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1. Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration

Author: Noordam, R. (Raymond), Bos, M.M. (Maxime M.), Wang, H. (Heming), Winkler, T.W. (Thomas W.), Bentley, A.R. (Amy), Kilpeläinen, T.O. (Tuomas O.), Vries, P.S. (Paul) de, Sung, Y.J. (Yun Ju), Schwander, K., Cade, B., Manning, A.K. (Alisa), Aschard, H. (Hugues), Brown, M.R., Chen, H. (Han), Franceschini, N. (Nora), Musani, S.K. (Solomon K.), Richard, M. (Melissa), Vojinović, D. (Dina), Aslibekyan, S. (Stella), Bartz, T.M. (Traci M.), de Las Fuentes, L. (Lisa), Feitosa, M.F. (Mary Furlan), Horimoto, A.R. (Andrea R.), Ilkov, M. (Marjan), Kho, M. (Minjung), Kraja, A. (Aldi), Li, C. (Changwei), Lim, E. (Elise), Liu, Y. (YongMei), Mook-Kanamori, D.O. (Dennis O.), Rankinen, T. (Tuomo), Tajuddin, S.M. (Salman M.), Spek, A. (Ashley) van der, Wang, Z. (Zhe), Marten, J. (Jonathan), Laville, V. (Vincent), Alver, M. (Maris), Evangelou, E. (Evangelos), Graff, M.E. (Maria E.), He, M. (Meian), Kuhnel, B. (Brigitte), Lyytikäinen, L.-P. (Leo-Pekka), Marques-Vidal, P. (Pedro), Nolte, I.M. (Ilja), Palmer, N.D. (Nicholette), Rauramaa, R. (Rainer), Shu, X.-O. (Xiao-Ou), Snieder, H. (Harold), Weiss, S. (Stefan), Wen, W. (Wanqing), Yanek, L.R. (Lisa), Adolfo, C. (Correa), Ballantyne, C. (Christie), Bielak, L.F. (Lawrence F.), Biermasz, N.R., Boerwinkle, E.A. (Eric), Dimou, N. (Niki), Eiriksdottir, G. (Gudny), Gao, C. (Chuan), Gharib, S.A. (Sina), Gottlieb, D.J. (Daniel J.), Haba-Rubio, J. (José), Harris, T.B. (Tamara), Heikkinen, S. (Sami), Heinzer, R. (Raphaël), Hixson, J.E. (James E.), Homuth, G. (Georg), Ikram, M.A. (Arfan), Komulainen, P. (Pirjo), Krieger, J.E. (José), Lee, J. (Jiwon), Liu, J. (Jingmin), Lohman, K.K. (Kurt K.), Luik, A.I. (Annemarie), Mägi, R. (Reedik), Martin, L.W. (Lisa), Meitinger, T. (Thomas), Metspalu, A. (Andres), Milaneschi, Y. (Yuri), Nalls, M.A. (Michael), O´Connell, J.R., Peters, A. (Annette), Peyser, P.A. (Patricia A.), Raitakari, O. (Olli), Reiner, A. (Alexander), Rensen, P.C.N. (Patrick), Rice, T.K. (Treva K.), Rich, S.S. (Stephen), Roenneberg, T., Rotter, J.I. (Jerome I.), Schreiner, P.J. (Pamela), Shikany, J. (James), Sidney, S.S. (Stephen S.), Sims, M. (Mario), Sitlani, C.M. (Colleen M.), Sofer, T. (Tamar), Strauch, K. (Konstantin), Swertz, M.A. (Morris A.), Taylor, K.D. (Kent), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Völzke, H. (Henry), Waldenberger, M. (Melanie), Wallance, R.B. (Robert B.), van Dijk, K.W. (Ko Willems), Yu, C. (Caizheng), Zonderman, A.B. (Alan B.), Becker, D.M. (Diane), Elliott, P. (Paul), Esko, T. (Tõnu), Gieger, C. (Christian), Grabe, H.J. (Hans Jörgen), Lakka, T.A. (Timo), Lehtimäki, T. (Terho), North, K.E. (Kari), Penninx, B.W.J.H. (Brenda), Vollenweider, P. (Peter), Wagenknecht, L.E. (Lynne), Wu, T. (Tangchun), Xiang, Y.-B. (Yong-Bing), Zheng, W. (Wei), Arnett, D.K. (Donna), Bouchard, C. (Claude), Evans, M.K. (Michele), Gudnason, V. (Vilmundur), Kardia, S.L.R. (Sharon), Kelly, T.N. (Tanika N.), Kritchevsky, S.B. (Stephen), Loos, R.J.F. (Ruth), Pereira, A. (A.), Province, M.A. (Mike), Psaty, B.M. (Bruce), Rotimi, C. (Charles), Zhu, X. (Xiaofeng), Amin, N. (Najaf), Cupples, L.A. (L Adrienne), Fornage, M. (Myriam), Fox, E.F. (Ervin F.), Guo, X. (Xiuqing), Gauderman, W.J. (W James), Rice, K.M. (Kenneth), Kooperberg, C. (Charles), Munroe, P. (Patricia), Liu, C.-T. (Ching-Ti), Morrison, A.C. (Alanna), Rao, D.C. (Dabeeru C.), Heemst, D. (Diana) van, Redline, S. (Susan), Noordam, R. (Raymond), Bos, M.M. (Maxime M.), Wang, H. (Heming), Winkler, T.W. (Thomas W.), Bentley, A.R. (Amy), Kilpeläinen, T.O. (Tuomas O.), Vries, P.S. (Paul) de, Sung, Y.J. (Yun Ju), Schwander, K., Cade, B., Manning, A.K. (Alisa), Aschard, H. (Hugues), Brown, M.R., Chen, H. (Han), Franceschini, N. (Nora), Musani, S.K. (Solomon K.), Richard, M. (Melissa), Vojinović, D. (Dina), Aslibekyan, S. (Stella), Bartz, T.M. (Traci M.), de Las Fuentes, L. (Lisa), Feitosa, M.F. (Mary Furlan), Horimoto, A.R. (Andrea R.), Ilkov, M. (Marjan), Kho, M. (Minjung), Kraja, A. (Aldi), Li, C. (Changwei), Lim, E. (Elise), Liu, Y. (YongMei), Mook-Kanamori, D.O. (Dennis O.), Rankinen, T. (Tuomo), Tajuddin, S.M. (Salman M.), Spek, A. (Ashley) van der, Wang, Z. (Zhe), Marten, J. (Jonathan), Laville, V. (Vincent), Alver, M. (Maris), Evangelou, E. (Evangelos), Graff, M.E. (Maria E.), He, M. (Meian), Kuhnel, B. (Brigitte), Lyytikäinen, L.-P. (Leo-Pekka), Marques-Vidal, P. (Pedro), Nolte, I.M. (Ilja), Palmer, N.D. (Nicholette), Rauramaa, R. (Rainer), Shu, X.-O. (Xiao-Ou), Snieder, H. (Harold), Weiss, S. (Stefan), Wen, W. (Wanqing), Yanek, L.R. (Lisa), Adolfo, C. (Correa), Ballantyne, C. (Christie), Bielak, L.F. (Lawrence F.), Biermasz, N.R., Boerwinkle, E.A. (Eric), Dimou, N. (Niki), Eiriksdottir, G. (Gudny), Gao, C. (Chuan), Gharib, S.A. (Sina), Gottlieb, D.J. (Daniel J.), Haba-Rubio, J. (José), Harris, T.B. (Tamara), Heikkinen, S. (Sami), Heinzer, R. (Raphaël), Hixson, J.E. (James E.), Homuth, G. (Georg), Ikram, M.A. (Arfan), Komulainen, P. (Pirjo), Krieger, J.E. (José), Lee, J. (Jiwon), Liu, J. (Jingmin), Lohman, K.K. (Kurt K.), Luik, A.I. (Annemarie), Mägi, R. (Reedik), Martin, L.W. (Lisa), Meitinger, T. (Thomas), Metspalu, A. (Andres), Milaneschi, Y. (Yuri), Nalls, M.A. (Michael), O´Connell, J.R., Peters, A. (Annette), Peyser, P.A. (Patricia A.), Raitakari, O. (Olli), Reiner, A. (Alexander), Rensen, P.C.N. (Patrick), Rice, T.K. (Treva K.), Rich, S.S. (Stephen), Roenneberg, T., Rotter, J.I. (Jerome I.), Schreiner, P.J. (Pamela), Shikany, J. (James), Sidney, S.S. (Stephen S.), Sims, M. (Mario), Sitlani, C.M. (Colleen M.), Sofer, T. (Tamar), Strauch, K. (Konstantin), Swertz, M.A. (Morris A.), Taylor, K.D. (Kent), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Völzke, H. (Henry), Waldenberger, M. (Melanie), Wallance, R.B. (Robert B.), van Dijk, K.W. (Ko Willems), Yu, C. (Caizheng), Zonderman, A.B. (Alan B.), Becker, D.M. (Diane), Elliott, P. (Paul), Esko, T. (Tõnu), Gieger, C. (Christian), Grabe, H.J. (Hans Jörgen), Lakka, T.A. (Timo), Lehtimäki, T. (Terho), North, K.E. (Kari), Penninx, B.W.J.H. (Brenda), Vollenweider, P. (Peter), Wagenknecht, L.E. (Lynne), Wu, T. (Tangchun), Xiang, Y.-B. (Yong-Bing), Zheng, W. (Wei), Arnett, D.K. (Donna), Bouchard, C. (Claude), Evans, M.K. (Michele), Gudnason, V. (Vilmundur), Kardia, S.L.R. (Sharon), Kelly, T.N. (Tanika N.), Kritchevsky, S.B. (Stephen), Loos, R.J.F. (Ruth), Pereira, A. (A.), Province, M.A. (Mike), Psaty, B.M. (Bruce), Rotimi, C. (Charles), Zhu, X. (Xiaofeng), Amin, N. (Najaf), Cupples, L.A. (L Adrienne), Fornage, M. (Myriam), Fox, E.F. (Ervin F.), Guo, X. (Xiuqing), Gauderman, W.J. (W James), Rice, K.M. (Kenneth), Kooperberg, C. (Charles), Munroe, P. (Patricia), Liu, C.-T. (Ching-Ti), Morrison, A.C. (Alanna), Rao, D.C. (Dabeeru C.), Heemst, D. (Diana) van, and Redline, S. (Susan)
Abstract: Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
Published: 2019
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2. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author: Vries, P.S. (Paul) de, Brown, M.R., Bentley, A.R. (Amy), Sung, Y.J. (Yun J.), Winkler, T.W. (Thomas W.), Ntalla, I. (Ioanna), Schwander, K., Kraja, A. (Aldi), Guo, X. (Xiuqing), Franceschini, N. (Nora), Cheng, C.-Y. (Ching-Yu), Sim, X. (Xueling), Vojinović, D. (Dina), Huffman, J.E. (Jennifer E.), Musani, S.K. (Solomon K.), Li, C. (Changwei), Feitosa, M.F. (Mary Furlan), Richard, M.A. (Melissa A.), Noordam, R. (Raymond), Aschard, H. (Hugues), Bartz, T.M. (Traci M.), Bielak, L.F. (Lawrence F.), Deng, X. (Xuan), Dorajoo, R. (Rajkumar), Lohman, K.K. (Kurt K.), Manning, A.K. (Alisa), Rankinen, T. (Tuomo), Smith, A.V. (Albert), Tajuddin, S.M. (Salman M.), Evangelou, E. (Evangelos), Graff, M.J. (Maud J.L.), Alver, M. (Maris), Boissel, M. (Mathilde), Chai, J.F. (Jin Fang), Chen, X. (Xu), Divers, J. (Jasmin), Gandin, I. (Ilaria), Gao, C. (Chuan), Goel, A. (Anuj), Hagemeijer, Y. (Yanick), Harris, S.E. (Sarah), Hartwig, F.P. (Fernando P.), He, M. (Meian), Horimoto, A.R.V.R. (Andrea R V R), Hsu, F.-C. (Fang-Chi), Jackson, A.U. (Anne), Kasturiratne, A. (Anuradhani), Komulainen, P. (Pirjo), Kuhnel, B. (Brigitte), Laguzzi, F. (Federica), Lee, J.H. (Joseph H.), Luan, J. (Jian'an), Lyytikäinen, L.-P. (Leo-Pekka), Matoba, N. (Nana), Nolte, I.M. (Ilja), Pietzner, M. (Maik), Riaz, M. (Muhammad), Said, M.A. (M Abdullah), Scott, R.A. (Robert), Sofer, T. (Tamar), Stancáková, A. (Alena), Takeuchi, F. (Fumihiko), Tayo, B. (Bamidele), Most, P.J. (Peter) van der, Varga, T.V. (Tibor V.), Wang, Y. (Yajuan), Ware, E.B. (Erin B.), Wen, W. (Wanqing), Yanek, L.R. (Lisa), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Afaq, S. (Saima), Amin, N. (Najaf), Amini, M. (Marzyeh), Arking, D.E. (Dan), Aung, T. (Tin), Ballantyne, C. (Christie), Boerwinkle, E.A. (Eric), Broeckel, U. (Ulrich), Campbell, A. (Archie), Canouil, M. (Mickaël), Charumathi, S. (Sabanayagam), Chen, Y.D.I. (Yii-Der Ida), Connell, J. (John), Faire, U. (Ulf) de, de Las Fuentes, L. (Lisa), Mutsert, R. (Reneé) de, de Silva, H.J. (H Janaka), Ding, J. (Jingzhong), Dominiczak, A.F. (Anna F.), Duan, Q. (Qing), Eaton, C.B. (Charles B.), Eppinga, R.N. (Ruben N.), Faul, J.D. (Jessica D.), Fisher, V. (Virginia), Forrester, T. (Terrence), Franco, O.H. (Oscar), Friedlander, Y. (Yechiel), Ghanbari, M. (Mohsen), Giulianini, F. (Franco), Grabe, H.J. (Hans Jörgen), Grove, M.L. (Megan), Gu, C. (Charles), Harris, T.B. (Tamara), Heikkinen, S. (Sami), Heng, C.K. (Chew-Kiat), Hirata, M. (Makoto), Hixson, J.E. (James E.), Howard, B.V. (Barbara V.), Ikram, M.A. (Arfan), Jacobs, D.R. (David R.), Johnson, C. (Craig), Jonas, J.B., Kammerer, C.M. (Candace), Katsuya, T. (Tomohiro), Khor, C.C., Kilpeläinen, T.O. (Tuomas O.), Koh, W.-P. (Woon-Puay), Koistinen, H.A. (Heikki A.), Kolcic, I. (Ivana), Kooperberg, C. (Charles), Krieger, J.E. (José), Kritchevsky, S.B. (Steve B.), Kubo, M. (Michiaki), Kuusisto, J. (Johanna), Lakka, T.A. (Timo), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lemaitre, R.N. (Rozenn ), Li, Y. (Yize), Liang, J. (Jingjing), Liu, J. (Jianjun), Liu, K. (Kiang), Loh, M. (Marie), Louie, T. (Tin), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W.), McKenzie, C.A. (Colin A.), Meitinger, T. (Thomas), Metspalu, A. (Andres), Milaneschi, Y. (Yuri), Milani, L. (Lili), Mohlke, K.L. (Karen L.), Mosley, T.H. (Thomas H.), Mukamal, K. (Kenneth), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nelson, C.P. (Christopher P.), Sotoodehnia, N. (Nona), O´Connell, J.R., Palmer, N.D. (Nicholette), Pazoki, R. (Raha), Pedersen, N.L. (Nancy), Peters, A. (Annette), Peyser, P.A. (Patricia A.), Polasek, O. (Ozren), Poulter, N.R. (Neil), Raffel, L.J. (Leslie J.), Raitakari, O. (Olli), Reiner, A.P. (Alex P.), Rice, T.K. (Treva K.), Rich, S.S. (Stephen), Robino, A. (Antonietta), Robinson, J.G. (Jennifer), Rose, L.M. (Lynda M.), Rudan, I. (Igor), Schmidt, C.O. (Carsten O.), Schreiner, P.J. (Pamela), Scott, W.R. (William R.), Sever, P. (Peter), Shi, Y. (Yuan), Sidney, S. (Stephen), Sims, M. (Mario), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Snieder, H. (Harold), Starr, J.M. (John), Strauch, K. (Konstantin), Tan, N. (Nicholas), Taylor, K.D. (Kent), Teo, Y.Y. (Yik Ying), Tham, Y.C. (Yih Chung), Uitterlinden, A.G. (André), Heemst, D. (Diana) van, Vuckovic, D. (Dragana), Waldenberger, M. (Melanie), Wang, L. (Lihua), Wang, Y. (Yujie), Wang, Z. (Zhe), Wei, W.B. (Wen Bin), Williams, C. (Christine), Wilson, G. (Gregory), Wojczynski, M.K. (Mary ), Yao, J. (Jie), Yu, B. (Bing), Yu, C. (Caizheng), Yuan, J.-M. (Jian-Min), Zhao, W. (Wei), Zonderman, A.B., Becker, D.M. (Diane), Boehnke, M. (Michael), Bowden, D.W. (Donald W.), Chambers, J.C. (John C.), Deary, I.J. (Ian), Esko, T. (Tõnu), Farrall, M. (Martin), Franks, P.W. (Paul W.), Freedman, B.I. (Barry), Froguel, P. (Philippe), Gasparini, P. (Paolo), Gieger, C. (Christian), Horta, B.L. (Bernardo L.), Kamatani, Y. (Yoichiro), Kato, N. (Norihiro), Kooner, J.S. (Jaspal S.), Laakso, M. (Markku), Leander, K. (Karin), Lehtimäki, T. (Terho), Magnusson, P.K. (Patrik), Penninx, B.W.J.H. (Brenda), Pereira, A.C. (Alexandre C.), Rauramaa, R. (Rainer), Samani, N.J. (Nilesh), Scott, J. (James), Shu, X.-O. (Xiao-Ou), Harst, P. (Pim) van der, Wagenknecht, L.E. (Lynne), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Watkins, H. (Hugh), Weir, D.R. (David R.), Wickremasinghe, A.R. (Ananda R.), Zheng, W. (Wei), Elliott, P. (Paul), North, K.E. (Kari), Bouchard, C. (Claude), Evans, M.K. (Michele), Gudnason, V. (Vilmundur), Liu, C.-T. (Ching-Ti), Liu, Y. (YongMei), Psaty, B.M. (Bruce M.), Jarvelin, M.-R. (Marjo-Riitta), Dam, R.M. (Rob) van, Kardia, S.L.R. (Sharon), Dominiczak, A. (Anna), Rotimi, C. (Charles), Mook-Kanamori, D.O. (Dennis O.), Fornage, M. (Myriam), Kelly, T.N. (Tanika N.), Fox, E.R. (Ervin R.), Hayward, C. (Caroline), Duijn, C.M. (Cornelia) van, Tai, E.S. (Shyong), Wong, T.Y. (Tien Yin), Liu, J. (Jingmin), Rotter, J.I. (Jerome I.), Gauderman, W.J. (W James), Province, M.A. (Michael A.), Munroe, P. (Patricia), Rice, K. (Kenneth), Chasman, D.I. (Daniel), Cupples, L.A. (L Adrienne), Tobin, M.D. (Martin), Morrison, A.C. (Alanna), Vries, P.S. (Paul) de, Brown, M.R., Bentley, A.R. (Amy), Sung, Y.J. (Yun J.), Winkler, T.W. (Thomas W.), Ntalla, I. (Ioanna), Schwander, K., Kraja, A. (Aldi), Guo, X. (Xiuqing), Franceschini, N. (Nora), Cheng, C.-Y. (Ching-Yu), Sim, X. (Xueling), Vojinović, D. (Dina), Huffman, J.E. (Jennifer E.), Musani, S.K. (Solomon K.), Li, C. (Changwei), Feitosa, M.F. (Mary Furlan), Richard, M.A. (Melissa A.), Noordam, R. (Raymond), Aschard, H. (Hugues), Bartz, T.M. (Traci M.), Bielak, L.F. (Lawrence F.), Deng, X. (Xuan), Dorajoo, R. (Rajkumar), Lohman, K.K. (Kurt K.), Manning, A.K. (Alisa), Rankinen, T. (Tuomo), Smith, A.V. (Albert), Tajuddin, S.M. (Salman M.), Evangelou, E. (Evangelos), Graff, M.J. (Maud J.L.), Alver, M. (Maris), Boissel, M. (Mathilde), Chai, J.F. (Jin Fang), Chen, X. (Xu), Divers, J. (Jasmin), Gandin, I. (Ilaria), Gao, C. (Chuan), Goel, A. (Anuj), Hagemeijer, Y. (Yanick), Harris, S.E. (Sarah), Hartwig, F.P. (Fernando P.), He, M. (Meian), Horimoto, A.R.V.R. (Andrea R V R), Hsu, F.-C. (Fang-Chi), Jackson, A.U. (Anne), Kasturiratne, A. (Anuradhani), Komulainen, P. (Pirjo), Kuhnel, B. (Brigitte), Laguzzi, F. (Federica), Lee, J.H. (Joseph H.), Luan, J. (Jian'an), Lyytikäinen, L.-P. (Leo-Pekka), Matoba, N. (Nana), Nolte, I.M. (Ilja), Pietzner, M. (Maik), Riaz, M. (Muhammad), Said, M.A. (M Abdullah), Scott, R.A. (Robert), Sofer, T. (Tamar), Stancáková, A. (Alena), Takeuchi, F. (Fumihiko), Tayo, B. (Bamidele), Most, P.J. (Peter) van der, Varga, T.V. (Tibor V.), Wang, Y. (Yajuan), Ware, E.B. (Erin B.), Wen, W. (Wanqing), Yanek, L.R. (Lisa), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Afaq, S. (Saima), Amin, N. (Najaf), Amini, M. (Marzyeh), Arking, D.E. (Dan), Aung, T. (Tin), Ballantyne, C. (Christie), Boerwinkle, E.A. (Eric), Broeckel, U. (Ulrich), Campbell, A. (Archie), Canouil, M. (Mickaël), Charumathi, S. (Sabanayagam), Chen, Y.D.I. (Yii-Der Ida), Connell, J. (John), Faire, U. (Ulf) de, de Las Fuentes, L. (Lisa), Mutsert, R. (Reneé) de, de Silva, H.J. (H Janaka), Ding, J. (Jingzhong), Dominiczak, A.F. (Anna F.), Duan, Q. (Qing), Eaton, C.B. (Charles B.), Eppinga, R.N. (Ruben N.), Faul, J.D. (Jessica D.), Fisher, V. (Virginia), Forrester, T. (Terrence), Franco, O.H. (Oscar), Friedlander, Y. (Yechiel), Ghanbari, M. (Mohsen), Giulianini, F. (Franco), Grabe, H.J. (Hans Jörgen), Grove, M.L. (Megan), Gu, C. (Charles), Harris, T.B. (Tamara), Heikkinen, S. (Sami), Heng, C.K. (Chew-Kiat), Hirata, M. (Makoto), Hixson, J.E. (James E.), Howard, B.V. (Barbara V.), Ikram, M.A. (Arfan), Jacobs, D.R. (David R.), Johnson, C. (Craig), Jonas, J.B., Kammerer, C.M. (Candace), Katsuya, T. (Tomohiro), Khor, C.C., Kilpeläinen, T.O. (Tuomas O.), Koh, W.-P. (Woon-Puay), Koistinen, H.A. (Heikki A.), Kolcic, I. (Ivana), Kooperberg, C. (Charles), Krieger, J.E. (José), Kritchevsky, S.B. (Steve B.), Kubo, M. (Michiaki), Kuusisto, J. (Johanna), Lakka, T.A. (Timo), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lemaitre, R.N. (Rozenn ), Li, Y. (Yize), Liang, J. (Jingjing), Liu, J. (Jianjun), Liu, K. (Kiang), Loh, M. (Marie), Louie, T. (Tin), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W.), McKenzie, C.A. (Colin A.), Meitinger, T. (Thomas), Metspalu, A. (Andres), Milaneschi, Y. (Yuri), Milani, L. (Lili), Mohlke, K.L. (Karen L.), Mosley, T.H. (Thomas H.), Mukamal, K. (Kenneth), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nelson, C.P. (Christopher P.), Sotoodehnia, N. (Nona), O´Connell, J.R., Palmer, N.D. (Nicholette), Pazoki, R. (Raha), Pedersen, N.L. (Nancy), Peters, A. (Annette), Peyser, P.A. (Patricia A.), Polasek, O. (Ozren), Poulter, N.R. (Neil), Raffel, L.J. (Leslie J.), Raitakari, O. (Olli), Reiner, A.P. (Alex P.), Rice, T.K. (Treva K.), Rich, S.S. (Stephen), Robino, A. (Antonietta), Robinson, J.G. (Jennifer), Rose, L.M. (Lynda M.), Rudan, I. (Igor), Schmidt, C.O. (Carsten O.), Schreiner, P.J. (Pamela), Scott, W.R. (William R.), Sever, P. (Peter), Shi, Y. (Yuan), Sidney, S. (Stephen), Sims, M. (Mario), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Snieder, H. (Harold), Starr, J.M. (John), Strauch, K. (Konstantin), Tan, N. (Nicholas), Taylor, K.D. (Kent), Teo, Y.Y. (Yik Ying), Tham, Y.C. (Yih Chung), Uitterlinden, A.G. (André), Heemst, D. (Diana) van, Vuckovic, D. (Dragana), Waldenberger, M. (Melanie), Wang, L. (Lihua), Wang, Y. (Yujie), Wang, Z. (Zhe), Wei, W.B. (Wen Bin), Williams, C. (Christine), Wilson, G. (Gregory), Wojczynski, M.K. (Mary ), Yao, J. (Jie), Yu, B. (Bing), Yu, C. (Caizheng), Yuan, J.-M. (Jian-Min), Zhao, W. (Wei), Zonderman, A.B., Becker, D.M. (Diane), Boehnke, M. (Michael), Bowden, D.W. (Donald W.), Chambers, J.C. (John C.), Deary, I.J. (Ian), Esko, T. (Tõnu), Farrall, M. (Martin), Franks, P.W. (Paul W.), Freedman, B.I. (Barry), Froguel, P. (Philippe), Gasparini, P. (Paolo), Gieger, C. (Christian), Horta, B.L. (Bernardo L.), Kamatani, Y. (Yoichiro), Kato, N. (Norihiro), Kooner, J.S. (Jaspal S.), Laakso, M. (Markku), Leander, K. (Karin), Lehtimäki, T. (Terho), Magnusson, P.K. (Patrik), Penninx, B.W.J.H. (Brenda), Pereira, A.C. (Alexandre C.), Rauramaa, R. (Rainer), Samani, N.J. (Nilesh), Scott, J. (James), Shu, X.-O. (Xiao-Ou), Harst, P. (Pim) van der, Wagenknecht, L.E. (Lynne), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Watkins, H. (Hugh), Weir, D.R. (David R.), Wickremasinghe, A.R. (Ananda R.), Zheng, W. (Wei), Elliott, P. (Paul), North, K.E. (Kari), Bouchard, C. (Claude), Evans, M.K. (Michele), Gudnason, V. (Vilmundur), Liu, C.-T. (Ching-Ti), Liu, Y. (YongMei), Psaty, B.M. (Bruce M.), Jarvelin, M.-R. (Marjo-Riitta), Dam, R.M. (Rob) van, Kardia, S.L.R. (Sharon), Dominiczak, A. (Anna), Rotimi, C. (Charles), Mook-Kanamori, D.O. (Dennis O.), Fornage, M. (Myriam), Kelly, T.N. (Tanika N.), Fox, E.R. (Ervin R.), Hayward, C. (Caroline), Duijn, C.M. (Cornelia) van, Tai, E.S. (Shyong), Wong, T.Y. (Tien Yin), Liu, J. (Jingmin), Rotter, J.I. (Jerome I.), Gauderman, W.J. (W James), Province, M.A. (Michael A.), Munroe, P. (Patricia), Rice, K. (Kenneth), Chasman, D.I. (Daniel), Cupples, L.A. (L Adrienne), Tobin, M.D. (Martin), and Morrison, A.C. (Alanna)
Abstract: A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
Published: 2019
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3. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author: Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), Morris, R.W. (Richard), Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), and Morris, R.W. (Richard)
Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Published: 2018
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4. Von Willebrand factor and ADAMTS13 activity in relation to risk of dementia

Author: Wolters, F.J. (Frank), Boender, J. (Johan), Vries, P.S. (Paul) de, Sonneveld, M.A.H. (Michelle), Koudstaal, P.J. (Peter), Maat, M.P.M. (Moniek) de, Franco, O.H. (Oscar), Ikram, M.K. (Kamran), Leebeek, F.W.G. (Frank), Ikram, M.A. (Arfan), Wolters, F.J. (Frank), Boender, J. (Johan), Vries, P.S. (Paul) de, Sonneveld, M.A.H. (Michelle), Koudstaal, P.J. (Peter), Maat, M.P.M. (Moniek) de, Franco, O.H. (Oscar), Ikram, M.K. (Kamran), Leebeek, F.W.G. (Frank), and Ikram, M.A. (Arfan)
Abstract: Low ADAMTS13 activity is associated with an increased risk of cardiovascular disease, which is generally attributed to its proteolytic effects on Von Willebrand factor (VWF). Cardiovascular health is an important determinant of cognitive decline, but the association of either VWF or ADAMTS13 with risk of dementia is unknown. Between 1997-2002, we measured VWF antigen and ADAMTS13 activity in 6055 participants of the population-based Rotterdam Study (mean age 69.3 years, 57.2% women). At baseline, 85 participants had dementia, and during 15 years of follow-up 821 developed dementia. Higher VWF was associated with prevalence and risk of dementia, unaffected by concurrent ADAMTS13 activity, but estimates strongly attenuated over time and were no longer statistically significant at 4 years of follow-up (relative risks [95% CI] per standard deviation increase- cross-sectional: 1.37 [1.06-1.77], and longitudinal: 1.05 [0.97-1.14]). In contrast, low ADAMTS13 was associated with increased risk of dementia throughout follow-up (hazard ratio per SD decrease- 1.16 [1.06-1.28]), which alike for ischaemic stroke, was modified by the presence of diabetes (P-interaction = 0.003). In conclusion, higher VWF and low ADAMTS13 activity are associated with increased risk of dementia, but differences in time-course and lack of synergistic effects may indicate in part independent underlying mechanisms.
Published: 2018
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5. Epigenome-Wide Association Study Identifies Methylation Sites Associated With Liver Enzymes and Hepatic Steatosis

Author: Nano, J. (Jana), Ghanbari, M. (Mohsen), Wang, W. (Wenshi), Vries, P.S. (Paul) de, Dhana, K. (Klodian), Muka, T. (Taulant), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Hofman, A. (Albert), Franco, O.H. (Oscar), Pan, Q. (Qiuwei), Darwish Murad, S. (Sarwa), Dehghan, A. (Abbas), Nano, J. (Jana), Ghanbari, M. (Mohsen), Wang, W. (Wenshi), Vries, P.S. (Paul) de, Dhana, K. (Klodian), Muka, T. (Taulant), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Hofman, A. (Albert), Franco, O.H. (Oscar), Pan, Q. (Qiuwei), Darwish Murad, S. (Sarwa), and Dehghan, A. (Abbas)
Abstract: _BACKGROUND & AIMS:_ Epigenetic mechanisms might be involved in the regulation of liver enzyme level. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of liver enzymes and hepatic steatosis. _METHODS:_ We conducted an epigenome-wide association study in whole blood for liver enzyme levels, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), among a discovery set of 731 participants of the Rotterdam Study and sought replication in a non-overlapping sample of 719 individuals. Significant DNA methylation changes were further analyzed to evaluate their relation with hepatic steatosis. Expression levels of the top identified gene were measured in 9 human liver cell lines and compared with expression profiles of its potential targets associated with lipid traits. The candidate gene was subsequently knocked down in human hepatoma cells using lentiviral vectors expressing small hairpin RNAs. _RESULTS:_ Eight probes annotated to SLC7A11, SLC1A5, SLC43A1, PHGDH, PSORS1C1, SREBF1, ANKS3 were associated with GGT and 1 probe annotated to SLC7A11 was associated with ALT after Bonferroni correction (1.0 × 10-7). No probe was identified for AST levels. Four probes for GGT levels including cg06690548 (SLC7A11), cg11376147 (SLC43A1), cg22304262 (SLC1A5), and cg14476101 (PHGDH), and 1 for ALT cg06690548 (SLC7A11) were replicated. DNA methylation at SLC7A11 was associated with reduced risk of hepatic steatosis in participants (odds ratio, 0.69; 95% CI= 0.55-0.93; P value: 2.7 × 10-3). In functional experiments, SLC7A11 was highly expressed in human liver cells; its expression is positively correlated with expression of a panel of lipid-associated genes, indicating a role of SLC7A11 in lipid metabolism. _CONCLUSIONS:_ Our results provide new insights into epigenetic mechanisms associated with markers of liver function and hepatic steatosis, laying the groundwork for future diagno
Published: 2017
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6. Epigenome-wide association study (EWAS) on lipids: the Rotterdam Study

Author: Braun, K.V.E. (Kim), Dhana, K. (Klodian), Vries, P.S. (Paul) de, Voortman, R.G. (Trudy), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Hu, F.B. (Frank B.), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Braun, K.V.E. (Kim), Dhana, K. (Klodian), Vries, P.S. (Paul) de, Voortman, R.G. (Trudy), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Hu, F.B. (Frank B.), Franco, O.H. (Oscar), and Dehghan, A. (Abbas)
Abstract: Background: DNA methylation is a key epigenetic mechanism that is suggested to be associated with blood lipid levels. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol in 725 participants of the Rotterdam Study, a population-based cohort study. Subsequently, we sought replication in a non-overlapping set of 760 participants. Results: Genome-wide methylation levels were measured in whole blood using the Illumina Methylation 450 array. Associations between lipid levels and DNA methylation beta values were examined using linear mixed-effect models. All models were adjusted for sex, age, smoking, white blood cell proportions, array number, and position on array. A Bonferroni-corrected p value lower than 1.08 × 10−7 was considered statistically significant. Five CpG sites annotated to genes including DHCR24, CPT1A, ABCG1, and SREBF1 were identified and replicated. Four CpG sites were associated with triglycerides, including CpG sites annotated to CPT1A (cg00574958 and cg17058475), ABCG1 (cg06500161), and SREBF1 (cg11024682). Two CpG sites were associated with HDL-C, including ABCG1 (cg06500161) and DHCR24 (cg17901584). No significant associations were observed with LDL-C or total cholesterol. Conclusions: We report an association of HDL-C levels with methylation of a CpG site near DHCR24, a protein-coding gene involved in cholesterol biosynthesis, which has previously been reported to be associated with other metabolic traits. Furthermore, we confirmed previously reported associations of methylation of CpG sites within CPT1A, ABCG1, and SREBF1 and lipids. These results provide insight in the mechanisms that are involved in lipid metabolism.
Published: 2017
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7. Comparison of HapMap and 1000 genomes reference panels in a large-scale genome-wide association study

Author: Vries, P.S. (Paul) de, Sabater-Lleal, M. (Maria), Chasman, D.I. (Daniel), Trompet, S. (Stella), Ahluwalia, T.S. (Tarunveer Singh), Teumer, A. (Alexander), Kleber, M.E. (Marcus), Chen, M.-H. (Ming-Huei), Wang, J.J. (Jie Jin), Attia, J. (John), Marioni, R.E. (Riccardo), Steri, M. (Maristella), Weng, L.-C. (Lu-Chen), Pool, R. (Reńe), Grossmann, V. (Vera), Brody, J.A. (Jennifer A.), Venturini, C. (Cristina), Tanaka, T. (Toshiko), Rose, L.M. (Lynda), Oldmeadow, C. (Christopher), Mazur, J. (Johanna), Basu, S. (Saonli), Frånberg, M. (Mattias), Yang, Q. (Qiong), Ligthart, S. (Symen), Hottenga, J.J. (Jouke Jan), Rumley, A. (Ann), Mulas, A. (Antonella), Craen, A.J. (Anton) de, Grotevendt, A. (Anne), Taylor, K.D. (Kent D.), Delgado, G., Kifley, A. (Annette), Lopez, L.M. (Lorna), Berentzen, T.L. (Tina L.), Mangino, M. (Massimo), Bandinelli, S. (Stefania), Morrison, A.C. (Alanna C.), Hamsten, A. (Anders), Tofler, G.H. (Geoffrey), Maat, M.P.M. (Moniek) de, Draisma, G. (Gerrit), Lowe, G.D. (Gordon D.), Zoledziewska, M. (Magdalena), Sattar, N. (Naveed), Lackner, K.J. (Karl J.), Völker, U. (Uwe), McKnight, B. (Barbara), Huang, J. (Jian), Holliday, E.G. (Elizabeth), McEvoy, M.A. (Mark A.), Starr, J.M. (John), Hysi, P.G. (Pirro), Hernandez, D.G. (Dena), Guan, W. (Weihua), Rivadeneira Ramirez, F. (Fernando), McArdle, W.L. (Wendy), Slagboom, P.E. (Eline), Zeller, T. (Tanja), Psaty, B.M. (Bruce), Uitterlinden, A.G. (André), Geus, E.J.C. (Eco) de, Stott, D.J. (David J.), Binder, H. (Harald), Hofman, A. (Albert), Franco, O.H. (Oscar), Rotter, J.I. (Jerome I.), Ferrucci, L. (Luigi), Spector, T.D. (Tim D.), Deary, I.J. (Ian), März, W. (Winfried), Greinacher, A. (Andreas), Wild, P.S. (Philipp S.), Cucca, F. (Francesco), Boomsma, D.I. (Dorret), Watkins, H. (Hugh), Tang, W. (Weihong), Ridker, P.M. (Paul), Jukema, J.W., Scott, R.J. (Rodney J.), Mitchell, P. (Paul), Hansen, T. (T.), O'Donnell, C.J. (Christopher J.), Smith, N.L. (Nicholas L.), Strachan, D.P. (David P.), Dehghan, A. (Abbas), Vries, P.S. (Paul) de, Sabater-Lleal, M. (Maria), Chasman, D.I. (Daniel), Trompet, S. (Stella), Ahluwalia, T.S. (Tarunveer Singh), Teumer, A. (Alexander), Kleber, M.E. (Marcus), Chen, M.-H. (Ming-Huei), Wang, J.J. (Jie Jin), Attia, J. (John), Marioni, R.E. (Riccardo), Steri, M. (Maristella), Weng, L.-C. (Lu-Chen), Pool, R. (Reńe), Grossmann, V. (Vera), Brody, J.A. (Jennifer A.), Venturini, C. (Cristina), Tanaka, T. (Toshiko), Rose, L.M. (Lynda), Oldmeadow, C. (Christopher), Mazur, J. (Johanna), Basu, S. (Saonli), Frånberg, M. (Mattias), Yang, Q. (Qiong), Ligthart, S. (Symen), Hottenga, J.J. (Jouke Jan), Rumley, A. (Ann), Mulas, A. (Antonella), Craen, A.J. (Anton) de, Grotevendt, A. (Anne), Taylor, K.D. (Kent D.), Delgado, G., Kifley, A. (Annette), Lopez, L.M. (Lorna), Berentzen, T.L. (Tina L.), Mangino, M. (Massimo), Bandinelli, S. (Stefania), Morrison, A.C. (Alanna C.), Hamsten, A. (Anders), Tofler, G.H. (Geoffrey), Maat, M.P.M. (Moniek) de, Draisma, G. (Gerrit), Lowe, G.D. (Gordon D.), Zoledziewska, M. (Magdalena), Sattar, N. (Naveed), Lackner, K.J. (Karl J.), Völker, U. (Uwe), McKnight, B. (Barbara), Huang, J. (Jian), Holliday, E.G. (Elizabeth), McEvoy, M.A. (Mark A.), Starr, J.M. (John), Hysi, P.G. (Pirro), Hernandez, D.G. (Dena), Guan, W. (Weihua), Rivadeneira Ramirez, F. (Fernando), McArdle, W.L. (Wendy), Slagboom, P.E. (Eline), Zeller, T. (Tanja), Psaty, B.M. (Bruce), Uitterlinden, A.G. (André), Geus, E.J.C. (Eco) de, Stott, D.J. (David J.), Binder, H. (Harald), Hofman, A. (Albert), Franco, O.H. (Oscar), Rotter, J.I. (Jerome I.), Ferrucci, L. (Luigi), Spector, T.D. (Tim D.), Deary, I.J. (Ian), März, W. (Winfried), Greinacher, A. (Andreas), Wild, P.S. (Philipp S.), Cucca, F. (Francesco), Boomsma, D.I. (Dorret), Watkins, H. (Hugh), Tang, W. (Weihong), Ridker, P.M. (Paul), Jukema, J.W., Scott, R.J. (Rodney J.), Mitchell, P. (Paul), Hansen, T. (T.), O'Donnell, C.J. (Christopher J.), Smith, N.L. (Nicholas L.), Strachan, D.P. (David P.), and Dehghan, A. (Abbas)
Abstract: An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.
Published: 2017
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8. ADAMTS13 activity as a novel risk factor for incident type 2 diabetes mellitus: a population-based cohort study

Author: Vries, P.S. (Paul) de, Herpt, T.W. (Thijs) van, Ligthart, S. (Symen), Hofman, A. (Albert), Ikram, M.A. (Arfan), Hoek, M. (Mandy) van, Sijbrands, E.J.G. (Eric), Franco, O.H. (Oscar), Maat, M.P.M. (Moniek) de, Leebeek, F.W.G. (Frank), Dehghan, A. (Abbas), Vries, P.S. (Paul) de, Herpt, T.W. (Thijs) van, Ligthart, S. (Symen), Hofman, A. (Albert), Ikram, M.A. (Arfan), Hoek, M. (Mandy) van, Sijbrands, E.J.G. (Eric), Franco, O.H. (Oscar), Maat, M.P.M. (Moniek) de, Leebeek, F.W.G. (Frank), and Dehghan, A. (Abbas)
Abstract: Aims/hypothesis: ADAMTS13 is a protease that breaks down von Willebrand factor (VWF) multimers into smaller, less active particles. VWF has been associated with an increased risk of incident type 2 diabetes mellitus. Here, we determine whether ADAMTS13 activity and VWF antigen are associated with incident diabetes. Methods: This study included 5176 participants from the Rotterdam Study, a prospective population-based cohort study. Participants were free of diabetes at baseline and followed up for more than 20 years. Cox proportional hazards models were used to examine the association of ADAMTS13 activity and VWF antigen with incident diabetes. Results: ADAMTS13 activity was associated with an increased risk of incident diabetes (HR 1.17 [95% CI 1.08, 1.27]) after adjust
Published: 2017
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9. von Willebrand Factor, ADAMTS13 Activity, and Decline in Kidney Function: A Population-Based Cohort Study

Author: Sedaghat, S. (Sanaz), Vries, P.S. (Paul) de, Boender, J. (Johan), Sonneveld, M.A.H. (Michelle), Hoorn, E.J. (Ewout), Hofman, A. (Albert), Maat, M.P.M. (Moniek) de, Franco, O.H. (Oscar), Ikram, M.K. (Kamran), Leebeek, F.W.G. (Frank), Dehghan, A. (Abbas), Sedaghat, S. (Sanaz), Vries, P.S. (Paul) de, Boender, J. (Johan), Sonneveld, M.A.H. (Michelle), Hoorn, E.J. (Ewout), Hofman, A. (Albert), Maat, M.P.M. (Moniek) de, Franco, O.H. (Oscar), Ikram, M.K. (Kamran), Leebeek, F.W.G. (Frank), and Dehghan, A. (Abbas)
Abstract: Background Altered levels of von Willebrand factor (vWF) and ADAMTS13 can promote thrombosis and disturb blood flow in kidney microcirculations. We investigated the association of serum vWF:ADAMTS13 ratio in relation to decline in kidney function. Study Design Prospective cohort study. Setting & Participants 2,479 individuals (mean age, 65.1 ± 5.9 [SD] years; 43% men) from the population-based Rotterdam Study. Predictors vWF, ADAMTS13, and vWF:ADAMTS13 ratio. Outcomes & Measurements Annual decline in estimated glomerular filtration rate (eGFR), halving of eGFR, and new-onset eGFR < 60 mL/min/1.73 m2 were assessed. Results During a median follow-up of 11 (range, 7.81-13.57) years, 500 cases of new-onset eGFR < 60 mL/min/1.73 m2 occurred. The population had a mean eGFR decline of 0.96 ± 0.92 mL/min/1.73 m2 per year. Higher vWF:ADAMTS13 ratio was associated with steeper annual decline in eGFR (difference, −0.06 [95% CI, −0.09 to −0.02] mL/min/1.73 m2 per year) and higher risk for new-onset eGFR < 60 mL/min/1.73 m2 (OR, 1.13; 95% CI, 1.01-1.27). Likewise, higher vWF:ADAMTS13 ratio was associated with higher risk for halving of eGFR (OR, 1.40; 95% CI, 1.02-1.93). After adjustment for cardiovascular risk factors and blood group, effect estimates remained the same. Limitations No data available for albuminuria. Participants were classified based on a single measurement of vWF and ADAMTS13. Conclusions In this population-based study, we showed that higher vWF:ADAMTS13 ratio is associated with decline in kidney function, suggesting a role of elevated prothrombotic factors in the development and progression of kidney disease.
Published: 2016
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10. Hemostasis and Cardiovascular Disease : a molecular epidemiology approach

Author: Vries, P.S. (Paul) de and Vries, P.S. (Paul) de
Published: 2016

11. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Author: Vries, P.S. (Paul) de, Chasman, D.I. (Daniel), Sabater-Lleal, M. (Maria), Chen, M.-H. (Ming-Huei), Huffman, J.E. (Jennifer E.), Steri, M. (Maristella), Tang, W. (Weihong), Teumer, A. (Alexander), Marioni, R.E. (Riccardo), Grossmann, V. (Vera), Hottenga, J.J. (Jouke Jan), Trompet, S. (Stella), Müller-Nurasyid, M. (Martina), Zhao, J.H. (Jing Hua), Brody, J.A. (Jennifer A.), Kleber, M.E. (Marcus), Guo, X. (Xiuqing), Wang, J.J. (Jie Jin), Auer, P. (Paul), Attia, J. (John), Yanek, L.R. (Lisa), Ahluwalia, T.S. (Tarunveer Singh), Lahti, J. (Jari), Venturini, C. (Cristina), Tanaka, T. (Toshiko), Bielak, L.F. (Lawrence F.), Joshi, P.K. (Peter), Rocanin-Arjo, A. (Ares), Kolcic, I. (Ivana), Navarro, P. (Pau), Rose, L.M. (Lynda), Oldmeadow, C. (Christopher), Riess, H. (Helene), Mazur, J. (Johanna), Basu, S. (Saonli), Goel, A. (Anuj), Yang, Q. (Qiong), Ghanbari, M. (Mohsen), Willemsen, G. (Gonneke), Rumley, A. (Ann), Fiorillo, E. (Edoardo), Craen, A.J. (Anton) de, Grotevendt, A. (Anne), Scott, R.A. (Robert), Taylor, K.D. (Kent D.), Delgado, G.E. (Graciela E.), Yao, J. (Jie), Kifley, A. (Annette), Kooperberg, C. (Charles), Qayyum, Q. (Rehan), Lopez, L. (Lornam), Berentzen, T.L. (Tina L.), Räikkönen, K. (Katri), Mangino, M. (Massimo), Bandinelli, S. (Stefania), Peyser, P.A. (Patricia A.), Wild, S. (Sarah), Tregouet, D.-A. (David-Alexandre), Wright, A.F. (Alan), Marten, J. (Jonathan), Zemunik, T. (Tatijana), Morrison, A.C. (Alanna), Sennblad, B. (Bengt), Tofler, G.H. (Geoffrey), Maat, M.P.M. (Moniek) de, Geus, E.J.C. (Eco) de, Lowe, G.D. (Gordon D.), Zoledziewska, M. (Magdalena), Sattar, N. (Naveed), Binder, H. (Harald), Völker, U. (Uwe), Waldenberger, M. (Melanie), Khaw, K.-T. (Kay-Tee), McKnight, B. (Barbara), Huang, J. (Jian), Jenny, N.S. (Nancy), Holliday, E.G. (Elizabeth), Qi, L. (Lihong), Mcevoy, M.G. (Mark G.), Becker, D.M. (Diane), Starr, J.M. (John), Sarin, A.-P., Hysi, P.G. (Pirro), Hernandez, D.G. (Dena), Jhun, M.A. (Min A.), Campbell, H. (Harry), Hamsten, A. (Anders), Sarin, F. (Fernando), McArdle, W.L. (Wendy), Slagboom, P.E. (Eline), Zeller, T. (Tanja), Koenig, W. (Wolfgang), Psaty, B. (Brucem), Haritunians, T. (Talin), Liu, J. (Jingmin), Palotie, A. (Aarno), Uitterlinden, A.G. (André), Stott, D.J. (David J.), Hofman, A. (Albert), Franco, O.H. (Oscar), Polasek, O. (Ozren), Rudan, I. (Igor), Morange, P.-E. (P.), Wilson, J.F. (James F.), Kardia, S.L. (Sharon L.r), Ferrucci, L. (Luigi), Spector, T.D. (Timothy), Eriksson, J.G. (Johan G.), Hansen, T. (Torben), Deary, I.J. (Ian), Becker, L.C. (Lewis), Scott, R.J. (Rodney), Mitchell, P. (Paul), März, W. (Winfried), Wareham, N.J. (Nick J.), Peters, A. (Annette), Greinacher, A. (Andreas), Wild, P.S. (Philipp S.), Jukema, J.W. (Jan Wouter), Boomsma, D.I. (Dorret), Hayward, C. (Caroline), Cucca, F. (Francesco), Tracy, R.P. (Russell), Watkins, H. (Hugh), Reiner, A.P. (Alex P.), Folsom, A.R. (Aaron), Ridker, P.M. (Paul), O'Donnell, C.J. (Christopher J.), Smith, N.L. (Nicholas L.), Strachan, D.P. (David P.), Dehghan, A. (Abbas), Vries, P.S. (Paul) de, Chasman, D.I. (Daniel), Sabater-Lleal, M. (Maria), Chen, M.-H. (Ming-Huei), Huffman, J.E. (Jennifer E.), Steri, M. (Maristella), Tang, W. (Weihong), Teumer, A. (Alexander), Marioni, R.E. (Riccardo), Grossmann, V. (Vera), Hottenga, J.J. (Jouke Jan), Trompet, S. (Stella), Müller-Nurasyid, M. (Martina), Zhao, J.H. (Jing Hua), Brody, J.A. (Jennifer A.), Kleber, M.E. (Marcus), Guo, X. (Xiuqing), Wang, J.J. (Jie Jin), Auer, P. (Paul), Attia, J. (John), Yanek, L.R. (Lisa), Ahluwalia, T.S. (Tarunveer Singh), Lahti, J. (Jari), Venturini, C. (Cristina), Tanaka, T. (Toshiko), Bielak, L.F. (Lawrence F.), Joshi, P.K. (Peter), Rocanin-Arjo, A. (Ares), Kolcic, I. (Ivana), Navarro, P. (Pau), Rose, L.M. (Lynda), Oldmeadow, C. (Christopher), Riess, H. (Helene), Mazur, J. (Johanna), Basu, S. (Saonli), Goel, A. (Anuj), Yang, Q. (Qiong), Ghanbari, M. (Mohsen), Willemsen, G. (Gonneke), Rumley, A. (Ann), Fiorillo, E. (Edoardo), Craen, A.J. (Anton) de, Grotevendt, A. (Anne), Scott, R.A. (Robert), Taylor, K.D. (Kent D.), Delgado, G.E. (Graciela E.), Yao, J. (Jie), Kifley, A. (Annette), Kooperberg, C. (Charles), Qayyum, Q. (Rehan), Lopez, L. (Lornam), Berentzen, T.L. (Tina L.), Räikkönen, K. (Katri), Mangino, M. (Massimo), Bandinelli, S. (Stefania), Peyser, P.A. (Patricia A.), Wild, S. (Sarah), Tregouet, D.-A. (David-Alexandre), Wright, A.F. (Alan), Marten, J. (Jonathan), Zemunik, T. (Tatijana), Morrison, A.C. (Alanna), Sennblad, B. (Bengt), Tofler, G.H. (Geoffrey), Maat, M.P.M. (Moniek) de, Geus, E.J.C. (Eco) de, Lowe, G.D. (Gordon D.), Zoledziewska, M. (Magdalena), Sattar, N. (Naveed), Binder, H. (Harald), Völker, U. (Uwe), Waldenberger, M. (Melanie), Khaw, K.-T. (Kay-Tee), McKnight, B. (Barbara), Huang, J. (Jian), Jenny, N.S. (Nancy), Holliday, E.G. (Elizabeth), Qi, L. (Lihong), Mcevoy, M.G. (Mark G.), Becker, D.M. (Diane), Starr, J.M. (John), Sarin, A.-P., Hysi, P.G. (Pirro), Hernandez, D.G. (Dena), Jhun, M.A. (Min A.), Campbell, H. (Harry), Hamsten, A. (Anders), Sarin, F. (Fernando), McArdle, W.L. (Wendy), Slagboom, P.E. (Eline), Zeller, T. (Tanja), Koenig, W. (Wolfgang), Psaty, B. (Brucem), Haritunians, T. (Talin), Liu, J. (Jingmin), Palotie, A. (Aarno), Uitterlinden, A.G. (André), Stott, D.J. (David J.), Hofman, A. (Albert), Franco, O.H. (Oscar), Polasek, O. (Ozren), Rudan, I. (Igor), Morange, P.-E. (P.), Wilson, J.F. (James F.), Kardia, S.L. (Sharon L.r), Ferrucci, L. (Luigi), Spector, T.D. (Timothy), Eriksson, J.G. (Johan G.), Hansen, T. (Torben), Deary, I.J. (Ian), Becker, L.C. (Lewis), Scott, R.J. (Rodney), Mitchell, P. (Paul), März, W. (Winfried), Wareham, N.J. (Nick J.), Peters, A. (Annette), Greinacher, A. (Andreas), Wild, P.S. (Philipp S.), Jukema, J.W. (Jan Wouter), Boomsma, D.I. (Dorret), Hayward, C. (Caroline), Cucca, F. (Francesco), Tracy, R.P. (Russell), Watkins, H. (Hugh), Reiner, A.P. (Alex P.), Folsom, A.R. (Aaron), Ridker, P.M. (Paul), O'Donnell, C.J. (Christopher J.), Smith, N.L. (Nicholas L.), Strachan, D.P. (David P.), and Dehghan, A. (Abbas)
Abstract: Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels.We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ~120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indelswere examined.We identified 41 genome-wide significant fibrinogen loci; of which, 18were newly identified. Therewere no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
Published: 2016
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12. Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein

Author: Ligthart, S. (Symen), Vries, P.S. (Paul) de, Uitterlinden, A.G. (André), Hofman, A. (Albert), Franco, O.H. (Oscar), Chasman, D.I. (Daniel), Dehghan, A. (Abbas), Dupuis, J. (Josée), Barbalic, M. (maja), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Lu, C. (Chen), Pellikka, N. (Niina), Wallaschofski, H. (Henri), Kettunen, J. (Johannes), Henneman, P. (Peter), Baumert, J. (Jens), Strachan, D.P. (David), Fuchsberger, C. (Christian), Vitart, V. (Veronique), Wilson, J.F. (James F), Paré, G. (Guillaume), Naitza, S. (Silvia), Rudock, M.E. (Megan), Surakka, I. (Ida), Geus, E.J.C. (Eco) de, Alizadeh, B.Z. (Behrooz), Guralnik, J.M. (Jack), Shuldiner, A.R. (Alan), Tanaka, T. (Toshiko), Zee, R.Y.L. (Robert), Schnabel, R.B. (Renate), Nambi, V. (Vijay), Kavousi, M. (Maryam), Ripatti, S. (Samuli), Nauck, M. (Matthias), Smith, N.L. (Nicholas L.), Smith, A.V. (Albert Vernon), Sundvall, J. (Jouko), Scheet, P. (Paul), Liu, Y. (YongMei), Ruokonen, A. (Aimo), Rose, L.M. (Lynda), Larson, M.G. (Martin), Hoogeveen, R.C. (Ron), Freimer, N.B. (Nelson), Teumer, A. (Alexander), Tracy, R.P. (Russell), Launer, L.J. (Lenore), Buring, J.E. (Julie), Yamamoto, J.F. (Jennifer), Folsom, A.R. (Aaron), Sijbrands, E.J.G. (Eric), Pankow, J.S. (James), Elliott, P. (Paul), Keaney, J.F. (John), Sun, W. (Wei), Sarin, A.-P., Fontes, M. (Michel), Badola, S. (Sunita), Astor, B.C. (Brad), Pouta, A. (Anneli), Werda, K. (Karl), Greiser, K.H. (Karin Halina), Kuss, O. (Oliver), Schwabedissen, H.E.M.Z. (Henriette E. Meyer Zu), Thiery, J. (Joachim), Jamshidi, Y. (Yalda), Nolte, I.M. (Ilja M.), Soranzo, N. (Nicole), Spector, T.D. (Timothy), Völzke, H. (Henry), Parker, A.N. (Alex), Aspelund, T. (Thor), Bates, D. (David), Young, L. (Lauren), Tsui, K. (Kim), Siscovick, D.S. (David), Guo, X. (Xiuqing), Rotter, J.I. (Jerome I.), Uda, M. (Manuela), Schlessinger, D., Rudan, I. (Igor), Hicks, A.A. (Andrew), Penninx, B.W.J.H. (Brenda), Thorand, B. (Barbara), Gieger, C. (Christian), Coresh, J. (Josef), Willemsen, G.A.H.M. (Gonneke), Harris, T.B. (Tamara), Jarvelin, M.-R. (Marjo-Riitta), Rice, K.M. (Kenneth), Radke, D. (Dörte), Salomaa, V. (Veikko), Willems van Dijk, J.A.P. (Ko), Boerwinkle, E.A. (Eric), Vasan, R.S. (Ramachandran Srini), Ferrucci, L. (Luigi), Gibson, Q. (Quince), Bandinelli, S. (Stefania), Snieder, H. (Harold), Boomsma, D.I. (Dorret), Xiao, X. (Xiangjun), Campbell, H. (Harry), Hayward, C. (Caroline), Pramstaller, P.P. (Peter Paul), Duijn, C.M. (Cornelia) van, Peltonen, L. (Leena Johanna), Psaty, B.M. (Bruce), Gudnason, V. (Vilmundur), Ridker, P.M. (Paul), Homuth, G. (Georg), Koenig, W. (Wolfgang), Ballantyne, C. (Christie), Witteman, J.C.M. (Jacqueline), Benjamin, E.J. (Emelia), Perola, M. (Markus), Chasman., D.I. (Daniel I.), Ligthart, S. (Symen), Vries, P.S. (Paul) de, Uitterlinden, A.G. (André), Hofman, A. (Albert), Franco, O.H. (Oscar), Chasman, D.I. (Daniel), Dehghan, A. (Abbas), Dupuis, J. (Josée), Barbalic, M. (maja), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Lu, C. (Chen), Pellikka, N. (Niina), Wallaschofski, H. (Henri), Kettunen, J. (Johannes), Henneman, P. (Peter), Baumert, J. (Jens), Strachan, D.P. (David), Fuchsberger, C. (Christian), Vitart, V. (Veronique), Wilson, J.F. (James F), Paré, G. (Guillaume), Naitza, S. (Silvia), Rudock, M.E. (Megan), Surakka, I. (Ida), Geus, E.J.C. (Eco) de, Alizadeh, B.Z. (Behrooz), Guralnik, J.M. (Jack), Shuldiner, A.R. (Alan), Tanaka, T. (Toshiko), Zee, R.Y.L. (Robert), Schnabel, R.B. (Renate), Nambi, V. (Vijay), Kavousi, M. (Maryam), Ripatti, S. (Samuli), Nauck, M. (Matthias), Smith, N.L. (Nicholas L.), Smith, A.V. (Albert Vernon), Sundvall, J. (Jouko), Scheet, P. (Paul), Liu, Y. (YongMei), Ruokonen, A. (Aimo), Rose, L.M. (Lynda), Larson, M.G. (Martin), Hoogeveen, R.C. (Ron), Freimer, N.B. (Nelson), Teumer, A. (Alexander), Tracy, R.P. (Russell), Launer, L.J. (Lenore), Buring, J.E. (Julie), Yamamoto, J.F. (Jennifer), Folsom, A.R. (Aaron), Sijbrands, E.J.G. (Eric), Pankow, J.S. (James), Elliott, P. (Paul), Keaney, J.F. (John), Sun, W. (Wei), Sarin, A.-P., Fontes, M. (Michel), Badola, S. (Sunita), Astor, B.C. (Brad), Pouta, A. (Anneli), Werda, K. (Karl), Greiser, K.H. (Karin Halina), Kuss, O. (Oliver), Schwabedissen, H.E.M.Z. (Henriette E. Meyer Zu), Thiery, J. (Joachim), Jamshidi, Y. (Yalda), Nolte, I.M. (Ilja M.), Soranzo, N. (Nicole), Spector, T.D. (Timothy), Völzke, H. (Henry), Parker, A.N. (Alex), Aspelund, T. (Thor), Bates, D. (David), Young, L. (Lauren), Tsui, K. (Kim), Siscovick, D.S. (David), Guo, X. (Xiuqing), Rotter, J.I. (Jerome I.), Uda, M. (Manuela), Schlessinger, D., Rudan, I. (Igor), Hicks, A.A. (Andrew), Penninx, B.W.J.H. (Brenda), Thorand, B. (Barbara), Gieger, C. (Christian), Coresh, J. (Josef), Willemsen, G.A.H.M. (Gonneke), Harris, T.B. (Tamara), Jarvelin, M.-R. (Marjo-Riitta), Rice, K.M. (Kenneth), Radke, D. (Dörte), Salomaa, V. (Veikko), Willems van Dijk, J.A.P. (Ko), Boerwinkle, E.A. (Eric), Vasan, R.S. (Ramachandran Srini), Ferrucci, L. (Luigi), Gibson, Q. (Quince), Bandinelli, S. (Stefania), Snieder, H. (Harold), Boomsma, D.I. (Dorret), Xiao, X. (Xiangjun), Campbell, H. (Harry), Hayward, C. (Caroline), Pramstaller, P.P. (Peter Paul), Duijn, C.M. (Cornelia) van, Peltonen, L. (Leena Johanna), Psaty, B.M. (Bruce), Gudnason, V. (Vilmundur), Ridker, P.M. (Paul), Homuth, G. (Georg), Koenig, W. (Wolfgang), Ballantyne, C. (Christie), Witteman, J.C.M. (Jacqueline), Benjamin, E.J. (Emelia), Perola, M. (Markus), and Chasman., D.I. (Daniel I.)
Abstract: Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes.
Published: 2015
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13. Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein

Author: Ligthart, S. (Symen), Vries, P.S. (Paul) de, Uitterlinden, A.G. (André), Hofman, A. (Albert), Franco, O.H. (Oscar), Chasman, D.I. (Daniel), Dehghan, A. (Abbas), Dupuis, J. (Josée), Barbalic, M. (maja), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Lu, C. (Chen), Pellikka, N. (Niina), Wallaschofski, H. (Henri), Kettunen, J. (Johannes), Henneman, P. (Peter), Baumert, J. (Jens), Strachan, D.P. (David), Fuchsberger, C. (Christian), Vitart, V. (Veronique), Wilson, J.F. (James F), Paré, G. (Guillaume), Naitza, S. (Silvia), Rudock, M.E. (Megan), Surakka, I. (Ida), Geus, E.J.C. (Eco) de, Alizadeh, B.Z. (Behrooz), Guralnik, J.M. (Jack), Shuldiner, A.R. (Alan), Tanaka, T. (Toshiko), Zee, R.Y.L. (Robert), Schnabel, R.B. (Renate), Nambi, V. (Vijay), Kavousi, M. (Maryam), Ripatti, S. (Samuli), Nauck, M. (Matthias), Smith, N.L. (Nicholas L.), Smith, A.V. (Albert Vernon), Sundvall, J. (Jouko), Scheet, P. (Paul), Liu, Y. (YongMei), Ruokonen, A. (Aimo), Rose, L.M. (Lynda), Larson, M.G. (Martin), Hoogeveen, R.C. (Ron), Freimer, N.B. (Nelson), Teumer, A. (Alexander), Tracy, R.P. (Russell), Launer, L.J. (Lenore), Buring, J.E. (Julie), Yamamoto, J.F. (Jennifer), Folsom, A.R. (Aaron), Sijbrands, E.J.G. (Eric), Pankow, J.S. (James), Elliott, P. (Paul), Keaney, J.F. (John), Sun, W. (Wei), Sarin, A.-P., Fontes, M. (Michel), Badola, S. (Sunita), Astor, B.C. (Brad), Pouta, A. (Anneli), Werda, K. (Karl), Greiser, K.H. (Karin Halina), Kuss, O. (Oliver), Schwabedissen, H.E.M.Z. (Henriette E. Meyer Zu), Thiery, J. (Joachim), Jamshidi, Y. (Yalda), Nolte, I.M. (Ilja M.), Soranzo, N. (Nicole), Spector, T.D. (Timothy), Völzke, H. (Henry), Parker, A.N. (Alex), Aspelund, T. (Thor), Bates, D. (David), Young, L. (Lauren), Tsui, K. (Kim), Siscovick, D.S. (David), Guo, X. (Xiuqing), Rotter, J.I. (Jerome I.), Uda, M. (Manuela), Schlessinger, D., Rudan, I. (Igor), Hicks, A.A. (Andrew), Penninx, B.W.J.H. (Brenda), Thorand, B. (Barbara), Gieger, C. (Christian), Coresh, J. (Josef), Willemsen, G.A.H.M. (Gonneke), Harris, T.B. (Tamara), Jarvelin, M.-R. (Marjo-Riitta), Rice, K.M. (Kenneth), Radke, D. (Dörte), Salomaa, V. (Veikko), Willems van Dijk, J.A.P. (Ko), Boerwinkle, E.A. (Eric), Vasan, R.S. (Ramachandran Srini), Ferrucci, L. (Luigi), Gibson, Q. (Quince), Bandinelli, S. (Stefania), Snieder, H. (Harold), Boomsma, D.I. (Dorret), Xiao, X. (Xiangjun), Campbell, H. (Harry), Hayward, C. (Caroline), Pramstaller, P.P. (Peter Paul), Duijn, C.M. (Cornelia) van, Peltonen, L. (Leena Johanna), Psaty, B.M. (Bruce), Gudnason, V. (Vilmundur), Ridker, P.M. (Paul), Homuth, G. (Georg), Koenig, W. (Wolfgang), Ballantyne, C. (Christie), Witteman, J.C.M. (Jacqueline), Benjamin, E.J. (Emelia), Perola, M. (Markus), Chasman., D.I. (Daniel I.), Ligthart, S. (Symen), Vries, P.S. (Paul) de, Uitterlinden, A.G. (André), Hofman, A. (Albert), Franco, O.H. (Oscar), Chasman, D.I. (Daniel), Dehghan, A. (Abbas), Dupuis, J. (Josée), Barbalic, M. (maja), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Lu, C. (Chen), Pellikka, N. (Niina), Wallaschofski, H. (Henri), Kettunen, J. (Johannes), Henneman, P. (Peter), Baumert, J. (Jens), Strachan, D.P. (David), Fuchsberger, C. (Christian), Vitart, V. (Veronique), Wilson, J.F. (James F), Paré, G. (Guillaume), Naitza, S. (Silvia), Rudock, M.E. (Megan), Surakka, I. (Ida), Geus, E.J.C. (Eco) de, Alizadeh, B.Z. (Behrooz), Guralnik, J.M. (Jack), Shuldiner, A.R. (Alan), Tanaka, T. (Toshiko), Zee, R.Y.L. (Robert), Schnabel, R.B. (Renate), Nambi, V. (Vijay), Kavousi, M. (Maryam), Ripatti, S. (Samuli), Nauck, M. (Matthias), Smith, N.L. (Nicholas L.), Smith, A.V. (Albert Vernon), Sundvall, J. (Jouko), Scheet, P. (Paul), Liu, Y. (YongMei), Ruokonen, A. (Aimo), Rose, L.M. (Lynda), Larson, M.G. (Martin), Hoogeveen, R.C. (Ron), Freimer, N.B. (Nelson), Teumer, A. (Alexander), Tracy, R.P. (Russell), Launer, L.J. (Lenore), Buring, J.E. (Julie), Yamamoto, J.F. (Jennifer), Folsom, A.R. (Aaron), Sijbrands, E.J.G. (Eric), Pankow, J.S. (James), Elliott, P. (Paul), Keaney, J.F. (John), Sun, W. (Wei), Sarin, A.-P., Fontes, M. (Michel), Badola, S. (Sunita), Astor, B.C. (Brad), Pouta, A. (Anneli), Werda, K. (Karl), Greiser, K.H. (Karin Halina), Kuss, O. (Oliver), Schwabedissen, H.E.M.Z. (Henriette E. Meyer Zu), Thiery, J. (Joachim), Jamshidi, Y. (Yalda), Nolte, I.M. (Ilja M.), Soranzo, N. (Nicole), Spector, T.D. (Timothy), Völzke, H. (Henry), Parker, A.N. (Alex), Aspelund, T. (Thor), Bates, D. (David), Young, L. (Lauren), Tsui, K. (Kim), Siscovick, D.S. (David), Guo, X. (Xiuqing), Rotter, J.I. (Jerome I.), Uda, M. (Manuela), Schlessinger, D., Rudan, I. (Igor), Hicks, A.A. (Andrew), Penninx, B.W.J.H. (Brenda), Thorand, B. (Barbara), Gieger, C. (Christian), Coresh, J. (Josef), Willemsen, G.A.H.M. (Gonneke), Harris, T.B. (Tamara), Jarvelin, M.-R. (Marjo-Riitta), Rice, K.M. (Kenneth), Radke, D. (Dörte), Salomaa, V. (Veikko), Willems van Dijk, J.A.P. (Ko), Boerwinkle, E.A. (Eric), Vasan, R.S. (Ramachandran Srini), Ferrucci, L. (Luigi), Gibson, Q. (Quince), Bandinelli, S. (Stefania), Snieder, H. (Harold), Boomsma, D.I. (Dorret), Xiao, X. (Xiangjun), Campbell, H. (Harry), Hayward, C. (Caroline), Pramstaller, P.P. (Peter Paul), Duijn, C.M. (Cornelia) van, Peltonen, L. (Leena Johanna), Psaty, B.M. (Bruce), Gudnason, V. (Vilmundur), Ridker, P.M. (Paul), Homuth, G. (Georg), Koenig, W. (Wolfgang), Ballantyne, C. (Christie), Witteman, J.C.M. (Jacqueline), Benjamin, E.J. (Emelia), Perola, M. (Markus), and Chasman., D.I. (Daniel I.)
Abstract: Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes.
Published: 2015
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14. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

Author: Huffman, J.E. (Jennifer), Vries, P.S. (Paul) de, Morrison, A.C. (Alanna), Sabater-Lleal, M. (Maria), Kacprowski, T. (Tim), Auer, P. (Paul), Brody, J.A. (Jennifer A.), Chasman, D.I. (Daniel), Chen, M.-H. (Ming-Huei), Guo, X. (Xiuqing), Lin, L.-A. (Li-An), Marioni, R.E. (Riccardo), Müller-Nurasyid, M. (Martina), Yanek, L.R. (Lisa), Pankratz, V.S. (Shane), Grove, M.L. (Megan L.), Maat, M.P.M. (Moniek) de, Cushman, M. (Mary Ann), Wiggins, K.L. (Kerri), Qi, L. (Lihong), Sennblad, B. (Bengt), Harris, S.E. (Sarah), Polasek, O. (Ozren), Riess, H. (Helene), Rivadeneira Ramirez, F. (Fernando), Rose, L.M. (Lynda), Goel, A. (Anuj), Taylor, K.D. (Kent D.), Teumer, A. (Alexander), Uitterlinden, A.G. (André), Vaidya, D. (Dhananjay), Yao, J. (Jiefen), Tang, W. (Weihong), Levy, D. (Daniel), Waldenberger, M. (Melanie), Becker, D.M. (Diane), Folsom, A.R. (Aaron), Giulianini, F. (Franco), Greinacher, A. (Andreas), Hofman, A. (Albert), Huang, C.-C. (Chiang-Ching), Kooperberg, C. (Charles), Silveira, A. (Angela), Starr, J.M. (John), Strauch, K. (Konstantin), Strawbridge, R.J. (Rona), Wright, A. (Alan), McKnight, B. (Barbara), Franco, O.H. (Oscar), Zakai, N.A. (Neil), Mathias, J. (Jasmine), Psaty, B.M. (Bruce), Ridker, P.M. (Paul), Tofler, G.H. (Geoffrey), Völker, U. (Uwe), Watkins, H. (Hugh), Fornage, M. (Myriam), Hamsten, A. (Anders), Deary, I.J. (Ian), Boerwinkle, E.A. (Eric), Koenig, W. (Wolfgang), Rotter, J.I. (Jerome I.), Hayward, C. (Caroline), Dehghan, A. (Abbas), Reiner, A. (Alexander), O'Donnell, C.J. (Christopher), Smith, N.L. (Nicholas), Huffman, J.E. (Jennifer), Vries, P.S. (Paul) de, Morrison, A.C. (Alanna), Sabater-Lleal, M. (Maria), Kacprowski, T. (Tim), Auer, P. (Paul), Brody, J.A. (Jennifer A.), Chasman, D.I. (Daniel), Chen, M.-H. (Ming-Huei), Guo, X. (Xiuqing), Lin, L.-A. (Li-An), Marioni, R.E. (Riccardo), Müller-Nurasyid, M. (Martina), Yanek, L.R. (Lisa), Pankratz, V.S. (Shane), Grove, M.L. (Megan L.), Maat, M.P.M. (Moniek) de, Cushman, M. (Mary Ann), Wiggins, K.L. (Kerri), Qi, L. (Lihong), Sennblad, B. (Bengt), Harris, S.E. (Sarah), Polasek, O. (Ozren), Riess, H. (Helene), Rivadeneira Ramirez, F. (Fernando), Rose, L.M. (Lynda), Goel, A. (Anuj), Taylor, K.D. (Kent D.), Teumer, A. (Alexander), Uitterlinden, A.G. (André), Vaidya, D. (Dhananjay), Yao, J. (Jiefen), Tang, W. (Weihong), Levy, D. (Daniel), Waldenberger, M. (Melanie), Becker, D.M. (Diane), Folsom, A.R. (Aaron), Giulianini, F. (Franco), Greinacher, A. (Andreas), Hofman, A. (Albert), Huang, C.-C. (Chiang-Ching), Kooperberg, C. (Charles), Silveira, A. (Angela), Starr, J.M. (John), Strauch, K. (Konstantin), Strawbridge, R.J. (Rona), Wright, A. (Alan), McKnight, B. (Barbara), Franco, O.H. (Oscar), Zakai, N.A. (Neil), Mathias, J. (Jasmine), Psaty, B.M. (Bruce), Ridker, P.M. (Paul), Tofler, G.H. (Geoffrey), Völker, U. (Uwe), Watkins, H. (Hugh), Fornage, M. (Myriam), Hamsten, A. (Anders), Deary, I.J. (Ian), Boerwinkle, E.A. (Eric), Koenig, W. (Wolfgang), Rotter, J.I. (Jerome I.), Hayward, C. (Caroline), Dehghan, A. (Abbas), Reiner, A. (Alexander), O'Donnell, C.J. (Christopher), and Smith, N.L. (Nicholas)
Abstract: Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76 000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified
Published: 2015
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15. Age- and sex-specific causal effects of adiposity on cardiovascular risk factors

Author: Fall, M. (Magnus), Hägg, S. (Sara), Ploner, A. (Alexander), Mägi, R. (Reedik), Fischer, K. (Krista), Draisma, G. (Gerrit), Sarin, A.-P., Benyamin, B. (Beben), Ladenvall, C. (Claes), Åkerlund, M. (Mikael), Kals, M. (Mart), Esko, T. (Tõnu), Nelson, C.P. (Christopher P.), Kaakinen, M. (Marika), Huikari, V. (Ville), Mangino, M. (Massimo), Meirhaeghe, A. (Aline), Kristiansson, K. (Kati), Nuotio, M.-L. (Marja-Liisa), Kobl, M. (Michael), Grallert, H. (Harald), Dehghan, A. (Abbas), Kuningas, M. (Maris), Vries, P.S. (Paul) de, Bruijn, R.F.A.G. (Renée) de, Willems, S.M. (Sara), Heikkilä, K. (Kauko), Silventoinen, K. (Karri), Pietilainen, K.H. (Kirsi Hannele), Legry, V. (Vanessa), Giedraitis, V. (Vilmantas), Goumidi, L. (Louisa), Syvanen, A.C., Strauch, K. (Konstantin), Koenig, W. (Wolfgang), Lichtner, P. (Peter), Herder, C. (Christian), Palotie, A. (Aarno), Menni, C. (Cristina), Uitterlinden, A.G. (André), Kuulasmaa, K. (Kari), Havulinna, A.S. (Aki), Moreno, L. (Luis), Gonzalez-Gross, M. (Marcela), Evans, A. (Alun), Tregouet, D.-A. (David-Alexandre), Yarnell, J.W.G. (John W.), Virtamo, J. (Jarmo), Ferrieres, J. (Jean), Veronesi, G. (Giovanni), Perola, M. (Markus), Arveiler, D. (Dominique), Brambilla, P. (Paolo), Lind, L. (Lars), Kaprio, J. (Jaakko), Hofman, A. (Albert), Stricker, B.H.Ch. (Bruno), Duijn, C.M. (Cornelia) van, Ikram, M.A. (Arfan), Franco, O.H. (Oscar), Cottel, D. (Dominique), Dallongeville, J., Hall, A.S. (Alistair), Jula, A. (Antti), Tobin, M.D. (Martin), Penninx, B.W.J.H. (Brenda), Peters, A. (Annette), Gieger, C. (Christian), Samani, N.J. (Nilesh), Montgomery, G.W. (Grant), Whitfield, J. (John), Martin, N.G. (Nicholas), Groop, L. (Leif), Spector, T.D. (Timothy), Magnusson, P.K. (Patrik), Amouyel, P. (Philippe), Boomsma, D.I. (Dorret), Nilsson, P. (Peter), Jarvelin, M.-R. (Marjo-Riitta), Lyssenko, V. (Valeriya), Metspalu, A. (Andres), Strachan, D.P. (David), Salomaa, V. (Veikko), Ripatti, S. (Samuli), Pedersen, N.L. (Nancy), Prokopenko, I. (Inga), McCarthy, M.I. (Mark), Ingelsson, E. (Erik), Fall, M. (Magnus), Hägg, S. (Sara), Ploner, A. (Alexander), Mägi, R. (Reedik), Fischer, K. (Krista), Draisma, G. (Gerrit), Sarin, A.-P., Benyamin, B. (Beben), Ladenvall, C. (Claes), Åkerlund, M. (Mikael), Kals, M. (Mart), Esko, T. (Tõnu), Nelson, C.P. (Christopher P.), Kaakinen, M. (Marika), Huikari, V. (Ville), Mangino, M. (Massimo), Meirhaeghe, A. (Aline), Kristiansson, K. (Kati), Nuotio, M.-L. (Marja-Liisa), Kobl, M. (Michael), Grallert, H. (Harald), Dehghan, A. (Abbas), Kuningas, M. (Maris), Vries, P.S. (Paul) de, Bruijn, R.F.A.G. (Renée) de, Willems, S.M. (Sara), Heikkilä, K. (Kauko), Silventoinen, K. (Karri), Pietilainen, K.H. (Kirsi Hannele), Legry, V. (Vanessa), Giedraitis, V. (Vilmantas), Goumidi, L. (Louisa), Syvanen, A.C., Strauch, K. (Konstantin), Koenig, W. (Wolfgang), Lichtner, P. (Peter), Herder, C. (Christian), Palotie, A. (Aarno), Menni, C. (Cristina), Uitterlinden, A.G. (André), Kuulasmaa, K. (Kari), Havulinna, A.S. (Aki), Moreno, L. (Luis), Gonzalez-Gross, M. (Marcela), Evans, A. (Alun), Tregouet, D.-A. (David-Alexandre), Yarnell, J.W.G. (John W.), Virtamo, J. (Jarmo), Ferrieres, J. (Jean), Veronesi, G. (Giovanni), Perola, M. (Markus), Arveiler, D. (Dominique), Brambilla, P. (Paolo), Lind, L. (Lars), Kaprio, J. (Jaakko), Hofman, A. (Albert), Stricker, B.H.Ch. (Bruno), Duijn, C.M. (Cornelia) van, Ikram, M.A. (Arfan), Franco, O.H. (Oscar), Cottel, D. (Dominique), Dallongeville, J., Hall, A.S. (Alistair), Jula, A. (Antti), Tobin, M.D. (Martin), Penninx, B.W.J.H. (Brenda), Peters, A. (Annette), Gieger, C. (Christian), Samani, N.J. (Nilesh), Montgomery, G.W. (Grant), Whitfield, J. (John), Martin, N.G. (Nicholas), Groop, L. (Leif), Spector, T.D. (Timothy), Magnusson, P.K. (Patrik), Amouyel, P. (Philippe), Boomsma, D.I. (Dorret), Nilsson, P. (Peter), Jarvelin, M.-R. (Marjo-Riitta), Lyssenko, V. (Valeriya), Metspalu, A. (Andres), Strachan, D.P. (David), Salomaa, V. (Veikko), Ripatti, S. (Samuli), Pedersen, N.L. (Nancy), Prokopenko, I. (Inga), McCarthy, M.I. (Mark), and Ingelsson, E. (Erik)
Abstract: Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
Published: 2015
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16. A Genetic variant in the seed region of miR-4513 shows pleiotropic effects on lipid and glucose homeostasis, blood pressure, and coronary artery disease

Author: Ghanbari, M. (Mohsen), Vries, P.S. (Paul) de, Looper, H. (Hans) de, Peters, M.J. (Marjolein), Schurmann, C. (Claudia), Yaghootkar, H. (Hanieh), Dörr, M. (Marcus), Frayling, T.M. (Timothy), Uitterlinden, A.G. (André), Hofman, A. (Albert), Meurs, J.B.J. (Joyce) van, Erkeland, S.J. (Stefan), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Ghanbari, M. (Mohsen), Vries, P.S. (Paul) de, Looper, H. (Hans) de, Peters, M.J. (Marjolein), Schurmann, C. (Claudia), Yaghootkar, H. (Hanieh), Dörr, M. (Marcus), Frayling, T.M. (Timothy), Uitterlinden, A.G. (André), Hofman, A. (Albert), Meurs, J.B.J. (Joyce) van, Erkeland, S.J. (Stefan), Franco, O.H. (Oscar), and Dehghan, A. (Abbas)
Abstract: MicroRNAs (miRNA) play a crucial role in the regulation of diverse biological processes by post-transcriptional modulation of gene expression. Genetic polymorphisms in miRNA-related genes can potentially contribute to a wide range of phenotypes. The effect of such variants on cardiometabolic diseases has not yet been defined. We systematically investigated the association of genetic variants in the seed region of miRNAs with cardiometabolic phenotypes, using the thus far largest genome-wide association studies on 17 cardiometabolic traits/diseases. We found that rs2168518:G>A, a seed region variant of miR-4513, associates with fasting glucose, low-density lipoprotein-cholesterol, total cholesterol, systolic and diastolic blood pressure, and risk of coronary artery disease. We experimentally showed that miR-4513 expression is significantly reduced in the presence of the rs2168518 mutant allele. We sought to identify miR-4513
Published: 2014
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16 results on '"Vries, P.S. (Paul) de"'

1. Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration

2. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

3. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

4. Von Willebrand factor and ADAMTS13 activity in relation to risk of dementia

5. Epigenome-Wide Association Study Identifies Methylation Sites Associated With Liver Enzymes and Hepatic Steatosis

6. Epigenome-wide association study (EWAS) on lipids: the Rotterdam Study

7. Comparison of HapMap and 1000 genomes reference panels in a large-scale genome-wide association study

8. ADAMTS13 activity as a novel risk factor for incident type 2 diabetes mellitus: a population-based cohort study

9. von Willebrand Factor, ADAMTS13 Activity, and Decline in Kidney Function: A Population-Based Cohort Study

10. Hemostasis and Cardiovascular Disease : a molecular epidemiology approach

11. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

12. Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein

13. Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein

14. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

15. Age- and sex-specific causal effects of adiposity on cardiovascular risk factors

16. A Genetic variant in the seed region of miR-4513 shows pleiotropic effects on lipid and glucose homeostasis, blood pressure, and coronary artery disease

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16 results on '"Vries, P.S. (Paul) de"'

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