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6 results on '"Carty, C. (Cara)"'

1. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Author

Natarajan, P. (Pradeep), Pampana, A. (Akhil), Graham, S. E. (Sarah E.), Ruotsalainen, S. E. (Sanni E.), Perry, J. A. (James A.), de Vries, P. S. (Paul S.), Broome, J. G. (Jai G.), Pirruccello, J. P. (James P.), Honigbere, M. C. (Michael C.), Aragam, K. (Krishna), Wolford, B. (Brooke), Brody, J. A. (Jennifer A.), Antonacci-Fulton, L. (Lucinda), Arden, M. (Moscati), Aslibekyan, S. (Stella), Assimes, T. L. (Themistocles L.), Ballantyne, C. M. (Christie M.), Bielak, L. F. (Lawrence F.), Bisl, J. C. (Joshua C.), Cade, B. E. (Brian E.), Do, R. (Ron), Doddapaneni, H. (Harsha), Emery, L. S. (Leslie S.), Hung, Y.-J. (Yi-Jen), Irvin, M. R. (Marguerite R.), Khan, A. T. (Alyna T.), Lange, L. (Leslie), Lee, J. (Jiwon), Lemaitre, R. N. (Rozenn N.), Martin, L. W. (Lisa W.), Metcalf, G. (Ginger), Montasser, M. E. (May E.), Moon, J.-Y. (Jee-Young), Muzny, D. (Donna), Connell, J. R. (Jeffrey R. O.), Palmer, N. D. (Nicholette D.), Peralta, J. M. (Juan M.), Peyser, P. A. (Patricia A.), Stilp, A. M. (Adrienne M.), Tsai, M. (Michael), Wang, F. F. (Fei Fei), Weeks, D. E. (Daniel E.), Yanek, L. R. (Lisa R.), Wilson, J. G. (James G.), Abecasis, G. (Goncalo), Arnett, D. K. (Donna K.), Becker, L. C. (Lewis C.), Blangercy, J. (John), Boerwinkle, E. (Eric), Bowden, D. W. (Donald W.), Chang, Y.-C. (Yi-Cheng), Chen, Y. I. (Yii-Der, I), Choi, W. J. (Won Jung), Correa, A. (Adolfo), Curran, J. E. (Joanne E.), Daly, M. J. (Mark J.), DutcherE, S. K. (Susan K.), Ellinor, P. T. (Patrick T.), Fornage, M. (Myriam), Freedman, B. I. (Barry, I), Gabriel, S. (Stacey), Germer, S. (Soren), Gibbs, R. A. (Richard A.), He, J. (Jiang), Hveem, K. (Kristian), Jarvik, G. P. (Gail P.), Kaplan, R. C. (Robert C.), Kardia, S. L. (Sharon L. R.), Kennyn, E. (Eimear), Kim, R. W. (Ryan W.), Kooperberg, C. (Charles), Laurie, C. C. (Cathy C.), Lee, S. (Seonwook), Lloyd-Jones, D. M. (Don M.), Loos, R. J. (Ruth J. F.), Lubitz, S. A. (Steven A.), Mathias, R. A. (Rasika A.), Martinez, K. A. (Karine A. Viaud), McGarvey, S. T. (Stephen T.), Mitche, B. D. (Braxton D.), Nickerson, D. A. (Deborah A.), North, K. E. (Kari E.), Palotie, A. (Aarno), Park, C. J. (Cheol Joo), Psat, B. M. (Bruce M. Y.), Rao, D. C. (D. C.), Redline, S. (Susan), Reiner, A. P. (Alexander P.), Seo, D. (Daekwan), Seo, J.-S. (Jeong-Sun), Smith, A. V. (Albert, V), Tracy, R. P. (Russell P.), Kathiresan, S. (Sekar), Cupples, L. A. (L. Adrienne), Rotten, J. I. (Jerome, I), Morrison, A. C. (Alanna C.), Rich, S. S. (Stephen S.), Ripatti, S. (Samuli), Wilier, C. (Cristen), Peloso, G. M. (Gina M.), Vasan, R. S. (Ramachandran S.), Abe, N. (Namiko), Albert, C. (Christine), Almasy, L. (Laura), Alonso, A. (Alvaro), Ament, S. (Seth), Anderson, P. (Peter), Applebaum-Bowden, D. (Deborah), Arking, D. (Dan), Ashley-Koch, A. (Allison), Auer, P. (Paul), Avramopoulos, D. (Dimitrios), Barnard, J. (John), Barnes, K. (Kathleen), Barr, R. G. (R. Graham), Barron-Casella, E. (Emily), Beaty, T. (Terri), Becker, D. (Diane), Beer, R. (Rebecca), Begum, F. (Ferdouse), Beitelshees, A. (Amber), Benjamin, E. (Emelia), Bezerra, M. (Marcos), Bielak, L. (Larry), Blackwel, T. (Thomas), Bowler, R. (Russell), Broecke, U. (Ulrich), Bunting, K. (Karen), Burchard, E. (Esteban), Buth, E. (Erin), Cardwel, J. (Jonathan), Carty, C. (Cara), Casaburi, R. (Richard), Casella, J. (James), Chaffin, M. (Mark), Chang, C. (Christy), Chasman, D. (Daniel), Chavan, S. (Sameer), Chen, B.-J. (Bo-Juen), Chen, W.-M. (Wei-Min), Chol, M. (Michael), Choi, S. H. (Seung Hoan), Chuang, L.-M. (Lee-Ming), Chung, M. (Mina), Conomos, M. P. (Matthew P.), Cornell, E. (Elaine), Crapo, J. (James), Curtis, J. (Jeffrey), Custer, B. (Brian), Damcott, C. (Coleen), Darbar, D. (Dawood), Das, S. (Sayantan), David, S. (Sean), Davis, C. (Colleen), Daya, M. (Michelle), de Andrade, M. (Mariza), DeBaunuo, M. (Michael), Duan, Q. (Qing), Devine, R. D. (Ranjan Deka Dawn DeMeo Scott), Duggirala, Q. R. (Qing Ravi), Durda, J. P. (Jon Peter), Dutcher, S. (Susan), Eaton, C. (Charles), Ekunwe, L. (Lynette), Farber, C. (Charles), Farnaml, L. (Leanna), Fingerlin, T. (Tasha), Flickinger, M. (Matthew), Franceschini, N. (Nora), Fu, M. (Mao), Fullerton, S. M. (Stephanie M.), Fulton, L. (Lucinda), Gan, W. (Weiniu), Gao, Y. (Yan), Gass, M. (Margery), Ge, B. (Bruce), Geng, X. P. (Xiaoqi Priscilla), Gignoux, C. (Chris), Gladwin, M. (Mark), Glahn, D. (David), Gogarten, S. (Stephanie), Gong, D.-W. (Da-Wei), Goring, H. (Harald), Gu, C. C. (C. Charles), Guan, Y. (Yue), Guo, X. (Xiuqing), Haessler, J. (Jeff), Hall, M. (Michael), Harris, D. (Daniel), Hawle, N. Y. (Nicola Y.), Heavner, B. (Ben), Heckbert, S. (Susan), Hernandez, R. (Ryan), Herrington, D. (David), Hersh, C. (Craig), Hidalgo, B. (Bertha), Hixson, J. (James), Hokanson, J. (John), Hong, E. (Elliott), Hoth, K. (Karin), Hsiung, C. A. (Chao Agnes), Huston, H. (Haley), Hwu, C. M. (Chii Min), Jackson, R. (Rebecca), Jain, D. (Deepti), Jaquish, C. (Cashell), Jhun, M. A. (Min A.), Johnsen, J. (Jill), Johnson, A. (Andrew), Johnson, C. (Craig), Johnston, R. (Rich), Jones, K. (Kimberly), Kang, H. M. (Hyun Min), Kaufman, L. (Laura), Kell, S. Y. (Shannon Y.), Kessler, M. (Michael), Kinney, G. (Greg), Konkle, B. (Barbara), Kramer, H. (Holly), Krauter, S. (Stephanie), Lange, C. (Christoph), Lange, E. (Ethan), Laurie, C. (Cecelia), LeBoff, M. (Meryl), Lee, S. S. (Seunggeun Shawn), Lee, W.-J. (Wen-Jane), LeFaive, J. (Jonathon), Levine, D. (David), Levy, D. (Dan), Lewis, J. (Joshua), Li, Y. (Yun), Lin, H. (Honghuang), Lin, K. H. (Keng Han), Lin, X. (Xihong), Liu, S. (Simin), Liu, Y. (Yongmei), Lunetta, K. (Kathryn), Luo, J. (James), Mahaney, M. (Michael), Make, B. (Barry), Manichaikul, A. (Ani), Mansonl, J. (JoAnn), Margolin, L. (Lauren), Mathai, S. (Susan), McArdle, P. (Patrick), Mcdonald, M.-L. (Merry-Lynn), McFarland, S. (Sean), McHugh, C. (Caitlin), Mei, H. (Hao), Meyers, D. A. (Deborah A.), Mikulla, J. (Julie), Min, N. (Nancy), Minear, M. (Mollie), Minster, R. L. (Ryan L.), Musani, S. (Solomon), Mwasongwe, S. (Stanford), Mychaleckyj, J. C. (Josyf C.), Nadkarni, G. (Girish), Naik, R. (Rakhi), Naseri, T. (Take), Nekhai, S. (Sergei), Nelson, S. C. (Sarah C.), Nickerson, D. (Deborah), Connell, J. O. (Jeff O.), Connor, T. O. (Tim O.), Ochs-Balcom, H. (Heather), Pankow, J. (James), Papanicolaou, G. (George), Parkerl, M. (Margaret), Parsa, A. (Afshin), Penchey, S. (Sara), Perez, M. (Marco), Peters, U. (Ulrike), Phillips, L. S. (Lawrence S.), Phillips, S. (Sam), Pollin, T. (Toni), Post, W. (Wendy), Becker, J. P. (Julia Powers), Boorgula, M. P. (Meher Preethi), Preuss, M. (Michael), Prokopenko, D. (Dmitry), Qasba, P. (Pankaj), Qiao, D. (Dandi), Rafaels, N. (Nicholas), Raffield, L. (Laura), Rasmussen-Torvik, L. (Laura), Ratan, A. (Aakrosh), Reed, R. (Robert), Reganl, E. (Elizabeth), Reupena, M. S. (Muagututi Sefuiva), Rice, K. (Ken), Roden, D. (Dan), Roselli, C. (Carolina), Ruczinski, I. (Ingo), Russel, P. (Pamela), Ruuska, S. (Sarah), Ryan, K. (Kathleen), Sabino, E. C. (Ester Cerdeira), Sakornsakolpatl, P. (Phuwanat), Salzberg, S. (Steven), Sandow, K. (Kevin), Sankaran, V. G. (Vijay G.), Scheller, C. (Christopher), Schmidt, E. (Ellen), Schwander, K. (Karen), Schwartz, D. (David), Sciurba, F. (Frank), Seidman, C. (Christine), Seidman, J. (Jonathan), Sheehan, V. (Vivien), Shetty, A. (Amol), Shetty, A. (Aniket), Sheu, W. H. (Wayne Hui-Heng), Shoemaker, M. B. (M. Benjamin), Silver, B. (Brian), Silvermanl, E. (Edwin), Smith, J. (Jennifer), Smith, J. (Josh), Smith, N. (Nicholas), Smith, T. (Tanja), Smoller, S. (Sylvia), Snively, B. (Beverly), Soferlm, T. (Tamar), Streeten, E. (Elizabeth), Su, J. L. (Jessica Lasky), Sung, Y. J. (Yun Ju), Sylvia, J. (Jody), Sztalryd, C. (Carole), Taliun, D. (Daniel), Tang, H. (Hua), Taub, M. (Margaret), Taylor, K. D. (Kent D.), Taylor, S. (Simeon), Telen, M. (Marilyn), Thornton, T. A. (Timothy A.), Tinker, L. (Lesley), Tirschwel, D. (David), Tiwari, H. (Hemant), Vaidya, D. (Dhananjay), VandeHaar, P. (Peter), Vrieze, S. (Scott), Walker, T. (Tarik), Wallace, R. (Robert), Waits, A. (Avram), Wan, E. (Emily), Wang, H. (Heming), Watson, K. (Karol), Weir, B. (Bruce), Weiss, S. (Scott), Weng, L.-C. (Lu-Chen), Williams, K. (Kayleen), Williams, L. K. (L. Keoki), Wilson, C. (Carla), Wong, Q. (Quenna), Xu, H. (Huichun), Yang, I. (Ivana), Yang, R. (Rongze), Zaghlou, N. (Norann), Zekavat, M. (Maryam), Zhang, Y. (Yingze), Zhao, S. X. (Snow Xueyan), Zhao, W. (Wei), Zni, D. (Degui), Zhou, X. (Xiang), Zhu, X. (Xiaofeng), Zody, M. (Michael), Zoellner, S. (Sebastian), Daly, M. (Mark), Jacob, H. (Howard), Matakidou, A. (Athena), Runz, H. (Heiko), John, S. (Sally), Plenge, R. (Robert), McCarthy, M. (Mark), Hunkapiller, J. (Julie), Ehm, M. (Meg), Waterworth, D. (Dawn), Fox, C. (Caroline), Malarstig, A. (Anders), Klinger, K. (Kathy), Call, K. (Kathy), Mkel, T. (Tomi), Kaprio, J. (Jaakko), Virolainen, P. (Petri), Pulkki, K. (Kari), Kilpi, T. (Terhi), Perola, M. (Markus), Partanen, J. (Jukka), Pitkranta, A. (Anne), Kaarteenaho, R. (Riitta), Vainio, S. (Seppo), Savinainen, K. (Kimmo), Kosma, V.-M. (Veli-Matti), Kujala, U. (Urho), Tuovila, O. (Outi), Hendolin, M. (Minna), Pakkanen, R. (Raimo), Waring, J. (Jeff), Riley-Gillis, B. (Bridget), Liu, J. (Jimmy), Biswas, S. (Shameek), Diogo, D. (Dorothee), Marshall, C. (Catherine), Hu, X. (Xinli), Gossel, M. (Matthias), Schleutker, J. (Johanna), Arvas, M. (Mikko), Hinttala, R. (Reetta), Kettunen, J. (Johannes), Laaksonen, R. (Reijo), Mannermaa, A. (Arto), Paloneva, J. (Juha), Soininen, H. (Hilkka), Julkunen, V. (Valtteri), Remes, A. (Anne), Klviinen, R. (Reetta), Hiltunen, M. (Mikko), Peltola, J. (Jukka), Tienari, P. (Pentti), Rinne, J. (Juha), Ziemann, A. (Adam), Waring, J. (Jeffrey), Esmaeeli, S. (Sahar), Smaoui, N. (Nizar), Lehtonen, A. (Anne), Eaton, S. (Susan), Landenper, S. (Sanni), Michon, J. (John), Kerchner, G. (Geoff), Bowers, N. (Natalie), Teng, E. (Edmond), Eicher, J. (John), Mehta, V. (Vinay), Gormle, P. Y. (Padhraig Y.), Linden, K. (Kari), Whelan, C. (Christopher), Xu, F. (Fanli), Pulford, D. (David), Frkkil, M. (Martti), Pikkarainen, S. (Sampsa), Jussila, A. (Airi), Blomster, T. (Timo), Kiviniemi, M. (Mikko), Voutilainen, M. (Markku), Georgantas, B. (Bob), Heap, G. (Graham), Rahimov, F. (Fedik), Usiskin, K. (Keith), Maranville, J. (Joseph), Lu, T. (Tim), Oh, D. (Danny), Kalpala, K. (Kirsi), Miller, M. (Melissa), McCarthy, L. (Linda), Eklund, K. (Kari), Palomki, A. (Antti), Isomki, P. (Pia), Piri, L. (Laura), Kaipiainen-Seppnen, O. (Oili), Lertratanaku, A. (Apinya), Bing, D. C. (David Close Marla Hochfeld Nan), Gordillo, J. E. (Jorge Esparza), Mars, N. (Nina), Laitinen, T. (Tarja), Pelkonen, M. (Margit), Kauppi, P. (Paula), Kankaanranta, H. (Hannu), Harju, T. (Terttu), Greenberg, S. (Steven), Chen, H. (Hubert), Betts, J. (Jo), Ghosh, S. (Soumitra), Salomaa, V. (Veikko), Niiranen, T. (Teemu), Juonala, M. (Markus), Metsrinne, K. (Kaj), Khnen, M. (Mika), Junttila, J. (Juhani), Laakso, M. (Markku), Pihlajamki, J. (Jussi), Sinisalo, J. (Juha), Taskinen, M.-R. (Marja-Riitta), Tuomi, T. (Tiinamaija), Laukkanen, J. (Jari), Challis, B. (Ben), Peterson, A. (Andrew), Chu, A. (Audrey), Parkkinen, J. (Jaakko), Muslin, A. (Anthony), Joensuu, H. (Heikki), Meretoja, T. (Tuomo), Aaltonen, L. (Lauri), Auranen, A. (Annika), Karihtala, P. (Peeter), Kauppila, S. (Saila), Auvinen, P. (Pivi), Elenius, K. (Klaus), Popovic, R. (Relja), Schutzman, J. (Jennifer), Loboda, A. (Andrey), Chhibber, A. (Aparna), Lehtonen, H. (Heli), McDonough, S. (Stefan), Crohns, M. (Marika), Kulkarni, D. (Diptee), Kaarniranta, K. (Kai), Turunen, J. (Joni), Ollila, T. (Terhi), Seitsonen, S. (Sanna), Uusitalo, H. (Hannu), Aaltonen, V. (Vesa), Uusitalo-Jrvinen, H. (Hannele), Luodonp, M. (Marja), Hautala, N. (Nina), Strauss, E. (Erich), Chen, H. (Hao), Podgornaia, A. (Anna), Hoffman, J. (Joshua), Tasanen, K. (Kaisa), Huilaja, L. (Laura), Hannula-Jouppi, K. (Katariina), Salmi, T. (Teea), Peltonen, S. (Sirkku), Koulu, L. (Leena), Harvima, I. (Ilkka), Wu, Y. (Ying), Choy, D. (David), Jalanko, A. (Anu), Kajanne, R. (Risto), Lyhs, U. (Ulrike), Kaunisto, M. (Mari), Davis, J. W. (Justin Wade), Quarless, D. (Danjuma), Petrovski, S. (Slav), Chen, C.-Y. (Chia-Yen), Bronson, P. (Paola), Yang, R. (Robert), Chang, D. (Diana), Bhangale, T. (Tushar), Holzinger, E. (Emily), Wang, X. (Xulong), Chen, X. (Xing), Auro, K. (Kirsi), Wang, C. (Clarence), Xu, E. (Ethan), Auge, F. (Franck), Chatelain, C. (Clement), Kurki, M. (Mitja), Karjalainen, J. (Juha), Havulinna, A. (Aki), Palin, K. (Kimmo), Palta, P. (Priit), Parolo, P. D. (Pietro Della Briotta), Zhou, W. (Wei), Lemmel, S. (Susanna), Rivas, M. (Manuel), Harju, J. (Jarmo), Lehisto, A. (Arto), Ganna, A. (Andrea), Llorens, V. (Vincent), Karlsson, A. (Antti), Kristiansson, K. (Kati), Hyvrinen, K. (Kati), Ritari, J. (Jarmo), Wahlfors, T. (Tiina), Koskinen, M. (Miika), Pylkäs, K. (Katri), Kalaoja, M. (Marita), Karjalainen, M. (Minna), Mantere, T. (Tuomo), Kangasniemi, E. (Eeva), Heikkinen, S. (Sami), Laakkonen, E. (Eija), Kononen, J. (Juha), Loukola, A. (Anu), Laiho, P. (Pivi), Sistonen, T. (Tuuli), Kaiharju, E. (Essi), Laukkanen, M. (Markku), Jrvensivu, E. (Elina), Lhteenmki, S. (Sini), Mnnikk, L. (Lotta), Wong, R. (Regis), Mattsson, H. (Hannele), Hiekkalinna, T. (Tero), Jimnez, M. G. (Manuel Gonzlez), Donner, K. (Kati), Prn, K. (KaIle), Nunez-Fontarnau, J. (Javier), Kilpelinen, E. (Elina), Sipi, T. P. (Timo P.), Brein, G. (Georg), Dada, A. (Alexander), Awaisa, G. (Ghazal), Shcherban, A. (Anastasia), Sipil, T. (Tuomas), Laivuori, H. (Hannele), Kiiskinen, T. (Tuomo), Siirtola, H. (Harri), Tabuenca, J. G. (Javier Gracia), Kallio, L. (Lila), Soini, S. (Sirpa), Pitknen, K. (Kimmo), and Kuopio, T. (Teijo)

Subjects
Cardiovascular genetics, Genome-wide association studies
Abstract

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Published
2021

2. PCSK9 genetic variants and risk of type 2 diabetes: A mendelian randomisation study

Author

Schmidt, A.F. (Amand F.), Swerdlow, D.I. (Daniel), Holmes, M.V. (Michael), Patel, R.S. (Riyaz), Fairhurst-Hunter, Z. (Zammy), Lyall, D.M. (Donald M.), Hartwig, F.P. (Fernando Pires), Horta, B.L. (Bernardo Lessa), Hypponen, E. (Elina), Power, C. (Christopher), Moldovan, M. (Max), Iperen, E.P.A. (Erik) van, Hovingh, G.K. (Kees), Demuth, I. (Ilja), Norman, K. (Kristina), Steinhagen-Thiessen, E. (Elisabeth), Demuth, J. (Juri), Bertram, L. (Lars), Liu, T. (Tian), Coassin, S. (Stefan), Willeit, J. (Johann), Kiechl, S. (Stefan), Willeit, K. (Karin), Mason, D. (Dan), Wright, J. (Juliet), Morris, R.W. (Richard), Wanamethee, G. (Goya), Whincup, P.H. (Peter), Ben-Shlomo, Y., McLachlan, S. (Stela), Price, J.F. (Jackie F.), Kivimaki, M. (Mika), Welch, C. (Catherine), Sanchez-Galvez, A. (Adelaida), Marques-Vidal, P. (Pedro), Nicolaides, A.N. (Andrew), Panayiotou, A.G. (Andrie), Onland-Moret, N.C. (N Charlotte), Schouw, Y.T. (Yvonne) van der, Matullo, G., Fiorito, G. (Giovanni), Guarrera, S. (Simonetta), Sacerdote, C. (Carlotta), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Scott, R. (Robert), Luan, J. (Jian'an), Bobak, M. (Martin), Malyutina, S., Pajak, A. (Andrzej), Kubinova, R., Tamosiunas, A. (Abdonas), Pikhart, H. (Hynek), Husemoen, L.L.N. (Lise Lotte), Grarup, N. (Niels), Pedersen, O. (Oluf), Hansen, T. (T.), Linneberg, A. (Allan), Simonsen, K.S. (Kenneth Starup), Cooper, J. (Jim), Humphries, S.E. (Steve), Brilliant, M.H. (Murray H.), Kitchner, T.E. (Terrie E.), Hakonarson, H. (Hakon), Carrell, D.S. (David), McCarty, C.A. (Catherine A.), Kirchner, H.L. (H Lester), Larson, E.B. (Eric B.), Crosslin, D.R. (David), de Andrade, M. (Mariza), Roden, D.M. (Dan M.), Denny, J.C. (Joshua C.), Carty, C. (Cara), Hancock, S. (Stephen), Attia, J. (John), Holliday, E.G. (Elizabeth), Donnell, M.O.'. (Martin O'), Yusuf, S. (Salim), Chong, M. (Michael), Pare, G. (Guillame), Harst, P. (Pim) van der, Said, M.A. (M Abdullah), Eppinga, R.N. (Ruben N.), Verweij, N. (Niek), Snieder, H. (Harold), Christen, T. (Tim), Mook-Kanamori, D.O. (Dennis), Gustafsson, S. (Stefan), Kao, W.H.L. (Wen), Ingelsson, E. (Erik), Pazoki, R. (Raha), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Dehghan, A. (Abbas), Teumer, A. (Alexander), Baumeister, S.E. (Sebastian), Dörr, M. (Marcus), Lerch, M.M. (Markus M.), Völker, U. (Uwe), Völzke, H. (Henry), Ward, J. (Joey), Pell, J.P. (Jill P.), Smith, D.J. (Daniel J.), Meade, T. (Tom), Maitland-van der Zee, A-H. (Anke-Hilse), Baranova, E.V. (Ekaterina V.), Young, R. (Robin), Ford, I. (Ian), Campbell, A. (Archie), Padmanabhan, S. (Sandosh), Bots, M.L. (Michiel), Grobbee, D.E. (Diederick E.), Froguel, P. (Philippe), Thuillier, D. (Dorothee), Balkau, B. (Beverley), Bonnefond, A. (Amélie), Cariou, B. (Bertrand), Smart, M. (Melissa), Bao, Y. (Yanchun), Kumari, M. (Meena), Mahajan, A. (Anubha), Ridker, P.M. (Paul), Chasman, D.I. (Daniel I.), Reiner, A. (Alexander), Lange, L.A. (Leslie), Ritchie, M.D. (Marylyn D.), Asselbergs, F.W. (Folkert), Casas, J.P. (Juan), Keating, J. (John), Preiss, D. (David), Hingorani, A. (Aroon), Sattar, N. (Naveed), Schmidt, A.F. (Amand F.), Swerdlow, D.I. (Daniel), Holmes, M.V. (Michael), Patel, R.S. (Riyaz), Fairhurst-Hunter, Z. (Zammy), Lyall, D.M. (Donald M.), Hartwig, F.P. (Fernando Pires), Horta, B.L. (Bernardo Lessa), Hypponen, E. (Elina), Power, C. (Christopher), Moldovan, M. (Max), Iperen, E.P.A. (Erik) van, Hovingh, G.K. (Kees), Demuth, I. (Ilja), Norman, K. (Kristina), Steinhagen-Thiessen, E. (Elisabeth), Demuth, J. (Juri), Bertram, L. (Lars), Liu, T. (Tian), Coassin, S. (Stefan), Willeit, J. (Johann), Kiechl, S. (Stefan), Willeit, K. (Karin), Mason, D. (Dan), Wright, J. (Juliet), Morris, R.W. (Richard), Wanamethee, G. (Goya), Whincup, P.H. (Peter), Ben-Shlomo, Y., McLachlan, S. (Stela), Price, J.F. (Jackie F.), Kivimaki, M. (Mika), Welch, C. (Catherine), Sanchez-Galvez, A. (Adelaida), Marques-Vidal, P. (Pedro), Nicolaides, A.N. (Andrew), Panayiotou, A.G. (Andrie), Onland-Moret, N.C. (N Charlotte), Schouw, Y.T. (Yvonne) van der, Matullo, G., Fiorito, G. (Giovanni), Guarrera, S. (Simonetta), Sacerdote, C. (Carlotta), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Scott, R. (Robert), Luan, J. (Jian'an), Bobak, M. (Martin), Malyutina, S., Pajak, A. (Andrzej), Kubinova, R., Tamosiunas, A. (Abdonas), Pikhart, H. (Hynek), Husemoen, L.L.N. (Lise Lotte), Grarup, N. (Niels), Pedersen, O. (Oluf), Hansen, T. (T.), Linneberg, A. (Allan), Simonsen, K.S. (Kenneth Starup), Cooper, J. (Jim), Humphries, S.E. (Steve), Brilliant, M.H. (Murray H.), Kitchner, T.E. (Terrie E.), Hakonarson, H. (Hakon), Carrell, D.S. (David), McCarty, C.A. (Catherine A.), Kirchner, H.L. (H Lester), Larson, E.B. (Eric B.), Crosslin, D.R. (David), de Andrade, M. (Mariza), Roden, D.M. (Dan M.), Denny, J.C. (Joshua C.), Carty, C. (Cara), Hancock, S. (Stephen), Attia, J. (John), Holliday, E.G. (Elizabeth), Donnell, M.O.'. (Martin O'), Yusuf, S. (Salim), Chong, M. (Michael), Pare, G. (Guillame), Harst, P. (Pim) van der, Said, M.A. (M Abdullah), Eppinga, R.N. (Ruben N.), Verweij, N. (Niek), Snieder, H. (Harold), Christen, T. (Tim), Mook-Kanamori, D.O. (Dennis), Gustafsson, S. (Stefan), Kao, W.H.L. (Wen), Ingelsson, E. (Erik), Pazoki, R. (Raha), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Dehghan, A. (Abbas), Teumer, A. (Alexander), Baumeister, S.E. (Sebastian), Dörr, M. (Marcus), Lerch, M.M. (Markus M.), Völker, U. (Uwe), Völzke, H. (Henry), Ward, J. (Joey), Pell, J.P. (Jill P.), Smith, D.J. (Daniel J.), Meade, T. (Tom), Maitland-van der Zee, A-H. (Anke-Hilse), Baranova, E.V. (Ekaterina V.), Young, R. (Robin), Ford, I. (Ian), Campbell, A. (Archie), Padmanabhan, S. (Sandosh), Bots, M.L. (Michiel), Grobbee, D.E. (Diederick E.), Froguel, P. (Philippe), Thuillier, D. (Dorothee), Balkau, B. (Beverley), Bonnefond, A. (Amélie), Cariou, B. (Bertrand), Smart, M. (Melissa), Bao, Y. (Yanchun), Kumari, M. (Meena), Mahajan, A. (Anubha), Ridker, P.M. (Paul), Chasman, D.I. (Daniel I.), Reiner, A. (Alexander), Lange, L.A. (Leslie), Ritchie, M.D. (Marylyn D.), Asselbergs, F.W. (Folkert), Casas, J.P. (Juan), Keating, J. (John), Preiss, D. (David), Hingorani, A. (Aroon), and Sattar, N. (Naveed)

Abstract

Background: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering . PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. Methods: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30). Interpretation: . PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibi

Published
2016
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3. DNA methylation-based measures of biological age: Meta-analysis predicting time to death

Author

Chen, B.H. (Brian), Marioni, R.E. (Riccardo), Colicino, E. (Elena), Peters, M.J. (Marjolein), Ward-Caviness, C.K. (Cavin K.), Tsai, P.-C. (Pei-Chien), Roetker, N.S. (Nicholas S.), Just, A.C. (Allan C.), Demerath, E.W. (Ellen), Guan, W. (Weihua), Bressler, J. (Jan), Fornage, M. (Myriam), Studenski, S. (Stephanie), Vandiver, A.R. (Amy R.), Moore, A.Z. (Ann Zenobia), Tanaka, T. (Toshiko), Kiel, D.P. (Douglas P.), Liang, L. (Liming), Vokonas, P. (Pantel), Schwartz, J. (Joel), Lunetta, K.L. (Kathryn), Murabito, J. (Joanne), Bandinelli, S. (Stefania), Hernandez, D.G. (Dena), Melzer, D. (David), Nalls, M.A. (Michael), Pilling, L.C. (Luke), Price, T.R. (Timothy R.), Singleton, A. (Andrew), Gieger, C. (Christian), Holle, R. (Rolf), Kretschmer, A. (Anja), Kronenberg, F. (Florian), Kunze, S. (Sonja), Linseisen, J. (Jakob), Meisinger, C. (Christine), Rathmann, W. (Wolfgang), Waldenberger, M. (Melanie), Visscher, P.M. (Peter), Shah, S. (Sonia), Wray, N.R. (Naomi), McRae, A.F. (Allan F.), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Absher, D. (Devin), Assimes, T.L. (Themistocles), Levine, M.E. (Morgan E.), Lu, A.T. (Ake T.), Tsao, P.S. (Philip S.), Hou, L. (Lifang), Manson, J.E. (Joann), Carty, C. (Cara), LaCroix, A.Z. (Andrea Z.), Reiner, A. (Alexander), Spector, T.D. (Timothy), Feinberg, A.P. (Andrew P.), Levy, D. (Daniel), Baccarelli, A.A. (Andrea), Meurs, J. (Joyce van), Bell, J.T. (Jordana), Peters, A. (Annette), Deary, I.J. (Ian), Pankow, J.S. (James), Ferrucci, L. (Luigi), Horvath, S. (Steve), Chen, B.H. (Brian), Marioni, R.E. (Riccardo), Colicino, E. (Elena), Peters, M.J. (Marjolein), Ward-Caviness, C.K. (Cavin K.), Tsai, P.-C. (Pei-Chien), Roetker, N.S. (Nicholas S.), Just, A.C. (Allan C.), Demerath, E.W. (Ellen), Guan, W. (Weihua), Bressler, J. (Jan), Fornage, M. (Myriam), Studenski, S. (Stephanie), Vandiver, A.R. (Amy R.), Moore, A.Z. (Ann Zenobia), Tanaka, T. (Toshiko), Kiel, D.P. (Douglas P.), Liang, L. (Liming), Vokonas, P. (Pantel), Schwartz, J. (Joel), Lunetta, K.L. (Kathryn), Murabito, J. (Joanne), Bandinelli, S. (Stefania), Hernandez, D.G. (Dena), Melzer, D. (David), Nalls, M.A. (Michael), Pilling, L.C. (Luke), Price, T.R. (Timothy R.), Singleton, A. (Andrew), Gieger, C. (Christian), Holle, R. (Rolf), Kretschmer, A. (Anja), Kronenberg, F. (Florian), Kunze, S. (Sonja), Linseisen, J. (Jakob), Meisinger, C. (Christine), Rathmann, W. (Wolfgang), Waldenberger, M. (Melanie), Visscher, P.M. (Peter), Shah, S. (Sonia), Wray, N.R. (Naomi), McRae, A.F. (Allan F.), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Absher, D. (Devin), Assimes, T.L. (Themistocles), Levine, M.E. (Morgan E.), Lu, A.T. (Ake T.), Tsao, P.S. (Philip S.), Hou, L. (Lifang), Manson, J.E. (Joann), Carty, C. (Cara), LaCroix, A.Z. (Andrea Z.), Reiner, A. (Alexander), Spector, T.D. (Timothy), Feinberg, A.P. (Andrew P.), Levy, D. (Daniel), Baccarelli, A.A. (Andrea), Meurs, J. (Joyce van), Bell, J.T. (Jordana), Peters, A. (Annette), Deary, I.J. (Ian), Pankow, J.S. (James), Ferrucci, L. (Luigi), and Horvath, S. (Steve)

Abstract

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p ≤ 8.2 x 10-9), independent of chronological age, even after adjusting for additional risk factors (p < 5.4 x 10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p≤ 7.5 x 10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.

Published
2016
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4. Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium

Author

Dehghan, A. (Abbas), Bis, J.C. (Joshua), White, C.C. (Charles), Smith, A.V. (Albert V.), Morrison, A.C. (Alanna), Cupples, L.A. (Adrienne), Trompet, S. (Stella), Chasman, D.I. (Daniel I.), Lumley, T. (Thomas), Völker, U. (Uwe), Buckley, B.M. (Brendan M.), Ding, J. (Jingzhong), Jensen, M.K. (Majken K.), Folsom, A.R. (Aaron R.), Kritchevsky, S.B. (Stephen), Girman, C.J. (Cynthia J.), Ford, I., Dörr, M. (Marcus), Salomaa, V. (Veikko), Uitterlinden, A.G. (André), Eiriksdottir, G. (Gudny), Vasan, R.S. (Ramachandran S.), Franceschini, N. (Nora), Carty, C. (Cara), Virtamo, J. (Jarmo), Demissie, S. (Serkalem), Amouyel, P. (Philippe), Arveiler, D. (Dominique), Heckbert, S.R. (Susan), Ferrieres, J. (Jean), Ducimetiere, P. (P.), Smith, N.L. (Nicholas), Wang, Y.A. (Ying), Siscovick, D.S. (David), Rice, K.M. (Kenneth), Wiklund, P.-G. (Per-Gunnar), Taylor, K.D. (Kent), Evans, A. (Alun), Kee, F. (Frank), Rotter, J.I. (Jerome I.), Karvanen, J. (Juha), Kuulasmaa, K. (Kari), Heiss, G. (Gerardo), Kraft, P. (Peter), Launer, L.J. (Lenore), Hofman, A. (Albert), Markus, M.R.P. (Marcello R.P.), Rose, L.M. (Lynda), Silander, K. (Kaisa), Wagner, P.J. (Peter), Benjamin, E.J. (Emelia), Lohman, K. (Kurt), Stott, D.J. (David. J.), Rivadeneira Ramirez, F. (Fernando), Harris, T.B. (Tamara), Levy, D. (Daniel), Liu, Y. (YongMei), Rimm, E.B. (Eric B.), Jukema, J.W. (Jan Wouter), Volzke, H. (Henry), Ridker, P.M. (Paul M.), Blankenberg, S. (Stefan), Franco, O.H. (Oscar), Gudnason, V. (Vilmundur), Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), O'Donnell, C.J. (Christopher J.), Dehghan, A. (Abbas), Bis, J.C. (Joshua), White, C.C. (Charles), Smith, A.V. (Albert V.), Morrison, A.C. (Alanna), Cupples, L.A. (Adrienne), Trompet, S. (Stella), Chasman, D.I. (Daniel I.), Lumley, T. (Thomas), Völker, U. (Uwe), Buckley, B.M. (Brendan M.), Ding, J. (Jingzhong), Jensen, M.K. (Majken K.), Folsom, A.R. (Aaron R.), Kritchevsky, S.B. (Stephen), Girman, C.J. (Cynthia J.), Ford, I., Dörr, M. (Marcus), Salomaa, V. (Veikko), Uitterlinden, A.G. (André), Eiriksdottir, G. (Gudny), Vasan, R.S. (Ramachandran S.), Franceschini, N. (Nora), Carty, C. (Cara), Virtamo, J. (Jarmo), Demissie, S. (Serkalem), Amouyel, P. (Philippe), Arveiler, D. (Dominique), Heckbert, S.R. (Susan), Ferrieres, J. (Jean), Ducimetiere, P. (P.), Smith, N.L. (Nicholas), Wang, Y.A. (Ying), Siscovick, D.S. (David), Rice, K.M. (Kenneth), Wiklund, P.-G. (Per-Gunnar), Taylor, K.D. (Kent), Evans, A. (Alun), Kee, F. (Frank), Rotter, J.I. (Jerome I.), Karvanen, J. (Juha), Kuulasmaa, K. (Kari), Heiss, G. (Gerardo), Kraft, P. (Peter), Launer, L.J. (Lenore), Hofman, A. (Albert), Markus, M.R.P. (Marcello R.P.), Rose, L.M. (Lynda), Silander, K. (Kaisa), Wagner, P.J. (Peter), Benjamin, E.J. (Emelia), Lohman, K. (Kurt), Stott, D.J. (David. J.), Rivadeneira Ramirez, F. (Fernando), Harris, T.B. (Tamara), Levy, D. (Daniel), Liu, Y. (YongMei), Rimm, E.B. (Eric B.), Jukema, J.W. (Jan Wouter), Volzke, H. (Henry), Ridker, P.M. (Paul M.), Blankenberg, S. (Stefan), Franco, O.H. (Oscar), Gudnason, V. (Vilmundur), Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), and O'Donnell, C.J. (Christopher J.)

Abstract

Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stageGWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with totalmortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

Published
2016
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5. Prospective associations of coronary heart disease loci in African Americans using the MetaboChip

Author

Franceschini, N. (Nora), Hu, Y. (Yijuan), Reiner, A. (Alexander), Buyske, S. (Steven), Nalls, M.A. (Michael), Yanek, L.R. (Lisa), Li, Y. (Yun), Hindorff, L.A. (Lucia A), Cole, S.A. (Shelley A.), Howard, B.V. (Barbara V.), Stafford, J.M. (Jeanette M.), Carty, C. (Cara), Sethupathy, P. (Praveen), Martin, L.W. (Lisa W.), Lin, D.Y. (Dan), Johnson, K.C. (Karen C.), Becker, L.C. (Lewis), North, K.E. (Kari), Dehghan, A. (Abbas), Bis, J.C. (Joshua), Liu, Y. (YongMei), Greenland, P. (Philip), Manson, J.E. (Joann), Maeda, N. (Nobuyo), Garcia, M.E. (M.), Harris, T.B. (Tamara), Becker, D.M. (Diane), O'Donnell, C.J. (Christopher), Heiss, G. (Gerardo), Kooperberg, C. (Charles), Boerwinkle, E.A. (Eric), Franceschini, N. (Nora), Hu, Y. (Yijuan), Reiner, A. (Alexander), Buyske, S. (Steven), Nalls, M.A. (Michael), Yanek, L.R. (Lisa), Li, Y. (Yun), Hindorff, L.A. (Lucia A), Cole, S.A. (Shelley A.), Howard, B.V. (Barbara V.), Stafford, J.M. (Jeanette M.), Carty, C. (Cara), Sethupathy, P. (Praveen), Martin, L.W. (Lisa W.), Lin, D.Y. (Dan), Johnson, K.C. (Karen C.), Becker, L.C. (Lewis), North, K.E. (Kari), Dehghan, A. (Abbas), Bis, J.C. (Joshua), Liu, Y. (YongMei), Greenland, P. (Philip), Manson, J.E. (Joann), Maeda, N. (Nobuyo), Garcia, M.E. (M.), Harris, T.B. (Tamara), Becker, D.M. (Diane), O'Donnell, C.J. (Christopher), Heiss, G. (Gerardo), Kooperberg, C. (Charles), and Boerwinkle, E.A. (Eric)

Abstract

Background: Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published

Published
2014
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6. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): A meta-analysis of genome-wide association studies

Author

Traylor, M. (Matthew), Farrall, M. (Martin), Holliday, E.G. (Elizabeth), Sudlow, C. (Cathie), Hopewell, J., Cheng, Y.-C. (Yu-Ching), Fornage, M. (Myriam), Ikram, M.A. (Arfan), Malik, R. (Rainer), Bevan, S. (Steve), Thorsteinsdottir, U. (Unnur), Nalls, M.A. (Michael), Longstreth Jr, W.T., Wiggins, K.L. (Kerri), Yadav, S. (Sunaina), Parati, E.A. (Eugenio), DeStefano, A.L. (Anita), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Khan, M.I. (Muhammad), Reiner, A. (Alexander), Helgadottir, H.T. (Hafdis), Achterberg, S. (Sefanja), Fernandez-Cadenas, I. (Israel), Abboud, S. (Shimon), Schmidt, R. (Reinhold), Walters, M.R. (Matthew), Chen, W-M., Ringelstein, E.B. (E. Bernd), O'Donnell, M. (Martin), Ho, W.K. (Weang Kee), Pera, M.F. (Martin ), Lemmens, R. (Robin), Norrving, B. (Bo), Higgins, P. (Peter), Benn, M. (Marianne), Sale, P. (Patrizio), Kuhlenbäumer, G. (Gregor), Doney, A.S.F. (Alex), Vicente, A.M. (Astrid M), Delavaran, H. (Hossein), Algra, A. (Ale), Davies, G. (Gail), Oliveira, S.A. (Sofia), Palmer, C.N.A. (Colin), Deary, I.J. (Ian), Pandolfo, M. (Massimo), Montaner, J. (Joan), Carty, C. (Cara), Bakker, P.I.W. (Paul) de, Kostulas, K. (Konstantinos), Ferro, M.T. (María), Zuydam, N.R. (Natalie) van, Valdimarsson, E. (Einar), Nordestgaard, B.G. (Børge), Lindgren, A. (Arne), Thijs, V. (Vincent), Slowik, A. (Agnieszka), Saleheen, D., Paré, G. (Guillaume), Berger, K. (Klaus), Thorleifsson, G. (Gudmar), Hofman, A. (Albert), Mosley, T.H. (Thomas), Mitchell, B.D. (Braxton), Furie, K.L. (Karen), Clarke, R. (Robert), Levi, C. (Christopher), Seshadri, S. (Sudha), Gschwendtner, A. (Andreas), Boncoraglio, G. (Giorgio Battista), Sharma, P. (Pankaj), Bis, J.C. (Joshua), Gretarsdottir, S. (Solveig), Psaty, B.M. (Bruce), Rothwell, P.M. (Peter), Rosand, J. (Jonathan), Meschia, J.F. (James F.), Zwart, J-A. (John-Anker), Kubisch, C. (Christian), Markus, H.S. (Hugh), Traylor, M. (Matthew), Farrall, M. (Martin), Holliday, E.G. (Elizabeth), Sudlow, C. (Cathie), Hopewell, J., Cheng, Y.-C. (Yu-Ching), Fornage, M. (Myriam), Ikram, M.A. (Arfan), Malik, R. (Rainer), Bevan, S. (Steve), Thorsteinsdottir, U. (Unnur), Nalls, M.A. (Michael), Longstreth Jr, W.T., Wiggins, K.L. (Kerri), Yadav, S. (Sunaina), Parati, E.A. (Eugenio), DeStefano, A.L. (Anita), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Khan, M.I. (Muhammad), Reiner, A. (Alexander), Helgadottir, H.T. (Hafdis), Achterberg, S. (Sefanja), Fernandez-Cadenas, I. (Israel), Abboud, S. (Shimon), Schmidt, R. (Reinhold), Walters, M.R. (Matthew), Chen, W-M., Ringelstein, E.B. (E. Bernd), O'Donnell, M. (Martin), Ho, W.K. (Weang Kee), Pera, M.F. (Martin ), Lemmens, R. (Robin), Norrving, B. (Bo), Higgins, P. (Peter), Benn, M. (Marianne), Sale, P. (Patrizio), Kuhlenbäumer, G. (Gregor), Doney, A.S.F. (Alex), Vicente, A.M. (Astrid M), Delavaran, H. (Hossein), Algra, A. (Ale), Davies, G. (Gail), Oliveira, S.A. (Sofia), Palmer, C.N.A. (Colin), Deary, I.J. (Ian), Pandolfo, M. (Massimo), Montaner, J. (Joan), Carty, C. (Cara), Bakker, P.I.W. (Paul) de, Kostulas, K. (Konstantinos), Ferro, M.T. (María), Zuydam, N.R. (Natalie) van, Valdimarsson, E. (Einar), Nordestgaard, B.G. (Børge), Lindgren, A. (Arne), Thijs, V. (Vincent), Slowik, A. (Agnieszka), Saleheen, D., Paré, G. (Guillaume), Berger, K. (Klaus), Thorleifsson, G. (Gudmar), Hofman, A. (Albert), Mosley, T.H. (Thomas), Mitchell, B.D. (Braxton), Furie, K.L. (Karen), Clarke, R. (Robert), Levi, C. (Christopher), Seshadri, S. (Sudha), Gschwendtner, A. (Andreas), Boncoraglio, G. (Giorgio Battista), Sharma, P. (Pankaj), Bis, J.C. (Joshua), Gretarsdottir, S. (Solveig), Psaty, B.M. (Bruce), Rothwell, P.M. (Peter), Rosand, J. (Jonathan), Meschia, J.F. (James F.), Zwart, J-A. (John-Anker), Kubisch, C. (Christian), and Markus, H.S. (Hugh)

Abstract

Background: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10-16) and ZFHX3 (p=2·28×10-8), and for large-vessel stroke at a 9p21 locus (p=3·32×10-5) and HDAC9 (p=2·03×10-12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10-6. However, we were unable to replicate any of these novel associations in the replication cohort. Interpretation: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. Funding: Wellcome Trust, UK Medic

Published
2012
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