinichi, Posner, Daniel C., Kamanu, Frederick K., Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K., Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C., Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R., Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V., Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Cárcel-Márquez, Jara, Nygaard, Marianne, Leonard, Hampton L., Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J., Lewis, Adam J., Judy, Renae L., Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D., Bakker, Mark K., Bartz, Traci M., Bennett, David A., Bis, Joshua C., Bordes, Constance, Børte, Sigrid, Cain, Anael, Ridker, Paul M., Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W., de Jager, Phil L., de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E., Geerlings, Mirjam I., Gasca, Natalie C., Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K., Ho, Yuk-Lam, Havulinna, Aki S., Hopewell, Jemma C., Hyacinth, Hyacinth I., Inouye, Michael, Jacob, Mina A., Jeon, Christina E., Jern, Christina, Kamouchi, Masahiro, Keene, Keith L., Kitazono, Takanari, Kittner, Steven J., Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J., Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S., Marston, Nicholas A., Meitinger, Thomas, Mitchell, Braxton D., Montellano, Felipe A., Morisaki, Takayuki, Mosley, Thomas H., Nalls, Mike A., Nordestgaard, Børge G., O’Donnell, Martin J., Okada, Yukinori, Onland-Moret, N. Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M., Rich, Stephen S., Rosand, Jonathan, Sabatine, Marc S., Sacco, Ralph L., Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L., Schmidt, Carsten O., Shimizu, Atsushi, Smith, Nicholas L., Sloane, Kelly L., Sutoh, Yoichi, Sun, Yan V., Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P., Tiwari, Hemant K., Trégouët, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjærg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S., Wiggins, Kerri L., Wennberg, Patrik, Woo, Daniel, Wilson, Peter W. F., Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Millwood, Iona Y., Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J., Jukema, J. Wouter, Rissanen, Ina L., Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna M. M., Irvin, Marguerite R., Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A., Rundek, Tatjana, Worrall, Bradford B., Lathrop, G. Mark, Riaz, Moeen, Simonsick, Eleanor M., Kõrv, Janika, França, Paulo H. C., Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, de Leeuw, Frank-Erik, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M., Heuschmann, Peter Ulrich, Longstreth, W. T., Jung, Keum Ji, Bastarache, Lisa, Paré, Guillaume, Damrauer, Scott M., Chasman, Daniel I., Rotter, Jerome I., Anderson, Christopher D., Zwart, John-Anker, Niiranen, Teemu J., Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernández-Cadenas, Israel, Walters, Robin G., Ruff, Christian T., Owolabi, Mayowa O., Huffman, Jennifer E., Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Abstract

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P< 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2Aand FURIN) and variants (such as at GRK5and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Published
2022
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4. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Temprano‐Sagrera, Gerard, Sitlani, Colleen M., Bone, William P., Martin‐Bornez, Miguel, Voight, Benjamin F., Morrison, Alanna C., Damrauer, Scott M., de Vries, Paul S., Smith, Nicholas L., Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank W.G., Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Sabater‐Lleal, Maria, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L, Peyser, Patricia A, Elliot, Paul, de Vries, Paul S, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Chen, Ming‐Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Pankratz, Nathan, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean‐François, O’Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John‐Bjarne, Rosendaal, Frits R, Heit, John A, Psaty, Bruce M, Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre‐Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David‐Alexandre, Smith, Nicholas L, Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten‐Jacobs, Loes, Giese, Anne‐Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei‐Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang‐Chi, Hyacinth, Hyacinth I, Arfan Ikram, M, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez‐Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin‐Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei‐Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil‐Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu‐Ching, Hoan Choi, Seung, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean‐François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Mei Liu, Yong, Lopez, Oscar L, Makoto, Hirata, Martinez‐Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller‐Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Reddy Peddareddygari, Leema, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba‐Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti‐Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano‐Tárraga, Carolina, Stanne, Tara, Colin Stine, O, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres‐Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez‐Cadenas, Israel, Longstreth, W T, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Abstract

Multi‐phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.

Published
2022
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5. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Temprano‐Sagrera, Gerard, Sitlani, Colleen M., Bone, William P., Martin‐Bornez, Miguel, Voight, Benjamin F., Morrison, Alanna C., Damrauer, Scott M., de Vries, Paul S., Smith, Nicholas L., Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank W.G., Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Sabater‐Lleal, Maria, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L, Peyser, Patricia A, Elliot, Paul, de Vries, Paul S, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Chen, Ming‐Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Pankratz, Nathan, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean‐François, O’Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John‐Bjarne, Rosendaal, Frits R, Heit, John A, Psaty, Bruce M, Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre‐Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David‐Alexandre, Smith, Nicholas L, Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten‐Jacobs, Loes, Giese, Anne‐Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei‐Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang‐Chi, Hyacinth, Hyacinth I, Arfan Ikram, M, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez‐Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin‐Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei‐Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil‐Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu‐Ching, Hoan Choi, Seung, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean‐François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Mei Liu, Yong, Lopez, Oscar L, Makoto, Hirata, Martinez‐Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller‐Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Reddy Peddareddygari, Leema, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba‐Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti‐Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano‐Tárraga, Carolina, Stanne, Tara, Colin Stine, O, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres‐Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez‐Cadenas, Israel, Longstreth, W T, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Abstract

Multi‐phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Summary statistics from genome wide‐association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI‐1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi‐trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9obtained after applying Bonferroni correction for the number of multi‐trait combinations performed (n= 27). Across the 27 multi‐trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Published
2022
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7. Smoking and COVID-19 outcomes: an observational and Mendelian randomisation study using the UK Biobank cohort

Author

Clift, Ashley K, von Ende, Adam, Tan, Pui San, Sallis, Hannah M, Lindson, Nicola, Coupland, Carol A C, Munafò, Marcus R, Aveyard, Paul, Hippisley-Cox, Julia, and Hopewell, Jemma C

Abstract

BackgroundConflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity.MethodsWe undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase).ResultsThere were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1–9/day: OR 2.14, 95% CI 0.87 to 5.24; 10–19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72).InterpretationCongruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19.

Published
2022
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8. Cardiovascular care of patients with stroke and high risk of stroke: The need for interdisciplinary action: A consensus report from the European Society of Cardiology Cardiovascular Round Table

Author

Doehner, Wolfram, Mazighi, Mikael, Hofmann, Bernd M, Lautsch, Dominik, Hindricks, Gerhard, Bohula, Erin A, Byrne, Robert A, Camm, A John, Casadei, Barbara, Caso, Valeria, Cognard, Christophe, Diener, Hans-Christoph, Endres, Matthias, Goldstein, Patrick, Halliday, Alison, Hopewell, Jemma C, Jovanovic, Dejana R, Kobayashi, Adam, Kostrubiec, Maciej, Krajina, Antonin, Landmesser, Ulf, Markus, Hugh S, Ntaios, George, Pezzella, Francesca R, Ribo, Marc, Rosano, Giuseppe MC, Rubiera, Marta, Sharma, Mike, Touyz, Rhian M, and Widimsky, Petr

Abstract

Comprehensive stroke care is an interdisciplinary challenge. Close collaboration of cardiologists and stroke physicians is critical to ensure optimum utilisation of short- and long-term care and preventive measures in patients with stroke. Risk factor management is an important strategy that requires cardiologic involvement for primary and secondary stroke prevention. Treatment of stroke generally is led by stroke physicians, yet cardiologists need to be integrated care providers in stroke units to address all cardiovascular aspects of acute stroke care, including arrhythmia management, blood pressure control, elevated levels of cardiac troponins, valvular disease/endocarditis, and the general management of cardiovascular comorbidities. Despite substantial progress in stroke research and clinical care has been achieved, relevant gaps in clinical evidence remain and cause uncertainties in best practice for treatment and prevention of stroke. The Cardiovascular Round Table of the European Society of Cardiology together with the European Society of Cardiology Council on Stroke in cooperation with the European Stroke Organisation and partners from related scientific societies, regulatory authorities and industry conveyed a two-day workshop to discuss current and emerging concepts and apparent gaps in stroke care, including risk factor management, acute diagnostics, treatments and complications, and operational/logistic issues for health care systems and integrated networks. Joint initiatives of cardiologists and stroke physicians are needed in research and clinical care to target unresolved interdisciplinary problems and to promote the best possible outcomes for patients with stroke.

Published
2020
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9. Impact of ADCY9Genotype on Response to Anacetrapib

Author

Hopewell, Jemma C., Ibrahim, Maysson, Hill, Michael, Shaw, Peter M., Braunwald, Eugene, Blaustein, Robert O., Bowman, Louise, Landray, Martin J., Sabatine, Marc S., and Collins, Rory

Abstract

Supplemental Digital Content is available in the text.

Published
2019
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11. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data

Author

Oikonomou, Evangelos K, Marwan, Mohamed, Desai, Milind Y, Mancio, Jennifer, Alashi, Alaa, Hutt Centeno, Erika, Thomas, Sheena, Herdman, Laura, Kotanidis, Christos P, Thomas, Katharine E, Griffin, Brian P, Flamm, Scott D, Antonopoulos, Alexios S, Shirodaria, Cheerag, Sabharwal, Nikant, Deanfield, John, Neubauer, Stefan, Hopewell, Jemma C, Channon, Keith M, Achenbach, Stephan, and Antoniades, Charalambos

Abstract

Coronary artery inflammation inhibits adipogenesis in adjacent perivascular fat. A novel imaging biomarker—the perivascular fat attenuation index (FAI)—captures coronary inflammation by mapping spatial changes of perivascular fat attenuation on coronary computed tomography angiography (CTA). However, the ability of the perivascular FAI to predict clinical outcomes is unknown.

Published
2018
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12. The role of lipoprotein (a) in chronic kidney disease

Author

Hopewell, Jemma C., Haynes, Richard, and Baigent, Colin

Abstract

Lipoprotein (a) [Lp(a)] and its measurement, structure and function, the impact of ethnicity and environmental factors, epidemiological and genetic associations with vascular disease, and new prospects in drug development have been extensively examined throughout this Thematic Review Series on Lp(a). Studies suggest that the kidney has a role in Lp(a) catabolism, and that Lp(a) levels are increased in association with kidney disease only for people with large apo(a) isoforms. By contrast, in those patients with large protein losses, as in the nephrotic syndrome and continuous ambulatory peritoneal dialysis, Lp(a) is increased irrespective of apo(a) isoform size. Such acquired abnormalities can be reversed by kidney transplantation or remission of nephrosis. In this Thematic Review, we focus on the relationship between Lp(a), chronic kidney disease, and risk of cardiovascular events.

Published
2018
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13. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W., Gretarsdottir, Solveig, Anderson, Christopher D., Chong, Michael, Adams, Hieab H. H., Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M., Benavente, Oscar R., Bevan, Steve, Boncoraglio, Giorgio B., Brown, Robert D., Butterworth, Adam S., Carrera, Caty, Carty, Cara L., Chasman, Daniel I., Chen, Wei-Min, Cole, John W., Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul I. W., DeStefano, Anita L., den Hoed, Marcel, Duan, Qing, Engelter, Stefan T., Falcone, Guido J., Gottesman, Rebecca F., Grewal, Raji P., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B., Hassan, Ahamad, Havulinna, Aki S., Heckbert, Susan R., Holliday, Elizabeth G., Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I., Ikram, M. Arfan, Ingelsson, Erik, Irvin, Marguerite R., Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A., Jukema, J. Wouter, Kanai, Masahiro, Keene, Keith L., Kissela, Brett M., Kleindorfer, Dawn O., Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M., Lin, Wei-Yu, Lindgren, Arne G., Lorentzen, Erik, Magnusson, Patrik K., Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F., Meschia, James F., Mitchell, Braxton D., Mosley, Thomas H., Nalls, Michael A., Ninomiya, Toshiharu, O’Donnell, Martin J., Psaty, Bruce M., Pulit, Sara L., Rannikmäe, Kristiina, Reiner, Alexander P., Rexrode, Kathryn M., Rice, Kenneth, Rich, Stephen S., Ridker, Paul M., Rost, Natalia S., Rothwell, Peter M., Rotter, Jerome I., Rundek, Tatjana, Sacco, Ralph L., Sakaue, Saori, Sale, Michele M., Salomaa, Veikko, Sapkota, Bishwa R., Schmidt, Reinhold, Schmidt, Carsten O., Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie L. M., Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D., Thijs, Vincent N. S., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M., Walters, Matthew, Wareham, Nicholas J., Wassertheil-Smoller, Sylvia, Wilson, James G., Wiggins, Kerri L., Yang, Qiong, Yusuf, Salim, Bis, Joshua C., Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric E., Koplev, Simon, Björkegren, Johan L. M., Codoni, Veronica, Civelek, Mete, Smith, Nicholas L., Trégouët, David A., Christophersen, Ingrid E., Roselli, Carolina, Lubitz, Steven A., Ellinor, Patrick T., Tai, E. Shyong, Kooner, Jaspal S., Kato, Norihiro, He, Jiang, van der Harst, Pim, Elliott, Paul, Chambers, John C., Takeuchi, Fumihiko, Johnson, Andrew D., Sanghera, Dharambir K., Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, W. T., Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C., Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B., Kittner, Steven J., Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S., Howson, Joanna M. M., Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n= 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Published
2018
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14. Association analyses based on false discovery rate implicate new loci for coronary artery disease

Author

Nelson, Christopher P, Goel, Anuj, Butterworth, Adam S, Kanoni, Stavroula, Webb, Tom R, Marouli, Eirini, Zeng, Lingyao, Ntalla, Ioanna, Lai, Florence Y, Hopewell, Jemma C, Giannakopoulou, Olga, Jiang, Tao, Hamby, Stephen E, Di Angelantonio, Emanuele, Assimes, Themistocles L, Bottinger, Erwin P, Chambers, John C, Clarke, Robert, Palmer, Colin N A, Cubbon, Richard M, Ellinor, Patrick, Ermel, Raili, Evangelou, Evangelos, Franks, Paul W, Grace, Christopher, Gu, Dongfeng, Hingorani, Aroon D, Howson, Joanna M M, Ingelsson, Erik, Kastrati, Adnan, Kessler, Thorsten, Kyriakou, Theodosios, Lehtimäki, Terho, Lu, Xiangfeng, Lu, Yingchang, März, Winfried, McPherson, Ruth, Metspalu, Andres, Pujades-Rodriguez, Mar, Ruusalepp, Arno, Schadt, Eric E, Schmidt, Amand F, Sweeting, Michael J, Zalloua, Pierre A, AlGhalayini, Kamal, Keavney, Bernard D, Kooner, Jaspal S, Loos, Ruth J F, Patel, Riyaz S, Rutter, Martin K, Tomaszewski, Maciej, Tzoulaki, Ioanna, Zeggini, Eleftheria, Erdmann, Jeanette, Dedoussis, George, Björkegren, Johan L M, Schunkert, Heribert, Farrall, Martin, Danesh, John, Samani, Nilesh J, Watkins, Hugh, and Deloukas, Panos

Abstract

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10−8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; ncases= 10,801) as well as a stricter definition without angina (HARD; ncases= 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

Published
2017
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15. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Author

Christophersen, Ingrid E, Rienstra, Michiel, Roselli, Carolina, Yin, Xiaoyan, Geelhoed, Bastiaan, Barnard, John, Lin, Honghuang, Arking, Dan E, Smith, Albert V, Albert, Christine M, Chaffin, Mark, Tucker, Nathan R, Li, Molong, Klarin, Derek, Bihlmeyer, Nathan A, Low, Siew-Kee, Weeke, Peter E, Müller-Nurasyid, Martina, Smith, J Gustav, Brody, Jennifer A, Niemeijer, Maartje N, Dörr, Marcus, Trompet, Stella, Huffman, Jennifer, Gustafsson, Stefan, Schurmann, Claudia, Kleber, Marcus E, Lyytikäinen, Leo-Pekka, Seppälä, Ilkka, Malik, Rainer, Horimoto, Andrea R V R, Perez, Marco, Sinisalo, Juha, Aeschbacher, Stefanie, Thériault, Sébastien, Yao, Jie, Radmanesh, Farid, Weiss, Stefan, Teumer, Alexander, Choi, Seung Hoan, Weng, Lu-Chen, Clauss, Sebastian, Deo, Rajat, Rader, Daniel J, Shah, Svati H, Sun, Albert, Hopewell, Jemma C, Debette, Stephanie, Chauhan, Ganesh, Yang, Qiong, Worrall, Bradford B, Paré, Guillaume, Kamatani, Yoichiro, Hagemeijer, Yanick P, Verweij, Niek, Siland, Joylene E, Kubo, Michiaki, Smith, Jonathan D, Van Wagoner, David R, Bis, Joshua C, Perz, Siegfried, Psaty, Bruce M, Ridker, Paul M, Magnani, Jared W, Harris, Tamara B, Launer, Lenore J, Shoemaker, M Benjamin, Padmanabhan, Sandosh, Haessler, Jeffrey, Bartz, Traci M, Waldenberger, Melanie, Lichtner, Peter, Arendt, Marina, Krieger, Jose E, Kähönen, Mika, Risch, Lorenz, Mansur, Alfredo J, Peters, Annette, Smith, Blair H, Lind, Lars, Scott, Stuart A, Lu, Yingchang, Bottinger, Erwin B, Hernesniemi, Jussi, Lindgren, Cecilia M, Wong, Jorge A, Huang, Jie, Eskola, Markku, Morris, Andrew P, Ford, Ian, Reiner, Alex P, Delgado, Graciela, Chen, Lin Y, Chen, Yii-Der Ida, Sandhu, Roopinder K, Li, Man, Boerwinkle, Eric, Eisele, Lewin, Lannfelt, Lars, Rost, Natalia, Anderson, Christopher D, Taylor, Kent D, Campbell, Archie, Magnusson, Patrik K, Porteous, David, Hocking, Lynne J, Vlachopoulou, Efthymia, Pedersen, Nancy L, Nikus, Kjell, Orho-Melander, Marju, Hamsten, Anders, Heeringa, Jan, Denny, Joshua C, Kriebel, Jennifer, Darbar, Dawood, Newton-Cheh, Christopher, Shaffer, Christian, Macfarlane, Peter W, Heilmann-Heimbach, Stefanie, Almgren, Peter, Huang, Paul L, Sotoodehnia, Nona, Soliman, Elsayed Z, Uitterlinden, Andre G, Hofman, Albert, Franco, Oscar H, Völker, Uwe, Jöckel, Karl-Heinz, Sinner, Moritz F, Lin, Henry J, Guo, Xiuqing, Dichgans, Martin, Ingelsson, Erik, Kooperberg, Charles, Melander, Olle, Loos, Ruth J F, Laurikka, Jari, Conen, David, Rosand, Jonathan, van der Harst, Pim, Lokki, Marja-Liisa, Kathiresan, Sekar, Pereira, Alexandre, Jukema, J Wouter, Hayward, Caroline, Rotter, Jerome I, März, Winfried, Lehtimäki, Terho, Stricker, Bruno H, Chung, Mina K, Felix, Stephan B, Gudnason, Vilmundur, Alonso, Alvaro, Roden, Dan M, Kääb, Stefan, Chasman, Daniel I, Heckbert, Susan R, Benjamin, Emelia J, Tanaka, Toshihiro, Lunetta, Kathryn L, Lubitz, Steven A, and Ellinor, Patrick T

Abstract

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

Published
2017
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18. Low-frequency and common genetic variation in ischemic stroke

Author

Malik, Rainer, Traylor, Matthew, Pulit, Sara L., Bevan, Steve, Hopewell, Jemma C., Holliday, Elizabeth G., Zhao, Wei, Abrantes, Patricia, Amouyel, Philippe, Attia, John R., Battey, Thomas W.K., Berger, Klaus, Boncoraglio, Giorgio B., Chauhan, Ganesh, Cheng, Yu-Ching, Chen, Wei-Min, Clarke, Robert, Cotlarciuc, Ioana, Debette, Stephanie, Falcone, Guido J., Ferro, Jose M., Gamble, Dale M., Ilinca, Andreea, Kittner, Steven J., Kourkoulis, Christina E., Lemmens, Robin, Levi, Christopher R., Lichtner, Peter, Lindgren, Arne, Liu, Jingmin, Meschia, James F., Mitchell, Braxton D., Oliveira, Sofia A., Pera, Joana, Reiner, Alex P., Rothwell, Peter M., Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie L.M., Tatlisumak, Turgut, Thijs, Vincent, Vicente, Astrid M., Woo, Daniel, Seshadri, Sudha, Saleheen, Danish, Rosand, Jonathan, Markus, Hugh S., Worrall, Bradford B., and Dichgans, Martin

Published
2016
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19. Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2

Author

Cheng, Yu-Ching, Stanne, Tara M., Giese, Anne-Katrin, Ho, Weang Kee, Traylor, Matthew, Amouyel, Philippe, Holliday, Elizabeth G., Malik, Rainer, Xu, Huichun, Kittner, Steven J., Cole, John W., O’Connell, Jeffrey R., Danesh, John, Rasheed, Asif, Zhao, Wei, Engelter, Stefan, Grond-Ginsbach, Caspar, Kamatani, Yoichiro, Lathrop, Mark, Leys, Didier, Thijs, Vincent, Metso, Tiina M., Tatlisumak, Turgut, Pezzini, Alessandro, Parati, Eugenio A., Norrving, Bo, Bevan, Steve, Rothwell, Peter M., Sudlow, Cathie, Slowik, Agnieszka, Lindgren, Arne, Walters, Matthew R., Jannes, Jim, Shen, Jess, Crosslin, David, Doheny, Kimberly, Laurie, Cathy C., Kanse, Sandip M., Bis, Joshua C., Fornage, Myriam, Mosley, Thomas H., Hopewell, Jemma C., Strauch, Konstantin, Müller-Nurasyid, Martina, Gieger, Christian, Waldenberger, Melanie, Peters, Annette, Meisinger, Christine, Ikram, M. Arfan, Longstreth, W.T., Meschia, James F., Seshadri, Sudha, Sharma, Pankaj, Worrall, Bradford, Jern, Christina, Levi, Christopher, Dichgans, Martin, Boncoraglio, Giorgio B., Markus, Hugh S., Debette, Stephanie, Rolfs, Arndt, Saleheen, Danish, and Mitchell, Braxton D.

Abstract

Supplemental Digital Content is available in the text.

Published
2016
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20. Shared genetic basis for migraine and ischemic stroke

Author

Malik, Rainer, Freilinger, Tobias, Winsvold, Bendik S., Anttila, Verneri, Vander Heiden, Jason, Traylor, Matthew, de Vries, Boukje, Holliday, Elizabeth G., Terwindt, Gisela M., Sturm, Jonathan, Bis, Joshua C., Hopewell, Jemma C., Ferrari, Michel D., Rannikmae, Kristiina, Wessman, Maija, Kallela, Mikko, Kubisch, Christian, Fornage, Myriam, Meschia, James F., Lehtimäki, Terho, Sudlow, Cathie, Clarke, Robert, Chasman, Daniel I., Mitchell, Braxton D., Maguire, Jane, Kaprio, Jaakko, Farrall, Martin, Raitakari, Olli T., Kurth, Tobias, Ikram, M. Arfan, Reiner, Alex P., Longstreth, W.T., Rothwell, Peter M., Strachan, David P., Sharma, Pankaj, Seshadri, Sudha, Quaye, Lydia, Cherkas, Lynn, Schürks, Markus, Rosand, Jonathan, Ligthart, Lannie, Boncoraglio, Giorgio B., Davey Smith, George, van Duijn, Cornelia M., Stefansson, Kari, Worrall, Bradford B., Nyholt, Dale R., Markus, Hugh S., van den Maagdenberg, Arn M.J.M., Cotsapas, Chris, Zwart, John A., Palotie, Aarno, and Dichgans, Martin

Published
2015
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21. Genetic Overlap Between Diagnostic Subtypes of Ischemic Stroke

Author

Holliday, Elizabeth G., Traylor, Matthew, Malik, Rainer, Bevan, Steve, Falcone, Guido, Hopewell, Jemma C., Cheng, Yu-Ching, Cotlarciuc, Ioana, Bis, Joshua C., Boerwinkle, Eric, Boncoraglio, Giorgio B., Clarke, Robert, Cole, John W., Fornage, Myriam, Furie, Karen L., Ikram, M. Arfan, Jannes, Jim, Kittner, Steven J., Lincz, Lisa F., Maguire, Jane M., Meschia, James F., Mosley, Thomas H., Nalls, Mike A., Oldmeadow, Christopher, Parati, Eugenio A., Psaty, Bruce M., Rothwell, Peter M., Seshadri, Sudha, Scott, Rodney J., Sharma, Pankaj, Sudlow, Cathie, Wiggins, Kerri L., Worrall, Bradford B., Rosand, Jonathan, Mitchell, Braxton D., Dichgans, Martin, Markus, Hugh S., Levi, Christopher, Attia, John, and Wray, Naomi R.

Abstract

Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.

Published
2015
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23. Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12

Author

Kilarski, Laura L., Achterberg, Sefanja, Devan, William J., Traylor, Matthew, Malik, Rainer, Lindgren, Arne, Pare, Guillame, Sharma, Pankaj, Slowik, Agniesczka, Thijs, Vincent, Walters, Matthew, Worrall, Bradford B., Sale, Michele M., Algra, Ale, Kappelle, L. Jaap, Wijmenga, Cisca, Norrving, Bo, Sandling, Johanna K., Rönnblom, Lars, Goris, An, Franke, Andre, Sudlow, Cathie, Rothwell, Peter M., Levi, Christopher, Holliday, Elizabeth G., Fornage, Myriam, Psaty, Bruce, Gretarsdottir, Solveig, Thorsteinsdottir, Unnar, Seshadri, Sudha, Mitchell, Braxton D., Kittner, Steven, Clarke, Robert, Hopewell, Jemma C., Bis, Joshua C., Boncoraglio, Giorgio B., Meschia, James, Ikram, M. Arfan, Hansen, Bjorn M., Montaner, Joan, Thorleifsson, Gudmar, Stefanson, Kari, Rosand, Jonathan, Bakker, Paul I.W. de, Farrall, Martin, Dichgans, Martin, Markus, Hugh S., and Bevan, Steve

Abstract

To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.

Published
2014
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24. Shared Genetic Susceptibility to Ischemic Stroke and Coronary Artery Disease

Author

Dichgans, Martin, Malik, Rainer, König, Inke R., Rosand, Jonathan, Clarke, Robert, Gretarsdottir, Solveig, Thorleifsson, Gudmar, Mitchell, Braxton D., Assimes, Themistocles L., Levi, Christopher, O´Donnell, Christopher J., Fornage, Myriam, Thorsteinsdottir, Unnur, Psaty, Bruce M., Hengstenberg, Christian, Seshadri, Sudha, Erdmann, Jeanette, Bis, Joshua C., Peters, Annette, Boncoraglio, Giorgio B., März, Winfried, Meschia, James F., Kathiresan, Sekar, Ikram, M. Arfan, McPherson, Ruth, Stefansson, Kari, Sudlow, Cathie, Reilly, Muredach P., Thompson, John R., Sharma, Pankaj, Hopewell, Jemma C., Chambers, John C., Watkins, Hugh, Rothwell, Peter M., Roberts, Robert, Markus, Hugh S., Samani, Nilesh J., Farrall, Martin, Schunkert, Heribert, Gschwendtner, Andreas, Bevan, Steve, Chen, Yu-Ching, DeStefano, Anita L., Parati, Eugenio A., Quertermous, Tom, Ziegler, Andreas, Boerwinkle, Eric, Holm, Hilma, Fischer, Marcus, Kessler, Thorsten, Willenborg, Christina, Laaksonen, Reijo, Voight, Benjamin F., Stewart, Alexandre F.R., Rader, Daniel J., Hall, Alistair S., and Kooner, Jaspal S.

Abstract

Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.

Published
2014
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25. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

Author

Huang, Jie, Sabater-Lleal, Maria, Asselbergs, Folkert W., Tregouet, David, Shin, So-Youn, Ding, Jingzhong, Baumert, Jens, Oudot-Mellakh, Tiphaine, Folkersen, Lasse, Johnson, Andrew D., Smith, Nicholas L., Williams, Scott M., Ikram, Mohammad A., Kleber, Marcus E., Becker, Diane M., Truong, Vinh, Mychaleckyj, Josyf C., Tang, Weihong, Yang, Qiong, Sennblad, Bengt, Moore, Jason H., Williams, Frances M.K., Dehghan, Abbas, Silbernagel, Günther, Schrijvers, Elisabeth M.C., Smith, Shelly, Karakas, Mahir, Tofler, Geoffrey H., Silveira, Angela, Navis, Gerjan J., Lohman, Kurt, Chen, Ming-Huei, Peters, Annette, Goel, Anuj, Hopewell, Jemma C., Chambers, John C., Saleheen, Danish, Lundmark, Per, Psaty, Bruce M., Strawbridge, Rona J., Boehm, Bernhard O., Carter, Angela M., Meisinger, Christa, Peden, John F., Bis, Joshua C., McKnight, Barbara, Öhrvik, John, Taylor, Kent, Franzosi, Maria Grazia, Seedorf, Udo, Collins, Rory, Franco-Cereceda, Anders, Syvänen, Ann-Christine, Goodall, Alison H., Yanek, Lisa R., Cushman, Mary, Müller-Nurasyid, Martina, Folsom, Aaron R., Basu, Saonli, Matijevic, Nena, van Gilst, Wiek H., Kooner, Jaspal S., Hofman, Albert, Danesh, John, Clarke, Robert, Meigs, James B., Kathiresan, Sekar, Reilly, Muredach P., Klopp, Norman, Harris, Tamara B., Winkelmann, Bernhard R., Grant, Peter J., Hillege, Hans L., Watkins, Hugh, Spector, Timothy D., Becker, Lewis C., Tracy, Russell P., März, Winfried, Uitterlinden, Andre G., Eriksson, Per, Cambien, Francois, Morange, Pierre-Emmanuel, Koenig, Wolfgang, Soranzo, Nicole, van der Harst, Pim, Liu, Yongmei, O'Donnell, Christopher J., and Hamsten, Anders

Abstract

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P< 5 × 10−8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1(7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1(rs6976053, discovery P= 3.4 × 10−10); chromosome 11p15.2 within ARNTL(rs6486122, discovery P= 3.0 × 10−8); and chromosome 3p25.2 within PPARG(rs11128603, discovery P= 2.9 × 10−8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL(P< .05). Functional studies identified MUC3as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1and ARNTLand an SNP associated with the expression of MUC3were robustly associated with circulating levels of PAI-1.

Published
2012
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26. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

Author

Huang, Jie, Sabater-Lleal, Maria, Asselbergs, Folkert W., Tregouet, David, Shin, So-Youn, Ding, Jingzhong, Baumert, Jens, Oudot-Mellakh, Tiphaine, Folkersen, Lasse, Johnson, Andrew D., Smith, Nicholas L., Williams, Scott M., Ikram, Mohammad A., Kleber, Marcus E., Becker, Diane M., Truong, Vinh, Mychaleckyj, Josyf C., Tang, Weihong, Yang, Qiong, Sennblad, Bengt, Moore, Jason H., Williams, Frances M. K., Dehghan, Abbas, Silbernagel, Günther, Schrijvers, Elisabeth M. C., Smith, Shelly, Karakas, Mahir, Tofler, Geoffrey H., Silveira, Angela, Navis, Gerjan J., Lohman, Kurt, Chen, Ming-Huei, Peters, Annette, Goel, Anuj, Hopewell, Jemma C., Chambers, John C., Saleheen, Danish, Lundmark, Per, Psaty, Bruce M., Strawbridge, Rona J., Boehm, Bernhard O., Carter, Angela M., Meisinger, Christa, Peden, John F., Bis, Joshua C., McKnight, Barbara, Öhrvik, John, Taylor, Kent, Franzosi, Maria Grazia, Seedorf, Udo, Collins, Rory, Franco-Cereceda, Anders, Syvänen, Ann-Christine, Goodall, Alison H., Yanek, Lisa R., Cushman, Mary, Müller-Nurasyid, Martina, Folsom, Aaron R., Basu, Saonli, Matijevic, Nena, van Gilst, Wiek H., Kooner, Jaspal S., Hofman, Albert, Danesh, John, Clarke, Robert, Meigs, James B., Kathiresan, Sekar, Reilly, Muredach P., Klopp, Norman, Harris, Tamara B., Winkelmann, Bernhard R., Grant, Peter J., Hillege, Hans L., Watkins, Hugh, Spector, Timothy D., Becker, Lewis C., Tracy, Russell P., März, Winfried, Uitterlinden, Andre G., Eriksson, Per, Cambien, Francois, Morange, Pierre-Emmanuel, Koenig, Wolfgang, Soranzo, Nicole, van der Harst, Pim, Liu, Yongmei, O'Donnell, Christopher J., and Hamsten, Anders

Abstract

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10−8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10−10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10−8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10−8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

Published
2012
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27. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study

Author

Voight, Benjamin F, Peloso, Gina M, Orho-Melander, Marju, Frikke-Schmidt, Ruth, Barbalic, Maja, Jensen, Majken K, Hindy, George, Hólm, Hilma, Ding, Eric L, Johnson, Toby, Schunkert, Heribert, Samani, Nilesh J, Clarke, Robert, Hopewell, Jemma C, Thompson, John F, Li, Mingyao, Thorleifsson, Gudmar, Newton-Cheh, Christopher, Musunuru, Kiran, Pirruccello, James P, Saleheen, Danish, Chen, Li, Stewart, Alexandre FR, Schillert, Arne, Thorsteinsdottir, Unnur, Thorgeirsson, Gudmundur, Anand, Sonia, Engert, James C, Morgan, Thomas, Spertus, John, Stoll, Monika, Berger, Klaus, Martinelli, Nicola, Girelli, Domenico, McKeown, Pascal P, Patterson, Christopher C, Epstein, Stephen E, Devaney, Joseph, Burnett, Mary-Susan, Mooser, Vincent, Ripatti, Samuli, Surakka, Ida, Nieminen, Markku S, Sinisalo, Juha, Lokki, Marja-Liisa, Perola, Markus, Havulinna, Aki, de Faire, Ulf, Gigante, Bruna, Ingelsson, Erik, Zeller, Tanja, Wild, Philipp, de Bakker, Paul I W, Klungel, Olaf H, Maitland-van der Zee, Anke-Hilse, Peters, Bas J M, de Boer, Anthonius, Grobbee, Diederick E, Kamphuisen, Pieter W, Deneer, Vera H M, Elbers, Clara C, Onland-Moret, N Charlotte, Hofker, Marten H, Wijmenga, Cisca, Verschuren, WM Monique, Boer, Jolanda MA, van der Schouw, Yvonne T, Rasheed, Asif, Frossard, Philippe, Demissie, Serkalem, Willer, Cristen, Do, Ron, Ordovas, Jose M, Abecasis, Gonçalo R, Boehnke, Michael, Mohlke, Karen L, Daly, Mark J, Guiducci, Candace, Burtt, Noël P, Surti, Aarti, Gonzalez, Elena, Purcell, Shaun, Gabriel, Stacey, Marrugat, Jaume, Peden, John, Erdmann, Jeanette, Diemert, Patrick, Willenborg, Christina, König, Inke R, Fischer, Marcus, Hengstenberg, Christian, Ziegler, Andreas, Buysschaert, Ian, Lambrechts, Diether, Van de Werf, Frans, Fox, Keith A, El Mokhtari, Nour Eddine, Rubin, Diana, Schrezenmeir, Jürgen, Schreiber, Stefan, Schäfer, Arne, Danesh, John, Blankenberg, Stefan, Roberts, Robert, McPherson, Ruth, Watkins, Hugh, Hall, Alistair S, Overvad, Kim, Rimm, Eric, Boerwinkle, Eric, Tybjaerg-Hansen, Anne, Cupples, L Adrienne, Reilly, Muredach P, Melander, Olle, Mannucci, Pier M, Ardissino, Diego, Siscovick, David, Elosua, Roberto, Stefansson, Kari, O'Donnell, Christopher J, Salomaa, Veikko, Rader, Daniel J, Peltonen, Leena, Schwartz, Stephen M, Altshuler, David, and Kathiresan, Sekar

Abstract

High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.

Published
2012
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28. Lipids and Lipoproteins and Risk of Different Vascular Events in the MRCBHF Heart Protection Study

Author

Parish, Sarah, Offer, Alison, Clarke, Robert, Hopewell, Jemma C., Hill, Michael R., Otvos, James D., Armitage, Jane, and Collins, Rory

Abstract

Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk.

Published
2012
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29. Lipoprotein(a) Genetic Variants Associated With Coronary and Peripheral Vascular Disease but Not With Stroke Risk in the Heart Protection Study

Author

Hopewell, Jemma C., Clarke, Robert, Parish, Sarah, Armitage, Jane, Lathrop, Mark, Hager, Jorg, and Collins, Rory

Abstract

Genetic studies have identified 2 single-nucleotide polymorphisms (SNPs) at the LPAlocus (rs3798220 and rs10455872) that are strongly and independently related to lipoprotein(a) levels and to coronary disease risk, but their relevance for other atherothrombotic disease is uncertain.

Published
2011
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30. Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jürgenson, Tuuli, Namba, Shinichi, Posner, Daniel C., Kamanu, Frederick K., Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K., Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C., Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R., Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V., Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Cárcel-Márquez, Jara, Nygaard, Marianne, Leonard, Hampton L., Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J., Lewis, Adam J., Judy, Renae L., Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D., Bakker, Mark K., Bartz, Traci M., Bennett, David A., Bis, Joshua C., Bordes, Constance, Børte, Sigrid, Cain, Anael, Ridker, Paul M., Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W., de Jager, Phil L., de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E., Geerlings, Mirjam I., Gasca, Natalie C., Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K., Ho, Yuk-Lam, Havulinna, Aki S., Hopewell, Jemma C., Hyacinth, Hyacinth I., Inouye, Michael, Jacob, Mina A., Jeon, Christina E., Jern, Christina, Kamouchi, Masahiro, Keene, Keith L., Kitazono, Takanari, Kittner, Steven J., Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J., Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S., Marston, Nicholas A., Meitinger, Thomas, Mitchell, Braxton D., Montellano, Felipe A., Morisaki, Takayuki, Mosley, Thomas H., Nalls, Mike A., Nordestgaard, Børge G., O’Donnell, Martin J., Okada, Yukinori, Onland-Moret, N. Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M., Rich, Stephen S., Rosand, Jonathan, Sabatine, Marc S., Sacco, Ralph L., Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L., Schmidt, Carsten O., Shimizu, Atsushi, Smith, Nicholas L., Sloane, Kelly L., Sutoh, Yoichi, Sun, Yan V., Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P., Tiwari, Hemant K., Trégouët, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjærg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S., Wiggins, Kerri L., Wennberg, Patrik, Woo, Daniel, Wilson, Peter W. F., Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Millwood, Iona Y., Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J., Jukema, J. Wouter, Rissanen, Ina L., Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna M. M., Irvin, Marguerite R., Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A., Rundek, Tatjana, Worrall, Bradford B., Lathrop, G. Mark, Riaz, Moeen, Simonsick, Eleanor M., Kõrv, Janika, França, Paulo H. C., Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, de Leeuw, Frank-Erik, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M., Heuschmann, Peter Ulrich, Longstreth, W. T., Jung, Keum Ji, Bastarache, Lisa, Paré, Guillaume, Damrauer, Scott M., Chasman, Daniel I., Rotter, Jerome I., Anderson, Christopher D., Zwart, John-Anker, Niiranen, Teemu J., Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernández-Cadenas, Israel, Walters, Robin G., Ruff, Christian T., Owolabi, Mayowa O., Huffman, Jennifer E., Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Published
2022
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31. Abstract 15391: Genome-Wide Association Study of Over One Million Participants Identifies 49 Novel Loci Associated With Coronary Artery Disease

Author

Aragam, Krishna G, Jiang, Tao, Kanoni, Stavroula, Anuj, Goel, Wolford, Brooke, Surakka, Ida, Grace, Christopher, Thorleifsson, Gudmar, Nelson, Christopher, Roselli, Carolina, Hindy, George, Wang, Wallace, Munoz Venegas, Maria Loreto, Hopewell, Jemma C, Ruff, Christian, Sabatine, Marc S, Watkins, Hugh C, Danesh, John, Ellinor, Patrick T, Holm, Hilma, Clarke, Robert J, Schunkert, Heribert, Farrall, Martin, Erdmann, Jeanette, Stefansson, Kari, Thorsteinsdottir, Unnur, Willer, Cristen, Samani, Nilesh J, Deloukas, Panos, Kathiresan, Sekar, and Butterworth, Adam

Abstract

Genome-wide association studies (GWAS) have identified 164 common genetic loci associated with coronary artery disease (CAD), providing important biological and clinical insights, but the global burden of CAD remains high. Additional genetic discovery may further our understanding of CAD and related conditions and improve approaches to disease management. We performed GWAS and meta-analysis of CAD in 1,165,680 individuals across cohort studies, biobanks, and clinical trials (EPIC-CVD, HUNT, deCODE, GerMIFS, UK Biobank, Partners Biobank, Greek CAD, PEGASUS-TIMI 54, SAVOR-TIMI 53, ENGAGE-TIMI 48), as well as CARDIoGRAMplusC4D. Study-specific GWAS were performed by logistic regression or generalized mixed models. Conditional and joint analyses were used to identify independent genetic signals. We developed a genome-wide polygenic risk score (PRS) and tested it in the Malmo Diet and Cancer Study (MDCS; N= 22,872, N_CAD = 3,307; median follow-up 21 years). Analyses included 181,522 CAD cases and 984,158 controls. We identified 241 independent genetic variants associated with CAD at genome-wide significance (P < 5x10-8); 75 variants were not previously identified, representing 49 novel genomic regions. For the first time, genetic variation at HMG-CoA reductase, the target of statin therapy, reached genome-wide significance (HMGCR; p=1.31x10-8), validating the biological insights gained for CAD from such unbiased scans of the genome. Novel loci included regulators of: an anti-apoptotic protein (MCL1, p=1.0x10-14) and transmembrane tyrosine kinase (FER; p=1.1x10-9) linked to acute myeloid leukemia; fibrillin-2 (FBN2, p=9.7x10-10) and myosin heavy chain 11 (MYH11, p=2.5x10-9) associated with Marfan syndrome and thoracic aortic aneurysm; and an activin receptor (ACVR2A, p=1.5x10-8) involved in preeclampsia. Ingenuity analyses highlighted pathways mediating hepatic fibrosis. A genome-wide PRS predicted incident CAD in MDCS (HR=1.45 per-SD increase in PRS; p=1.1x10-100; C-stat=0.61). We identified 49 novel loci associated with CAD, bringing the total number of CAD-associated loci to 213. Our findings highlight non-traditional CAD risk factors with possible shared pathways, and provide a robust tool for genetic risk prediction.

Published
2019
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33. Erratum: Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Author

Christophersen, Ingrid E, Rienstra, Michiel, Roselli, Carolina, Yin, Xiaoyan, Geelhoed, Bastiaan, Barnard, John, Lin, Honghuang, Arking, Dan E, Smith, Albert V, Albert, Christine M, Chaffin, Mark, Tucker, Nathan R, Li, Molong, Klarin, Derek, Bihlmeyer, Nathan A, Low, Siew-Kee, Weeke, Peter E, Müller-Nurasyid, Martina, Smith, J Gustav, Brody, Jennifer A, Niemeijer, Maartje N, Dörr, Marcus, Trompet, Stella, Huffman, Jennifer, Gustafsson, Stefan, Schurmann, Claudia, Kleber, Marcus E, Lyytikäinen, Leo-Pekka, Seppälä, Ilkka, Malik, Rainer, R V R Horimoto, Andrea, Perez, Marco, Sinisalo, Juha, Aeschbacher, Stefanie, Thériault, Sébastien, Yao, Jie, Radmanesh, Farid, Weiss, Stefan, Teumer, Alexander, Choi, Seung Hoan, Weng, Lu-Chen, Clauss, Sebastian, Deo, Rajat, Rader, Daniel J, Shah, Svati H, Sun, Albert, Hopewell, Jemma C, Debette, Stephanie, Chauhan, Ganesh, Yang, Qiong, Worrall, Bradford B, Paré, Guillaume, Kamatani, Yoichiro, Hagemeijer, Yanick P, Verweij, Niek, Siland, Joylene E, Kubo, Michiaki, Smith, Jonathan D, Van Wagoner, David R, Bis, Joshua C, Perz, Siegfried, Psaty, Bruce M, Ridker, Paul M, Magnani, Jared W, Harris, Tamara B, Launer, Lenore J, Shoemaker, M Benjamin, Padmanabhan, Sandosh, Haessler, Jeffrey, Bartz, Traci M, Waldenberger, Melanie, Lichtner, Peter, Arendt, Marina, Krieger, Jose E, Kähönen, Mika, Risch, Lorenz, Mansur, Alfredo J, Peters, Annette, Smith, Blair H, Lind, Lars, Scott, Stuart A, Lu, Yingchang, Bottinger, Erwin B, Hernesniemi, Jussi, Lindgren, Cecilia M, Wong, Jorge A, Huang, Jie, Eskola, Markku, Morris, Andrew P, Ford, Ian, Reiner, Alex P, Delgado, Graciela, Chen, Lin Y, Chen, Yii-Der Ida, Sandhu, Roopinder K, Li, Man, Boerwinkle, Eric, Eisele, Lewin, Lannfelt, Lars, Rost, Natalia, Anderson, Christopher D, Taylor, Kent D, Campbell, Archie, Magnusson, Patrik K, Porteous, David, Hocking, Lynne J, Vlachopoulou, Efthymia, Pedersen, Nancy L, Nikus, Kjell, Orho-Melander, Marju, Hamsten, Anders, Heeringa, Jan, Denny, Joshua C, Kriebel, Jennifer, Darbar, Dawood, Newton-Cheh, Christopher, Shaffer, Christian, Macfarlane, Peter W, Heilmann-Heimbach, Stefanie, Almgren, Peter, Huang, Paul L, Sotoodehnia, Nona, Soliman, Elsayed Z, Uitterlinden, Andre G, Hofman, Albert, Franco, Oscar H, Völker, Uwe, Jöckel, Karl-Heinz, Sinner, Moritz F, Lin, Henry J, Guo, Xiuqing, Dichgans, Martin, Ingelsson, Erik, Kooperberg, Charles, Melander, Olle, J F Loos, Ruth, Laurikka, Jari, Conen, David, Rosand, Jonathan, van der Harst, Pim, Lokki, Marja-Liisa, Kathiresan, Sekar, Pereira, Alexandre, Jukema, J Wouter, Hayward, Caroline, Rotter, Jerome I, März, Winfried, Lehtimäki, Terho, Stricker, Bruno H, Chung, Mina K, Felix, Stephan B, Gudnason, Vilmundur, Alonso, Alvaro, Roden, Dan M, Kääb, Stefan, Chasman, Daniel I, Heckbert, Susan R, Benjamin, Emelia J, Tanaka, Toshihiro, Lunetta, Kathryn L, Lubitz, Steven A, and Ellinor, Patrick T

Published
2017
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