Search

Your search keyword '"Wiggins, K.L."' showing total 37 results
Start Over Author "Wiggins, K.L."
37 results on '"Wiggins, K.L."'

1. Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes

Author

de Haan, H.G., van Hylckama Vlieg, A., Lotta, L.A., Gorski, M.M., Bucciarelli, P., Martinelli, I., Baglin, T.P., Peyvandi, F., Rosendaal, F.R., Amouyel, P., de Andrade, M., Basu, S., Berr, C., Brody, J.A., Chasman, D. I, Dartigues, J.‐F., Folsom, A.R., Germain, M., Heit, J., Houwing‐Duitermaat, J., Kabrhel, C., Kraft, P., Le Gal, G., Lindström, S., Monajemi, R., Morange, P.‐E., Psaty, B.M., Reitsma, P.H., Ridker, P.M., Rose, L.M., Saut, N., Slagboom, E., Smadja, D., Smith, N.L., Suchon, P., Tang, W., Taylor, K.D., Trégouët, D.‐A., Tzourio, C., de Visser, M.C.H., Weng, L.‐C., and Wiggins, K.L.

Published
2018
Full Text
View/download PDF

5. Cross-ancestry investigation of venousc genomic predictors

Author

Thibord, F., Klarin, D., Brody, J.A., Chen, M.H., Levin, M.G., Chasman, D.I., Goode, E.L., Hveem, K., Teder-Laving, M., Martinez-Perez, A., Aissi, D., Daian-Bacq, D., Ito, K., Natarajan, P., Lutsey, P.L., Nadkarni, G.N., Vries, P.S. de, Cuellar-Partida, G., Wolford, B.N., Pattee, J.W., Kooperberg, C., Braekkan, S.K., Li-Gao, R.F., Saut, N., Sept, C., Germain, M., Judy, R.L., Wiggins, K.L., Ko, D., O'Donnell, C.J., Taylor, K.D., Giulianini, F., Andrade, M. de, Nost, T.H., Boland, A., Empana, J.P., Koyama, S., Gilliland, T., R. do, Huffman, J.E., Wang, X., Zhou, W., Soria, J.M., Souto, J.C., Pankratz, N., Haessler, J., Hindberg, K., Rosendaal, F.R., Turman, C., Olaso, R., Kember, R.L., Bartz, T.M., Lynch, J.A., Heckbert, S.R., Armasu, S.M., Brumpton, B., Smadja, D.M., Jouven, X., Komuro, I., Clapham, K.R., Loos, R.J.F., Willer, C.J., Sabater-Lleal, M., Pankow, J.S., Reiner, A.P., Morelli, V.M., Ridker, P.M., Vlieg, A.V., Deleuze, J.F., Kraft, P., Rader, D.J., Lee, K.M., Psaty, B.M., Skogholt, A.H., Emmerich, J., Suchon, P., Rich, S.S., Vy, H.T., Tang, W.H., Jackson, R.D., Hansen, J.B., Morange, P.E., Kabrhel, C., Tregouet, D.A., Damrauer, S.M., Johnson, A.D., and Smith, N.L.

Subjects
meta-analysis, genome-wide association study, venous thromboembolism, genetics, venous thrombosis
Abstract

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Published
2022

8. Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation

Author

Goumidi, L., Thibord, F., Wiggins, K.L., Li-Gao, R.F., Brown, M.R., Vlieg, A.V., Souto, J.C., Soria, J.M., Ibrahim-Kosta, M., Saut, N., Daian, D., Olaso, R., Amouyel, P., Debette, S., Boland, A., Bailly, P., Morrison, A.C., Mook-Kanamori, D.O., Deleuze, J.F., Johnson, A., Vries, P.S. de, Sabater-Lleal, M., Chiaroni, J., Smith, N.L., Rosendaal, F.R., Chasman, D.I., Tregouet, D.A., and Morange, P.E.

Subjects
Male, Venous Thrombosis, Factor VIII, Prognosis, Polymorphism, Single Nucleotide, ABO Blood-Group System, Thrombosis and Hemostasis, Phenotype, Haplotypes, Cardiovascular Diseases, Risk Factors, von Willebrand Factor, Humans, Female, Genetic Predisposition to Disease, Aged, Genome-Wide Association Study
Abstract

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact ofABOlocus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, similar to 1.2), the A1 and B haplotypes are associated with an similar to 1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, similar to 0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.

Published
2020

9. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Author

Lindstrom, S., Wang, L., Smith, E.N., Gordon, W., Vlieg, A.V., Andrade, M. de, Brody, J.A., Pattee, J.W., Haessler, J., Brumpton, B., Chasman, D.I., Suchon, P., Chen, M.H., Turman, C., Germain, M., Wiggins, K.L., MacDonald, J., Braekkan, S.K., Armasu, S.M., Pankratz, N., Jackson, R.D., Nielsen, J.B., Giulianini, F., Puurunen, M.K., Ibrahim, M., Heckbert, S.R., Damrauer, S.M., Natarajan, P., Klarin, D., Vries, P.S. de, Sabater-Lleal, M., Huffman, J.E., Bammler, T.K., Frazer, K.A., McCauley, B.M., Taylor, K., Pankow, J.S., Reiner, A.P., Gabrielsen, M.E., Deleuze, J.F., O'Donnell, C.J., Kim, J., McKnight, B., Kraft, P., Hansen, J.B., Rosendaal, F.R., Heit, J.A., Psaty, B.M., Tang, W.H., Kooperberg, C., Hveem, K., Ridker, P.M., Morange, P.E., Johnson, A.D., Kabrhel, C., Tregouet, D.A., Smith, N.L., Busenkell, E., Judy, R., Lynch, J., Levin, M., Aragam, J.H.K., Chaffin, M., Haas, M., Assimes, T.L., Huang, J., Lee, K.M., Shao, Q., Huang, Y.F., Sun, Y.V., Vujkovic, M., Saleheen, D., Miller, D.R., Reaven, P., DuVall, S., Boden, W., Pyarajan, S., Henke, P., Gaziano, J.M., Concato, J., Rader, D.J., Cho, K., Chang, K.M., Wilson, P.W.F., Tsao, P.S., Kathiresan, S., Obi, A., Million Veteran Program, CHARGE Hemostasis Working Grp, INVENT Consortium, Program in Genetic Epidemiology and Statistical Genetics (PGESG - BOSTON), Harvard School of Public Health, University of Washington [Seattle], The Scripps Translational Science Institute and Scripps Health, Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, University of Minnesota System, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Brigham and Women's Hospital [Boston], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), National Institutes of Health [Bethesda] (NIH), Harvard T.H. Chan School of Public Health, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biorobotics Lab (University of Washington), University of South-Eastern Norway (USN), Department of Health Sciences Research, Ohio State University [Columbus] (OSU), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Los Angeles Biomedical Research Institute (LA BioMed), University of Augsburg [Augsburg], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Epidemiology, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, University of Minnesota [Twin Cities] (UMN), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Department of Emergency Medicine, Massachusetts General Hospital [Boston], Universiteit Leiden-Universiteit Leiden, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Augsburg (UNIA), and Universiteit Leiden

Subjects
0301 basic medicine, Genetics, [SDV]Life Sciences [q-bio], Immunology, Genome-wide association study, Cell Biology, Hematology, 030204 cardiovascular system & hematology, Biology, equipment and supplies, Biochemistry, 3. Good health, Transcriptome, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Mendelian randomization, Expression quantitative trait loci, Gene expression, cardiovascular diseases, Gene, Genetic association, Whole blood
Abstract

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

Published
2019
Full Text
View/download PDF

10. Cerebral small vessel disease genomics and its implications across the lifespan

Author

Sargurupremraj, M. (Muralidharan), Suzuki, H. (Hideaki), Jian, X. (Xueqiu), Sarnowski, C., Evans, T.E (Tavia), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Sakaue, S. (Saori), Terzikhan, N. (Natalie), Habes, M. (Mohamad), Zhao, W. (Wei), Armstrong, N.J. (Nicola J.), Hofer, E. (Edith), Yanek, L.R. (Lisa), Hagenaars, S.P. (Saskia P.), Kumar, R.B. (Rajan B.), Akker, E.B. (Erik) van den, McWhirter, R.E. (Rebekah E.), Trompet, S. (Stella), Mishra, A. (Aniket), Saba, Y. (Yasaman), Satizabal, C.L. (Claudia), Beaudet, G. (Gregory), Petit, L. (Laurent), Tsuchida, A. (Ami), Zago, L. (Laure), Schilling, S. (Sabrina), Sigurdsson, S. (Stefan), Gottesman, R.F. (Rebecca), Lewis, C.E. (Cora E.), Aggarwal, N.T. (Neelum T.), Lopez, O.L. (Oscar), Smith, J.A. (Jennifer A), Valdés Hernández, M.C. (Maria C.), van der Grond, J. (Jeroen), Wright, M.J. (Margaret), Knol, M.J. (Maria J.), Dörr, M. (Marcus), Thomson, R. (Russell), Bordes, C. (Constance), Le Grand, Q. (Quentin), Duperron, M.-G. (Marie-Gabrielle), Smith, A.V. (Albert), Knopman, D.S. (David), Schreiner, P.J. (Pamela), Evans, D.A. (Denis A.), Rotter, J.I. (Jerome I.), Beiser, A. (Alexa), Maniega, S.M. (Susana Muñoz), Beekman, M. (Marian), Trollor, J., Stott, D.J. (David. J.), Vernooij, M.W. (Meike), Wittfeld, K. (Katharina), Niessen, W.J. (Wiro), Soumaré, A. (Aicha), Boerwinkle, E.A. (Eric), Sidney, S. (Stephen), Turner, S.T. (Stephen), Davies, G. (Gail), Thalamuthu, A. (Anbupalam), Völker, U. (Uwe), Buchem, M.A. (Mark) van, Bryan, R.N. (R. Nick), Amin, N. (Najaf), Bastin, M.E. (Mark), Ames, D.J. (David), Teumer, A. (Alexander), Amouyel, P. (Philippe), Kwok, J.B. (John B.), Bülow, R. (Robin), Deary, I.J. (Ian), Schofield, P.R. (Peter R.), Brodaty, H. (Henry), Jiang, J. (Jiyang), Tabara, Y. (Yasuharu), Setoh, K. (Kazuya), Miyamoto, S. (Susumu), Yoshida, K. (Kazumichi), Nagata, M. (Manabu), Kamatani, Y. (Yoichiro), Matsuda, F. (Fumihiko), Psaty, B.M. (Bruce), Bennett, D.A. (David), De Jager, P., Mosley, T.H. (Thomas H.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Warren, H. (Helen), Evangelou, E. (Evangelos), Trégouët, D.-A. (David-Alexandre), Andrade, M. (Mariza) de, Basu, S. (Saonli), Berr, C. (Claudine), Brody, J.A. (Jennifer A.), Chasman, D.I. (Daniel I.), Dartigues, J.-F., Folsom, A.R. (Aaron), Germain, M. (Marine), de Haan, H. (Hugoline), Heit, J.A. (John), Houwing-Duitermaat, J. (Jeanine), Kabrhel, C. (Christopher), Kraft, P. (Peter), Legal, G. (Grégoire), Lindström, S. (Sara), Monajemi, R. (Ramin), Morange, P.-E. (P.), Psaty, B.M. (Bruce M.), Reitsma, P.H. (Pieter H.), Jarvelin, M.-R. (Marjo-Riitta), Rose, L.M. (Lynda M.), Peyvandi, F. (Flora), Saut, N. (Noemie), Slagboom, E. (Eline), Smadja, D. (David), Smith, N.L. (Nicholas L.), Suchon, P. (Pierre), Tang, W. (Weihong), Taylor, K.D. (Kent D.), Tregouet, D.-A. (David-Alexandre), Tzourio, C. (Christophe), Visser, M.C.H. (Marieke) de, Hylckama Vlieg, A. (Astrid) van, Weng, L.-C., Wiggins, K.L. (Kerri L.), Gormley, A.M., Anttila, V. (Verneri), Winsvold, B.S. (Bendik S.), Palta, P. (Priit), Esko, T. (Tõnu), Pers, T.H. (Tune H.), Farh, K.-H. (Kai-How), Cuenca-Leon, E. (Ester), Muona, M. (Mikko), Furlotte, N.A. (Nicholas A.), Kurth, T. (Tobias), Ingason, A. (Andres), McMahon, G. (George), Ligthart, L. (Lannie), Terwindt, G.M. (Gisela M.), Todt, U. (Unda), Freilinger, T.M. (Tobias M.), Ran, C. (Caroline), Gordon, S.G. (Scott G.), Stam, A.H. (Anine), Steinberg, S. (Stacy), Borck, G. (Guntram), Koiranen, M. (Markku), Quaye, L. (Lydia), Adams, H.H.H. (Hieab H. H.), Lehtimäki, T. (Terho), Sarin, A.-P., Wedenoja, J. (Juho), Hinds, D.A. (David A.), Buring, J.E. (Julie), Schürks, M. (Markus), Ridker, P.M. (Paul M.), Gudlaug Hrafnsdottir, M. (Maria), Stefansson, H. (Hreinn), Ring, S.M. (Susan M.), Hottenga, J.J. (Jouke Jan), Penninx, B.W.J.H. (Brenda), Färkkilä, M. (Markus), Artto, V. (Ville), Kaunisto, M.A. (Mari), Vepsäläinen, S. (Salli), Malik, R. (Rainer), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela A. F.), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Kurki, M. (Mitja), Kals, M. (Mart), Mägi, R. (Reedik), Pärn, K. (Kalle), Hämäläinen, E. (Eija), Huang, H. (Hailiang), Byrnes, A.E. (Andrea E.), Franke, L. (Lude), Huang, J. (Jie), Stergiakouli, E. (Evie), Lee, P.H. (Phil H.), Sandor, C. (Cynthia), Webber, C. (Caleb), Cader, Z. (Zameel), Müller-Myhsok, B. (B.), Schreiber, S. (Stefan), Meitinger, T. (Thomas), Hagen, K. (Knut), Salomaa, V. (Veikko), Heikkilä, K. (Kauko), Loehrer, E. (Elizabeth), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Cherkas, L. (Lynn), Pedersen, L.M. (Linda M.), Stubhaug, A. (Audun), Nielsen, C.S. (Christopher S.), Männikkö, M. (Minna), Mihailov, E. (Evelin), Milani, L. (Lili), Esserlind, A.-L. (Ann-Louise), Francke Christensen, A. (Anne), Folkmann Hansen, T. (Thomas), Werge, T. (Thomas), Kaprio, J. (Jaakko), Aromaa, A. (Arpo), Raitakari, O. (Olli), Ikram, M.A. (M. Arfan), Spector, T.D. (Timothy), Järvelin, M.-R. (Marjo-Riitta), Metspalu, A. (Andres), Kubisch, C. (Christian), Beckmann, J.S. (Jacques), Ferrari, M.D. (Michel), Belin, A.C. (Andrea C.), Wessman, M. (Maija), van den Maagdenberg, A.M.J.M. (Arn M. J. M.), Zwart, J-A. (John-Anker), Boomsma, D.I. (Dorret), Davey Smith, G. (George), Eriksson, N. (Nicholas), Daly, M.J. (Mark), Neale, B.M. (Benjamin), Olesen, J. (Jes), Chasman, D.I. (Daniel), Nyholt, D.R. (Dale), Palotie, A. (Aarno), Ikram, M.A. (Arfan), Wen, W. (Wei), DeCarli, C. (Charles), Srikanth, V. (Velandai), Jukema, J.W. (Jan Wouter), Slagboom, P.E. (Eline), Kardia, S.L.R. (Sharon), Okada, Y. (Yukinori), Mazoyer, B. (Bernard), Wardlaw, J.M. (J.), Nyquist, P. (Paul), Mather, R., Grabe, H.J. (Hans Jörgen), Schmidt, H. (Helena), Van Duijn, C.M. (Cornelia M.), Gudnason, V. (Vilmundur), Longstreth Jr, W.T., Launer, L.J. (Lenore), Lathrop, M. (Mark), Seshadri, S. (Sudha), Adams, H.H.H. (Hieab), Matthews, P.M. (P.), Fornage, M. (Myriam), Debette, S. (Stéphanie), Sargurupremraj, M. (Muralidharan), Suzuki, H. (Hideaki), Jian, X. (Xueqiu), Sarnowski, C., Evans, T.E (Tavia), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Sakaue, S. (Saori), Terzikhan, N. (Natalie), Habes, M. (Mohamad), Zhao, W. (Wei), Armstrong, N.J. (Nicola J.), Hofer, E. (Edith), Yanek, L.R. (Lisa), Hagenaars, S.P. (Saskia P.), Kumar, R.B. (Rajan B.), Akker, E.B. (Erik) van den, McWhirter, R.E. (Rebekah E.), Trompet, S. (Stella), Mishra, A. (Aniket), Saba, Y. (Yasaman), Satizabal, C.L. (Claudia), Beaudet, G. (Gregory), Petit, L. (Laurent), Tsuchida, A. (Ami), Zago, L. (Laure), Schilling, S. (Sabrina), Sigurdsson, S. (Stefan), Gottesman, R.F. (Rebecca), Lewis, C.E. (Cora E.), Aggarwal, N.T. (Neelum T.), Lopez, O.L. (Oscar), Smith, J.A. (Jennifer A), Valdés Hernández, M.C. (Maria C.), van der Grond, J. (Jeroen), Wright, M.J. (Margaret), Knol, M.J. (Maria J.), Dörr, M. (Marcus), Thomson, R. (Russell), Bordes, C. (Constance), Le Grand, Q. (Quentin), Duperron, M.-G. (Marie-Gabrielle), Smith, A.V. (Albert), Knopman, D.S. (David), Schreiner, P.J. (Pamela), Evans, D.A. (Denis A.), Rotter, J.I. (Jerome I.), Beiser, A. (Alexa), Maniega, S.M. (Susana Muñoz), Beekman, M. (Marian), Trollor, J., Stott, D.J. (David. J.), Vernooij, M.W. (Meike), Wittfeld, K. (Katharina), Niessen, W.J. (Wiro), Soumaré, A. (Aicha), Boerwinkle, E.A. (Eric), Sidney, S. (Stephen), Turner, S.T. (Stephen), Davies, G. (Gail), Thalamuthu, A. (Anbupalam), Völker, U. (Uwe), Buchem, M.A. (Mark) van, Bryan, R.N. (R. Nick), Amin, N. (Najaf), Bastin, M.E. (Mark), Ames, D.J. (David), Teumer, A. (Alexander), Amouyel, P. (Philippe), Kwok, J.B. (John B.), Bülow, R. (Robin), Deary, I.J. (Ian), Schofield, P.R. (Peter R.), Brodaty, H. (Henry), Jiang, J. (Jiyang), Tabara, Y. (Yasuharu), Setoh, K. (Kazuya), Miyamoto, S. (Susumu), Yoshida, K. (Kazumichi), Nagata, M. (Manabu), Kamatani, Y. (Yoichiro), Matsuda, F. (Fumihiko), Psaty, B.M. (Bruce), Bennett, D.A. (David), De Jager, P., Mosley, T.H. (Thomas H.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Warren, H. (Helen), Evangelou, E. (Evangelos), Trégouët, D.-A. (David-Alexandre), Andrade, M. (Mariza) de, Basu, S. (Saonli), Berr, C. (Claudine), Brody, J.A. (Jennifer A.), Chasman, D.I. (Daniel I.), Dartigues, J.-F., Folsom, A.R. (Aaron), Germain, M. (Marine), de Haan, H. (Hugoline), Heit, J.A. (John), Houwing-Duitermaat, J. (Jeanine), Kabrhel, C. (Christopher), Kraft, P. (Peter), Legal, G. (Grégoire), Lindström, S. (Sara), Monajemi, R. (Ramin), Morange, P.-E. (P.), Psaty, B.M. (Bruce M.), Reitsma, P.H. (Pieter H.), Jarvelin, M.-R. (Marjo-Riitta), Rose, L.M. (Lynda M.), Peyvandi, F. (Flora), Saut, N. (Noemie), Slagboom, E. (Eline), Smadja, D. (David), Smith, N.L. (Nicholas L.), Suchon, P. (Pierre), Tang, W. (Weihong), Taylor, K.D. (Kent D.), Tregouet, D.-A. (David-Alexandre), Tzourio, C. (Christophe), Visser, M.C.H. (Marieke) de, Hylckama Vlieg, A. (Astrid) van, Weng, L.-C., Wiggins, K.L. (Kerri L.), Gormley, A.M., Anttila, V. (Verneri), Winsvold, B.S. (Bendik S.), Palta, P. (Priit), Esko, T. (Tõnu), Pers, T.H. (Tune H.), Farh, K.-H. (Kai-How), Cuenca-Leon, E. (Ester), Muona, M. (Mikko), Furlotte, N.A. (Nicholas A.), Kurth, T. (Tobias), Ingason, A. (Andres), McMahon, G. (George), Ligthart, L. (Lannie), Terwindt, G.M. (Gisela M.), Todt, U. (Unda), Freilinger, T.M. (Tobias M.), Ran, C. (Caroline), Gordon, S.G. (Scott G.), Stam, A.H. (Anine), Steinberg, S. (Stacy), Borck, G. (Guntram), Koiranen, M. (Markku), Quaye, L. (Lydia), Adams, H.H.H. (Hieab H. H.), Lehtimäki, T. (Terho), Sarin, A.-P., Wedenoja, J. (Juho), Hinds, D.A. (David A.), Buring, J.E. (Julie), Schürks, M. (Markus), Ridker, P.M. (Paul M.), Gudlaug Hrafnsdottir, M. (Maria), Stefansson, H. (Hreinn), Ring, S.M. (Susan M.), Hottenga, J.J. (Jouke Jan), Penninx, B.W.J.H. (Brenda), Färkkilä, M. (Markus), Artto, V. (Ville), Kaunisto, M.A. (Mari), Vepsäläinen, S. (Salli), Malik, R. (Rainer), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela A. F.), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Kurki, M. (Mitja), Kals, M. (Mart), Mägi, R. (Reedik), Pärn, K. (Kalle), Hämäläinen, E. (Eija), Huang, H. (Hailiang), Byrnes, A.E. (Andrea E.), Franke, L. (Lude), Huang, J. (Jie), Stergiakouli, E. (Evie), Lee, P.H. (Phil H.), Sandor, C. (Cynthia), Webber, C. (Caleb), Cader, Z. (Zameel), Müller-Myhsok, B. (B.), Schreiber, S. (Stefan), Meitinger, T. (Thomas), Hagen, K. (Knut), Salomaa, V. (Veikko), Heikkilä, K. (Kauko), Loehrer, E. (Elizabeth), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Cherkas, L. (Lynn), Pedersen, L.M. (Linda M.), Stubhaug, A. (Audun), Nielsen, C.S. (Christopher S.), Männikkö, M. (Minna), Mihailov, E. (Evelin), Milani, L. (Lili), Esserlind, A.-L. (Ann-Louise), Francke Christensen, A. (Anne), Folkmann Hansen, T. (Thomas), Werge, T. (Thomas), Kaprio, J. (Jaakko), Aromaa, A. (Arpo), Raitakari, O. (Olli), Ikram, M.A. (M. Arfan), Spector, T.D. (Timothy), Järvelin, M.-R. (Marjo-Riitta), Metspalu, A. (Andres), Kubisch, C. (Christian), Beckmann, J.S. (Jacques), Ferrari, M.D. (Michel), Belin, A.C. (Andrea C.), Wessman, M. (Maija), van den Maagdenberg, A.M.J.M. (Arn M. J. M.), Zwart, J-A. (John-Anker), Boomsma, D.I. (Dorret), Davey Smith, G. (George), Eriksson, N. (Nicholas), Daly, M.J. (Mark), Neale, B.M. (Benjamin), Olesen, J. (Jes), Chasman, D.I. (Daniel), Nyholt, D.R. (Dale), Palotie, A. (Aarno), Ikram, M.A. (Arfan), Wen, W. (Wei), DeCarli, C. (Charles), Srikanth, V. (Velandai), Jukema, J.W. (Jan Wouter), Slagboom, P.E. (Eline), Kardia, S.L.R. (Sharon), Okada, Y. (Yukinori), Mazoyer, B. (Bernard), Wardlaw, J.M. (J.), Nyquist, P. (Paul), Mather, R., Grabe, H.J. (Hans Jörgen), Schmidt, H. (Helena), Van Duijn, C.M. (Cornelia M.), Gudnason, V. (Vilmundur), Longstreth Jr, W.T., Launer, L.J. (Lenore), Lathrop, M. (Mark), Seshadri, S. (Sudha), Adams, H.H.H. (Hieab), Matthews, P.M. (P.), Fornage, M. (Myriam), and Debette, S. (Stéphanie)

Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Published
2020
Full Text
View/download PDF

11. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, S. (Sonia), Henry, A. (Albert), Roselli, C. (Carolina), Lin, H. (Honghuang), Sveinbjörnsson, G. (Garðar), Fatemifar, G. (Ghazaleh), Hedman, A.K. (Asa), Wilk, J.B. (Jemma), Morley, M.P. (Michael P.), Chaffin, M.D. (Mark D.), Helgadottir, H.T. (Hafdis), Verweij, N. (Niek), Dehghan, A. (Abbas), Almgren, P. (Peter), Andersson, C. (Charlotte), Aragam, K.G. (Krishna G.), Ärnlöv, J. (Johan), Backman, J.D. (Joshua D.), Biggs, M.L. (Mary L.), Bloom, H.L. (Heather L.), Brandimarto, J. (Jeffrey), Brown, M.R. (Michael R.), Buckbinder, L. (Leonard), Carey, D.J. (David J.), Chasman, D.I. (Daniel I.), Chen, X. (Xing), Chen, X. (Xu), Chung, J. (Jonathan), Chutkow, W. (William), Cook, J.P. (James P.), Delgado, G., Denaxas, S. (Spiros), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Dudley, S.C. (Samuel C.), Dunn, M.E. (Michael E.), Engström, G., Esko, T. (Tõnu), Felix, S.B. (Stephan B.), Finan, C. (Chris), Ford, I. (Ian), Ghanbari, M. (Mohsen), Ghasemi, S. (Sahar), Giedraitis, V. (Vilmantas), Giulianini, F. (Franco), Gottdiener, J.S. (John), Gross, S. (Stefan), Guðbjartsson, D.F. (Daníel F.), Gutmann, R. (Rebecca), Haggerty, C.M. (Christopher M.), Harst, P. (Pim) van der, Hyde, C.L. (Craig L.), Ingelsson, E. (Erik), Jukema, J.W. (Jan Wouter), Kavousi, M. (Maryam), Khaw, K.-T. (Kay-Tee), Kleber, M.E. (Marcus), Køber, L. (Lars), Koekemoer, A. (Andrea), Langenberg, C. (Claudia), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), London, B. (Barry), Lotta, L.A. (Luca A.), Lovering, R.C. (Ruth C.), Luan, J., Magnusson, P.K. (Patrik), Mahajan, A. (Anubha), Margulies, K.B. (Kenneth B.), Ye, S. (Shu), Melander, O. (Olle), Mordi, I.R. (Ify R.), Morgan, T. (Thomas), Morris, A.D. (Andrew D.), Morris, A.P. (Andrew), Morrison, A.C. (Alanna C.), Nagle, M.W. (Michael W.), Nelson, C.P. (Christopher P.), Niessner, A. (Alexander), Niiranen, T. (Teemu), O’Donoghue, M.L. (Michelle L.), Owens, A.T. (Anjali T.), Palmer, C.N.A. (Colin N. A.), Parry, H.M. (Helen M.), Perola, M. (Markus), Portilla-Fernandez, E. (Eliana), Psaty, B.M. (Bruce M.), Abecasis, G. (Goncalo), Backman, J. (Joshua), Bai, X. (Xiaodong), Balasubramanian, S. (Suganthi), Banerjee, N. (Nilanjana), Baras, A. (Aris), Barnard, L. (Leland), Beechert, C. (Christina), Blumenfeld, A. (Andrew), Cantor, M. (Michael), Chai, Y. (Yating), Coppola, G. (Giovanni), Damask, A. (Amy), Dewey, F. (Frederick), Economides, A. (Aris), Eom, G. (Gisu), Forsythe, C. (Caitlin), Fuller, E.D. (Erin D.), Gu, Z. (Zhenhua), Gurski, L. (Lauren), Guzzardo, P.M. (Paloma M.), Habegger, L. (Lukas), Hahn, Y. (Young), Hawes, A. (Alicia), van Hout, C. (Cristopher), Jones, M.B. (Marcus B.), Khalid, S. (Shareef), Lattari, M. (Michael), Li, A. (Alexander), Lin, N. (Nan), Liu, D. (Daren), Lopez, A. (Alexander), Manoochehri, K. (Kia), Marchini, J. (Jonathan), Marcketta, A. (Anthony), Maxwell, E.K. (Evan K.), McCarthy, S. (Shane), Mitnaul, L.J. (Lyndon), O’Dushlaine, C. (Colm), Overton, J.D. (John D.), Padilla, M.S. (Maria Sotiropoulos), Paulding, C. (Charles), Penn, J. (John), Pradhan, M. (Manasi), Reid, J.G. (Jeffrey G.), Schleicher, T.D. (Thomas D.), Schurmann, C. (Claudia), Shuldiner, A. (Alan), Staples, J.C. (Jeffrey C.), Sun, D. (Dylan), Toledo, K. (Karina), Ulloa, R.H. (Ricardo H.), Widom, L. (Louis), Wolf, S.E. (Sarah E.), Yadav, A. (Ashish), Ye, B. (Bin), Rice, K.M. (Kenneth), Ridker, P.M. (Paul M.), Romaine, S.P.R. (Simon P. R.), Rotter, J.I. (Jerome I.), Salo, P. (Perttu), Salomaa, V. (Veikko), Setten, J. (Jessica) van, Shalaby, A.A. (Alaa A.), Smelser, D.T. (Diane T.), Smith, N.L. (Nicholas L.), Stender, S. (Steen), Stott, D.J. (David. J.), Svensson, P. (Per), Tammesoo, M.L., Taylor, K.D. (Kent D.), Teder-Laving, M. (Maris), Teumer, A. (Alexander), Thorgeirsson, G. (Guðmundur), Thorsteinsdottir, U. (Unnur), Torp-Pedersen, C. (Christian Tobias), Trompet, S. (Stella), Tyl, B. (Benoit), Uitterlinden, A.G. (Andre G.), Veluchamy, A. (Abirami), Völker, U. (Uwe), Voors, A.A. (Adriaan A.), Wang, X. (Xiaosong), Wareham, N.J. (Nick), Waterworth, D. (Dawn), Weeke, P.E. (Peter E.), Weiss, R. (Ram), Wiggins, K.L. (Kerri L.), Xing, H. (Heming), Yerges-Armstrong, L.M. (Laura), Yu, B. (Bing), Zannad, F. (Faiez), Zhao, J.H. (Jing Hua), Hemingway, H., Samani, N.J. (Nilesh J.), McMurray, J.J.V. (John J. V.), Yang, J. (Jian), Visscher, P.M. (Peter M.), Newton-Cheh, C. (Christopher), Mälarstig, A. (Anders), Holm, H. (Hilma), Lubitz, S.A. (Steven), Sattar, N. (Naveed), Holmes, M.V. (Michael), Cappola, T.P. (Thomas P.), Asselbergs, F.W. (Folkert), Hingorani, A. (Aroon), Kuchenbaecker, K.B. (Karoline), Ellinor, P.T. (Patrick), Lang, C.C. (Chim C.), Stefansson, K. (Kari), Smith, J.G. (J Gustav), Vasan, R.S. (Ramachandran Srini), Swerdlow, D.I. (Daniel), Lumbers, R.T. (R. Thomas), Shah, S. (Sonia), Henry, A. (Albert), Roselli, C. (Carolina), Lin, H. (Honghuang), Sveinbjörnsson, G. (Garðar), Fatemifar, G. (Ghazaleh), Hedman, A.K. (Asa), Wilk, J.B. (Jemma), Morley, M.P. (Michael P.), Chaffin, M.D. (Mark D.), Helgadottir, H.T. (Hafdis), Verweij, N. (Niek), Dehghan, A. (Abbas), Almgren, P. (Peter), Andersson, C. (Charlotte), Aragam, K.G. (Krishna G.), Ärnlöv, J. (Johan), Backman, J.D. (Joshua D.), Biggs, M.L. (Mary L.), Bloom, H.L. (Heather L.), Brandimarto, J. (Jeffrey), Brown, M.R. (Michael R.), Buckbinder, L. (Leonard), Carey, D.J. (David J.), Chasman, D.I. (Daniel I.), Chen, X. (Xing), Chen, X. (Xu), Chung, J. (Jonathan), Chutkow, W. (William), Cook, J.P. (James P.), Delgado, G., Denaxas, S. (Spiros), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Dudley, S.C. (Samuel C.), Dunn, M.E. (Michael E.), Engström, G., Esko, T. (Tõnu), Felix, S.B. (Stephan B.), Finan, C. (Chris), Ford, I. (Ian), Ghanbari, M. (Mohsen), Ghasemi, S. (Sahar), Giedraitis, V. (Vilmantas), Giulianini, F. (Franco), Gottdiener, J.S. (John), Gross, S. (Stefan), Guðbjartsson, D.F. (Daníel F.), Gutmann, R. (Rebecca), Haggerty, C.M. (Christopher M.), Harst, P. (Pim) van der, Hyde, C.L. (Craig L.), Ingelsson, E. (Erik), Jukema, J.W. (Jan Wouter), Kavousi, M. (Maryam), Khaw, K.-T. (Kay-Tee), Kleber, M.E. (Marcus), Køber, L. (Lars), Koekemoer, A. (Andrea), Langenberg, C. (Claudia), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), London, B. (Barry), Lotta, L.A. (Luca A.), Lovering, R.C. (Ruth C.), Luan, J., Magnusson, P.K. (Patrik), Mahajan, A. (Anubha), Margulies, K.B. (Kenneth B.), Ye, S. (Shu), Melander, O. (Olle), Mordi, I.R. (Ify R.), Morgan, T. (Thomas), Morris, A.D. (Andrew D.), Morris, A.P. (Andrew), Morrison, A.C. (Alanna C.), Nagle, M.W. (Michael W.), Nelson, C.P. (Christopher P.), Niessner, A. (Alexander), Niiranen, T. (Teemu), O’Donoghue, M.L. (Michelle L.), Owens, A.T. (Anjali T.), Palmer, C.N.A. (Colin N. A.), Parry, H.M. (Helen M.), Perola, M. (Markus), Portilla-Fernandez, E. (Eliana), Psaty, B.M. (Bruce M.), Abecasis, G. (Goncalo), Backman, J. (Joshua), Bai, X. (Xiaodong), Balasubramanian, S. (Suganthi), Banerjee, N. (Nilanjana), Baras, A. (Aris), Barnard, L. (Leland), Beechert, C. (Christina), Blumenfeld, A. (Andrew), Cantor, M. (Michael), Chai, Y. (Yating), Coppola, G. (Giovanni), Damask, A. (Amy), Dewey, F. (Frederick), Economides, A. (Aris), Eom, G. (Gisu), Forsythe, C. (Caitlin), Fuller, E.D. (Erin D.), Gu, Z. (Zhenhua), Gurski, L. (Lauren), Guzzardo, P.M. (Paloma M.), Habegger, L. (Lukas), Hahn, Y. (Young), Hawes, A. (Alicia), van Hout, C. (Cristopher), Jones, M.B. (Marcus B.), Khalid, S. (Shareef), Lattari, M. (Michael), Li, A. (Alexander), Lin, N. (Nan), Liu, D. (Daren), Lopez, A. (Alexander), Manoochehri, K. (Kia), Marchini, J. (Jonathan), Marcketta, A. (Anthony), Maxwell, E.K. (Evan K.), McCarthy, S. (Shane), Mitnaul, L.J. (Lyndon), O’Dushlaine, C. (Colm), Overton, J.D. (John D.), Padilla, M.S. (Maria Sotiropoulos), Paulding, C. (Charles), Penn, J. (John), Pradhan, M. (Manasi), Reid, J.G. (Jeffrey G.), Schleicher, T.D. (Thomas D.), Schurmann, C. (Claudia), Shuldiner, A. (Alan), Staples, J.C. (Jeffrey C.), Sun, D. (Dylan), Toledo, K. (Karina), Ulloa, R.H. (Ricardo H.), Widom, L. (Louis), Wolf, S.E. (Sarah E.), Yadav, A. (Ashish), Ye, B. (Bin), Rice, K.M. (Kenneth), Ridker, P.M. (Paul M.), Romaine, S.P.R. (Simon P. R.), Rotter, J.I. (Jerome I.), Salo, P. (Perttu), Salomaa, V. (Veikko), Setten, J. (Jessica) van, Shalaby, A.A. (Alaa A.), Smelser, D.T. (Diane T.), Smith, N.L. (Nicholas L.), Stender, S. (Steen), Stott, D.J. (David. J.), Svensson, P. (Per), Tammesoo, M.L., Taylor, K.D. (Kent D.), Teder-Laving, M. (Maris), Teumer, A. (Alexander), Thorgeirsson, G. (Guðmundur), Thorsteinsdottir, U. (Unnur), Torp-Pedersen, C. (Christian Tobias), Trompet, S. (Stella), Tyl, B. (Benoit), Uitterlinden, A.G. (Andre G.), Veluchamy, A. (Abirami), Völker, U. (Uwe), Voors, A.A. (Adriaan A.), Wang, X. (Xiaosong), Wareham, N.J. (Nick), Waterworth, D. (Dawn), Weeke, P.E. (Peter E.), Weiss, R. (Ram), Wiggins, K.L. (Kerri L.), Xing, H. (Heming), Yerges-Armstrong, L.M. (Laura), Yu, B. (Bing), Zannad, F. (Faiez), Zhao, J.H. (Jing Hua), Hemingway, H., Samani, N.J. (Nilesh J.), McMurray, J.J.V. (John J. V.), Yang, J. (Jian), Visscher, P.M. (Peter M.), Newton-Cheh, C. (Christopher), Mälarstig, A. (Anders), Holm, H. (Hilma), Lubitz, S.A. (Steven), Sattar, N. (Naveed), Holmes, M.V. (Michael), Cappola, T.P. (Thomas P.), Asselbergs, F.W. (Folkert), Hingorani, A. (Aroon), Kuchenbaecker, K.B. (Karoline), Ellinor, P.T. (Patrick), Lang, C.C. (Chim C.), Stefansson, K. (Kari), Smith, J.G. (J Gustav), Vasan, R.S. (Ramachandran Srini), Swerdlow, D.I. (Daniel), and Lumbers, R.T. (R. Thomas)

Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Published
2020
Full Text
View/download PDF

12. Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Author

Cai, J., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Qian, H., Montgomery, C., Kelly, T.N., Cho, M.H., Weiss, S.T., Loos, R.J.F., Johnson, A.D., de Vries, P.S., Li, Y., Becker, L.C., Peralta, J.M., Wiggins, K.L., Bowden, D.W., Lasky-Su, J.A., Buyske, S., Shan, Y., Moon, J.-Y., Jorgenson, E., Cushman, M., Tiwari, H.K., Kooperberg, C., Faraday, N., Tapia, A.L., TOPMed Hematology & Hemostasis Working Group, Thornton, T.A., Choquet, H., Barnes, K.C., Bis, J.C., Hodonsky, C.J., Mathias, R.A., Wang, T., Taylor, K.D., He, J., Kaplan, R., Gupta, N., Lubitz, S.A., Smith, N.L., Daya, M., Rich, S.S., Peyser, P.A., Palmer, N.D., Silverman, E.K., Arnett, D.K., Choi, S.H., Cupples, L. A., Reiner, A.P., Argos, M., Boerwinkle, E., Hou, Z., Auer, P.L., Bien, S.A., Hidalgo, B., Ellinor, P.T., Heckbert, S.R., Gabriel, S., Tracy, R.P., Avery, C., Yanek, L.R., Raffield, L.M., Papanicolaou, G.J., Fornage, M., Z��llner, S., Graff, M., Wilson, J.G., Smith, J.A., Weng, L.-C., Morrison, A.C., Rosen, J.D., Irvin, M.R., North, K.E., Kardia, S.L.R., Pankratz, N., Rotter, J.I., Blangero, J., McHugh, C.P., Jain, D., Kowalski, M.H., and Ganesh, S.K.

Abstract

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

Published
2019
Full Text
View/download PDF

13. Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing

Author

Floyd, J.S. (James S.), Bloch, K.M. (Katarzyna M.), Brody, J.A. (Jennifer A.), Maroteau, C. (Cyrielle), Siddiqui, M.K. (Moneeza K.), Gregory, R. (Richard), Carr, D.F. (Daniel F.), Molokhia, M. (Mariam), Liu, X. (Xiaoming), Bis, J.C. (Joshua), Ahmed, A. (Ammar), Liu, X. (Xuan), Hallberg, P. (Pär), Yue, Q. (Qunying), Magnusson, P.K. (Patrik), Brisson, D. (Diane), Wiggins, K.L. (Kerri L.), Morrison, A.C. (Alanna C.), Khoury, E. (Etienne), Mckeigue, P.M. (Paul), Stricker, B.H.Ch. (Bruno), Lapeyre-Mestre, M. (Maryse), Heckbert, S.R. (Susan), Gallagher, A.M. (Arlene M.), Chinoy, H. (Hector), Gibbs, R.A. (Richard), Bondon-Guitton, E. (Emmanuelle), Tracy, R.P. (Russell), Boerwinkle, E.A. (Eric), Gaudet, D. (Daniel), Conforti, A. (Anita), Staa, T.P. (Tjeerd) van, Sitlani, C.M. (Colleen M.), Rice, K.M. (Kenneth M.), Maitland-van der Zee, A-H. (Anke-Hilse), Wadelius, M. (Mia), Morris, A.P. (Andrew), Pirmohamed, M. (Munir), Palmer, C.A.N. (Colin A N), Psaty, B.M. (Bruce M.), Alfirevic, A. (Ana), Floyd, J.S. (James S.), Bloch, K.M. (Katarzyna M.), Brody, J.A. (Jennifer A.), Maroteau, C. (Cyrielle), Siddiqui, M.K. (Moneeza K.), Gregory, R. (Richard), Carr, D.F. (Daniel F.), Molokhia, M. (Mariam), Liu, X. (Xiaoming), Bis, J.C. (Joshua), Ahmed, A. (Ammar), Liu, X. (Xuan), Hallberg, P. (Pär), Yue, Q. (Qunying), Magnusson, P.K. (Patrik), Brisson, D. (Diane), Wiggins, K.L. (Kerri L.), Morrison, A.C. (Alanna C.), Khoury, E. (Etienne), Mckeigue, P.M. (Paul), Stricker, B.H.Ch. (Bruno), Lapeyre-Mestre, M. (Maryse), Heckbert, S.R. (Susan), Gallagher, A.M. (Arlene M.), Chinoy, H. (Hector), Gibbs, R.A. (Richard), Bondon-Guitton, E. (Emmanuelle), Tracy, R.P. (Russell), Boerwinkle, E.A. (Eric), Gaudet, D. (Daniel), Conforti, A. (Anita), Staa, T.P. (Tjeerd) van, Sitlani, C.M. (Colleen M.), Rice, K.M. (Kenneth M.), Maitland-van der Zee, A-H. (Anke-Hilse), Wadelius, M. (Mia), Morris, A.P. (Andrew), Pirmohamed, M. (Munir), Palmer, C.A.N. (Colin A N), Psaty, B.M. (Bruce M.), and Alfirevic, A. (Ana)

Abstract

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

Published
2019
Full Text
View/download PDF

14. Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease

Author

Ward-Caviness, CK, de Vries, PS, Wiggins, K.L. (Kerri), Huffman, J.E. (Jennifer), Yanek, L.R. (Lisa), Bielak, L.F. (Lawrence F.), Ward-Caviness, CK, de Vries, PS, Wiggins, K.L. (Kerri), Huffman, J.E. (Jennifer), Yanek, L.R. (Lisa), and Bielak, L.F. (Lawrence F.)

Abstract

Background Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. Methods and findings We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. Conclusions A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approach

Published
2019
Full Text
View/download PDF

15. 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
Full Text
View/download PDF

16. A DNA methylation biomarker of alcohol consumption

Author

Liu, C. (C.), Marioni, R.E. (Riccardo), Hedman, A.K. (Asa), Pfeiffer, L. (L.), Tsai, P.-C. (P. C.), Reynolds, L.M. (Lindsay), Just, A.C. (A. C.), Duan, Q. (Qing), Boer, C.G. (Cindy), Tanaka, T. (T.), Elks, C.E. (Cathy), Aslibekyan, S. (S.), Brody, J.A. (Jennifer A.), Kuhnel, B. (Brigitte), Herder, C. (Christian), Almli, L.M. (L. M.), Zhi, D. (D.), Wang, Y. (Y.), Huan, T. (T.), Yao, C. (C.), Mendelson, M.M. (M. M.), Joehanes, R. (Roby), Liang, L. (Liming), Love, S.-A. (S. A.), Guan, W. (Weihua), Shah, S. (S.), McRae, A.F. (A. F.), Kretschmer, A. (A.), Prokisch, H. (Holger), Strauch, K. (K.), Peters, A. (Annette), Visscher, P.M. (Peter), Wray, N.R. (Naomi), Guo, X. (Xiuqing), Wiggins, K.L. (Kerri), Smith, A.K. (A. K.), Binder, E.B. (Elisabeth), Ressler, K.J. (Kerry), Irvin, M.R. (M. R.), Absher, D.M. (D. M.), Hernandez, D.G. (Dena), Ferrucci, L. (Luigi), Bandinelli, S. (Stefania), Lohman, K. (K.), Ding, J. (J.), Trevisi, L. (L.), Gustafsson, S. (Stefan), Sandling, J.K. (Johanna), Stolk, L. (Lisette), Uitterlinden, A.G. (André), Yet, I. (Idil), Castillo-Fernandez, J.E. (J. E.), Spector, T.D. (Timothy), Schwartz, J.D. (J. D.), Vokonas, P. (P.), Kao, W.H.L. (Wen), Li, Y. (Y.), Fornage, M. (Myriam), Arnett, D.K. (Donna), Wareham, N.J. (Nick), Sotoodehnia, N. (Nona), Ong, K.K. (Ken), Meurs, J.B.J. (Joyce) van, Conneely, K.N. (Karen N.), Baccarelli, A.A. (A. A.), Deary, I.J. (Ian), Bell, J.T. (J. T.), North, K.E. (Kari), Liu, Y. (YongMei), Waldenberger, M. (M.), London, S.J. (S. J.), Ingelsson, E. (Erik), Levy, D. (D.), Liu, C. (C.), Marioni, R.E. (Riccardo), Hedman, A.K. (Asa), Pfeiffer, L. (L.), Tsai, P.-C. (P. C.), Reynolds, L.M. (Lindsay), Just, A.C. (A. C.), Duan, Q. (Qing), Boer, C.G. (Cindy), Tanaka, T. (T.), Elks, C.E. (Cathy), Aslibekyan, S. (S.), Brody, J.A. (Jennifer A.), Kuhnel, B. (Brigitte), Herder, C. (Christian), Almli, L.M. (L. M.), Zhi, D. (D.), Wang, Y. (Y.), Huan, T. (T.), Yao, C. (C.), Mendelson, M.M. (M. M.), Joehanes, R. (Roby), Liang, L. (Liming), Love, S.-A. (S. A.), Guan, W. (Weihua), Shah, S. (S.), McRae, A.F. (A. F.), Kretschmer, A. (A.), Prokisch, H. (Holger), Strauch, K. (K.), Peters, A. (Annette), Visscher, P.M. (Peter), Wray, N.R. (Naomi), Guo, X. (Xiuqing), Wiggins, K.L. (Kerri), Smith, A.K. (A. K.), Binder, E.B. (Elisabeth), Ressler, K.J. (Kerry), Irvin, M.R. (M. R.), Absher, D.M. (D. M.), Hernandez, D.G. (Dena), Ferrucci, L. (Luigi), Bandinelli, S. (Stefania), Lohman, K. (K.), Ding, J. (J.), Trevisi, L. (L.), Gustafsson, S. (Stefan), Sandling, J.K. (Johanna), Stolk, L. (Lisette), Uitterlinden, A.G. (André), Yet, I. (Idil), Castillo-Fernandez, J.E. (J. E.), Spector, T.D. (Timothy), Schwartz, J.D. (J. D.), Vokonas, P. (P.), Kao, W.H.L. (Wen), Li, Y. (Y.), Fornage, M. (Myriam), Arnett, D.K. (Donna), Wareham, N.J. (Nick), Sotoodehnia, N. (Nona), Ong, K.K. (Ken), Meurs, J.B.J. (Joyce) van, Conneely, K.N. (Karen N.), Baccarelli, A.A. (A. A.), Deary, I.J. (Ian), Bell, J.T. (J. T.), North, K.E. (Kari), Liu, Y. (YongMei), Waldenberger, M. (M.), London, S.J. (S. J.), Ingelsson, E. (Erik), and Levy, D. (D.)

Abstract

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal = 13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n = 6926) and identified 144 CpGs that provided substantial discrimination (area under the curve = 0.90-0.99) for current heavy alcohol intake (≥42 g per day in men and ≥28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1×10-7. Analysis of the monocyte-derived DNA (n = 1251) identified 62 alcohol-related CpGs at P<1×10-7. In whole-blood samples of people of European ancestry, we detected differen

Published
2018
Full Text
View/download PDF

18. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Author

Ligthart, S. (Symen), Marzi, C. (Carola), Aslibekyan, S. (Stella), Mendelson, M.M. (Michael M.), Conneely, K.N. (Karen N.), Tanaka, T. (Toshiko), Colicino, E. (Elena), Waite, L. (Lindsay), Joehanes, R. (Roby), Guan, W. (Weihua), Brody, J.A. (Jennifer A.), Elks, C.E. (Cathy), Marioni, R.E. (Riccardo), Jhun, M.A. (Min A.), Agha, G. (Golareh), Bressler, J. (Jan), Ward-Caviness, C.K. (Cavin K.), Chen, B.H. (Brian), Huan, T. (Tianxiao), Bakulski, K.M. (Kelly M.), Salfati, E. (Elias), Fiorito, G. (Giovanni), Wahl, S. (Simone), Schramm, K. (Katharina), Sha, J. (Jin), Hernandez, D.G. (Dena), Just, A.C. (Allan C.), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Pilling, L.C. (Luke), Pankow, J.S. (James), Tsao, P.S. (Phil S.), Liu, C. (Chunyu), Zhao, W. (Wei), Guarrera, S. (Simonetta), Michopoulos, V.J. (Vasiliki J.), Smith, A.K. (Alicia K.), Peters, M.J. (Marjolein), Melzer, D. (David), Vokonas, P. (Pantel), Fornage, M. (Myriam), Prokisch, H. (Holger), Bis, J.C. (Joshua), Chu, A.Y. (Audrey), Herder, C. (Christian), Grallert, H. (Harald), Yao, C. (Chen), Shah, S. (Sonia), McRae, A.F. (Allan F.), Lin, H., Horvath, S. (Steve), Fallin, D. (Daniele), Hofman, A. (Albert), Wareham, N.J. (Nick), Wiggins, K.L. (Kerri), Feinberg, A.P. (Andrew P.), Starr, J.M. (John), Visscher, P.M. (Peter), Murabito, J. (Joanne), Kardia, S.L.R. (Sharon L.R.), Absher, D. (Devin), Binder, E.B. (Elisabeth), Singleton, A. (Andrew), Bandinelli, S. (Stefania), Peters, A. (Annette), Waldenberger, M. (Melanie), Matullo, G., Schwartz, J.D. (Joel D.), Demerath, E.W. (Ellen), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce B.J.), Franco, O.H. (Oscar), Chen, Y.D. (Y.), Levy, D. (Daniel), Turner, S.T. (Stephen), Deary, I.J. (Ian), Ressler, K.J. (Kerry), Dupuis, J. (Josée), Ferrucci, L. (Luigi), Ong, K.K. (Ken K.), Assimes, T.L. (Themistocles), Boerwinkle, E.A. (Eric), Koenig, W. (Wolfgang), Arnett, D.K. (Donna), Baccarelli, A.A. (Andrea), Benjamin, E.J. (Emelia), Dehghan, A. (Abbas), Ligthart, S. (Symen), Marzi, C. (Carola), Aslibekyan, S. (Stella), Mendelson, M.M. (Michael M.), Conneely, K.N. (Karen N.), Tanaka, T. (Toshiko), Colicino, E. (Elena), Waite, L. (Lindsay), Joehanes, R. (Roby), Guan, W. (Weihua), Brody, J.A. (Jennifer A.), Elks, C.E. (Cathy), Marioni, R.E. (Riccardo), Jhun, M.A. (Min A.), Agha, G. (Golareh), Bressler, J. (Jan), Ward-Caviness, C.K. (Cavin K.), Chen, B.H. (Brian), Huan, T. (Tianxiao), Bakulski, K.M. (Kelly M.), Salfati, E. (Elias), Fiorito, G. (Giovanni), Wahl, S. (Simone), Schramm, K. (Katharina), Sha, J. (Jin), Hernandez, D.G. (Dena), Just, A.C. (Allan C.), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Pilling, L.C. (Luke), Pankow, J.S. (James), Tsao, P.S. (Phil S.), Liu, C. (Chunyu), Zhao, W. (Wei), Guarrera, S. (Simonetta), Michopoulos, V.J. (Vasiliki J.), Smith, A.K. (Alicia K.), Peters, M.J. (Marjolein), Melzer, D. (David), Vokonas, P. (Pantel), Fornage, M. (Myriam), Prokisch, H. (Holger), Bis, J.C. (Joshua), Chu, A.Y. (Audrey), Herder, C. (Christian), Grallert, H. (Harald), Yao, C. (Chen), Shah, S. (Sonia), McRae, A.F. (Allan F.), Lin, H., Horvath, S. (Steve), Fallin, D. (Daniele), Hofman, A. (Albert), Wareham, N.J. (Nick), Wiggins, K.L. (Kerri), Feinberg, A.P. (Andrew P.), Starr, J.M. (John), Visscher, P.M. (Peter), Murabito, J. (Joanne), Kardia, S.L.R. (Sharon L.R.), Absher, D. (Devin), Binder, E.B. (Elisabeth), Singleton, A. (Andrew), Bandinelli, S. (Stefania), Peters, A. (Annette), Waldenberger, M. (Melanie), Matullo, G., Schwartz, J.D. (Joel D.), Demerath, E.W. (Ellen), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce B.J.), Franco, O.H. (Oscar), Chen, Y.D. (Y.), Levy, D. (Daniel), Turner, S.T. (Stephen), Deary, I.J. (Ian), Ressler, K.J. (Kerry), Dupuis, J. (Josée), Ferrucci, L. (Luigi), Ong, K.K. (Ken K.), Assimes, T.L. (Themistocles), Boerwinkle, E.A. (Eric), Koenig, W. (Wolfgang), Arnett, D.K. (Donna), Baccarelli, A.A. (Andrea), Benjamin, E.J. (Emelia), and Dehghan, A. (Abbas)

Abstract

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is as

Published
2016
Full Text
View/download PDF

19. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Pattaro, C., Teumer, A., Gorski, M., Chu, A.Y., Li, M., Mijatovic, V., Garnaas, M., Tin, A., Sorice, R., Li, Y., Taliun, D., Olden, M., Foster, M., Yang, Q., Chen, M.-H., Pers, T.H., Johnson, A.D., Ko, Y.-A., Fuchsberger, C., Tayo, B., Nalls, M., Feitosa, M.F., Isaacs, A., Dehghan, A., D'Adamo, P., Adeyemo, A., Dieffenbach, A.K., Zonderman, A.B., Nolte, I.M., Van Der Most, P.J., Wright, A.F., Shuldiner, A.R., Morrison, A.C., Hofman, A., Smith, A.V., Dreisbach, A.W., Franke, A., Uitterlinden, A.G., Metspalu, A., Tonjes, A., Lupo, A., Robino, A., Johansson, Å., Demirkan, A., Kollerits, B., Freedman, B.I., Ponte, B., Oostra, B.A., Paulweber, B., Krämer, B.K., Mitchell, B.D., Buckley, B.M., Peralta, C.A., Hayward, C., Helmer, C., Rotimi, C.N., Shaffer, C.M., Müller, C., Sala, C., Van Duijn, C.M., Saint-Pierre, A., Ackermann, D., Shriner, D., Ruggiero, D., Toniolo, D., Lu, Y., Cusi, D., Czamara, D., Ellinghaus, D., Siscovick, D.S., Ruderfer, D., Gieger, C., Grallert, H., Rochtchina, E., Atkinson, E.J., Holliday, E.G., Boerwinkle, E., Salvi, E., Bottinger, E.P., Murgia, F., Rivadeneira, F., Ernst, F., Kronenberg, F., Hu, F.B., Navis, G.J., Curhan, G.C., Ehret, G.B., Homuth, G., Coassin, S., Thun, G.-A., Pistis, G., Gambaro, G., Malerba, G., Montgomery, G.W., Eiriksdottir, G., Jacobs, G., Li, G., Wichmann, H.-E., Campbell, H., Schmidt, H., Wallaschofski, H., Völzke, H., Brenner, H., Kroemer, H.K., Kramer, H., Lin, H., Leach, I.M., Ford, I., Guessous, I., Rudan, I., Prokopenko, I., Borecki, I., Heid, I.M., Kolcic, I., Persico, I., Jukema, J.W., Wilson, J.F., Felix, J.F., Divers, J., Lambert, J.-C., Stafford, J.M., Gaspoz, J.-M., Smith, J.A., Faul, J.D., Wang, J.J., Ding, J., Hirschhorn, J.N., Attia, J., Whitfield, J.B., Chalmers, J., Viikari, J., Coresh, J., Denny, J.C., Karjalainen, J., Fernandes, J.K., Endlich, K., Butterbach, K., Keene, K.L., Lohman, K., Portas, L., Launer, L.J., Lyytikäinen, L.-P., Yengo, L., Franke, L., Ferrucci, L., Rose, L.M., Kedenko, L., Rao, M., Struchalin, M., Kleber, M.E., Cavalieri, M., Haun, M., Cornelis, M.C., Ciullo, M., Pirastu, M., De Andrade, M., McEvoy, M.A., Woodward, M., Adam, M., Cocca, M., Nauck, M., Imboden, M., Waldenberger, M., Pruijm, M., Metzger, M., Stumvoll, M., Evans, M.K., Sale, M.M., Kähönen, M., Boban, M., Bochud, M., Rheinberger, M., Verweij, N., Bouatia-Naji, N., Martin, N.G., Hastie, N., Probst-Hensch, N., Soranzo, N., Devuyst, O., Raitakari, O., Gottesman, O., Franco, O.H., Polasek, O., Gasparini, P., Munroe, P.B., Ridker, P.M., Mitchell, P., Muntner, P., Meisinger, C., Smit, J.H., Abecasis, G.R., Adair, L.S., Alexander, M., Altshuler, D., Amin, N., Arking, D.E., Arora, P., Aulchenko, Y., Bakker, S.J.L., Bandinelli, S., Barroso, I., Beckmann, J.S., Beilby, J.P., Bergman, R.N., Bergmann, S., Bis, J.C., Boehnke, M., Bonnycastle, L.L., Bornstein, S.R., Bots, M.L., Bragg-Gresham, J.L., Brand, S.-M., Brand, E., Braund, P.S., Brown, M.J., Burton, P.R., Casas, J.P., Caulfield, M.J., Chakravarti, A., Chambers, J.C., Chandak, G.R., Chang, Y.-P.C., Charchar, F.J., Chaturvedi, N., Cho, Y.S., Clarke, R., Collins, F.S., Collins, R., Connell, J.M., Cooper, J.A., Cooper, M.N., Cooper, R.S., Corsi, A.M., Dörr, M., Dahgam, S., Danesh, J., Smith, G.D., Day, I.N.M., Deloukas, P., Denniff, M., Dominiczak, A.F., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, F.G.R., Fox, E.R., Frayling, T.M., Galan, P., Ganesh, S.K., Garcia, M., Gaunt, T.R., Glazer, N.L., Go, M.J., Goel, A., Grässler, J., Grobbee, D.E., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, B.-G., Hardy, R., Hartikainen, A.-L., Heath, S., Heckbert, S.R., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, A.A., Hilton, G., Hingorani, A.D., Hoffman Bolton, J.A., Hopewell, J.C., Howard, P., Humphries, S.E., Hunt, S.C., Hveem, K., Ikram, M.A., Islam, M., Iwai, N., Jarvelin, M.-R., Jackson, A.U., Jafar, T.H., Janipalli, C.S., Johnson, T., Kathiresan, S., Khaw, K.-T., Kim, H.-L., Kinra, S., Kita, Y., Kivimaki, M., Kooner, J.S., Kumar, M.J.K., Kuh, D., Kulkarni, S.R., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, E.G., Langefeld, C.D., Larson, M.G., Lathrop, M., Lawlor, D.A., Lawrence, R.W., Lee, J.-Y., Lee, N.R., Levy, D., Longstreth, W.T., Luan, J., Lucas, G., Ludwig, B., Mangino, M., Mani, K.R., Marmot, M.G., Mattace-Raso, F.U.S., Matullo, G., McArdle, W.L., McKenzie, C.A., Meitinger, T., Melander, O., Meneton, P., Meschia, J.F., Miki, T., Milaneschi, Y., Mohlke, K.L., Mooser, V., Morken, M.A., Morris, R.W., Mosley, T.H., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, K.-D.H., Nilsson, P., Nyberg, F., O'Donnell, C.J., Ogihara, T., Ohkubo, T., Okamura, T., Ong, R.T.-H., Ongen, H., Onland-Moret, N.C., O'Reilly, P.F., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, L.J., Palmer, N.D., Parker, A.N., Peden, J.F., Peltonen, L., Perola, M., Pihur, V., Platou, C.G.P., Plump, A., Prabhakaran, D., Psaty, B.M., Raffel, L.J., Rao, D.C., Rasheed, A., Ricceri, F., Rice, K.M., Rosengren, A., Rotter, J.I., Rudock, M.E., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, N.J., Schwartz, S.M., Schwarz, P.E.H., Scott, L.J., Scott, J., Scuteri, A., Sehmi, J.S., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, N.R.G., Sijbrands, E.J.G., Sim, X., Singleton, A., Sjögren, M., Smith, N.L., Artigas, M.S., Spector, T.D., Staessen, J.A., Stancakova, A., Steinle, N.I., Strachan, D.P., Stringham, H.M., Sun, Y.V., Swift, A.J., Tabara, Y., Tai, E.-S., Talmud, P.J., Taylor, A., Terzic, J., Thelle, D.S., Tobin, M.D., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, C.S.P.M., Umemura, S., Van Der Harst, P., Van Der Schouw, Y.T., Van Gilst, W.H., Vartiainen, E., Vasan, R.S., Veldre, G., Verwoert, G.C., Viigimaa, M., Vinay, D.G., Vineis, P., Voight, B.F., Vollenweider, P., Wagenknecht, L.E., Wain, L.V., Wang, X., Wang, T.J., Wareham, N.J., Watkins, H., Weder, A.B., Whincup, P.H., Wiggins, K.L., Witteman, J.C.M., Wong, A., Wu, Y., Yajnik, C.S., Yao, J., Young, J.H., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, J.H., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, J.-Y., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, S.-C., Wong, T.-Y., Liu, J., Young, T.L., Aung, T., Teo, Y.-Y., Kim, Y.J., Kang, D., Chen, C.-H., Tsai, F.-J., Chang, L.-C., Fann, S.-J.C., Mei, H., Hixson, J.E., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, Y.-T., Tanaka, T., Reilly, M.P., Schunkert, H., Assimes, T.L., Hall, A., Hengstenberg, C., König, I.R., Laaksonen, R., McPherson, R., Thompson, J.R., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, L.A., Halperin, E., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, G.A., Holm, H., Roberts, R., Stewart, A.F.R., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, K.J., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, H.J., Perret, C., Proust, C., Münzel, T.F., Barbalic, M., Chen, I.Y.-D., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, K.D., Volcik, K., Gretarsdottir, S., Gulcher, J.R., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, A.K., Willenborg, C., Böhm, B.O., Dobnig, H., Grammer, T.B., Hoffmann, M.M., Meinitzer, A., Winkelmann, B.R., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, S.B., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, H.H., Devaney, J., Burnett, M.S., Pichard, A.D., Kent, K.M., Satler, L., Lindsay, J.M., Waksman, R., Knouff, C.W., Waterworth, D.M., Walker, M.C., Epstein, S.E., Rader, D.J., Nelson, C.P., Wright, B.J., Balmforth, A.J., Ball, S.G., Loehr, L.R., Rosamond, W.D., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, Y.A., Stricker, B.H., Chang, P.P., Willerson, J.T., Felix, S.B., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, R.J., Greiser, K.H., Deckers, J.W., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, M.M., Werdan, K., Mitchell, G.F., Arnett, D.K., Gottdiener, J.S., Blettner, M., Friedrich, N., Kovacs, P., Wild, P.S., Froguel, P., Rettig, R., Mägi, R., Biffar, R., Schmidt, R., Middelberg, R.P.S., Carroll, R.J., Penninx, B.W., Scott, R.J., Katz, R., Sedaghat, S., Wild, S.H., Kardia, S.L.R., Ulivi, S., Hwang, S.-J., Enroth, S., Kloiber, S., Trompet, S., Stengel, B., Hancock, S.J., Turner, S.T., Rosas, S.E., Stracke, S., Harris, T.B., Zeller, T., Zemunik, T., Lehtimäki, T., Illig, T., Aspelund, T., Nikopensius, T., Esko, T., Gyllensten, U., Völker, U., Emilsson, V., Vitart, V., Aalto, V., Gudnason, V., Chouraki, V., Chen, W.-M., Igl, W., März, W., Koenig, W., Lieb, W., Loos, R.J.F., Liu, Y., Snieder, H., Pramstaller, P.P., Parsa, A., O'Connell, J.R., Susztak, K., Hamet, P., Tremblay, J., De Boer, I.H., Böger, C.A., Goessling, W., Chasman, D.I., Köttgen, A., Kao, W.H.L., Fox, C.S., UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Pattaro, C., Teumer, A., Gorski, M., Chu, A.Y., Li, M., Mijatovic, V., Garnaas, M., Tin, A., Sorice, R., Li, Y., Taliun, D., Olden, M., Foster, M., Yang, Q., Chen, M.-H., Pers, T.H., Johnson, A.D., Ko, Y.-A., Fuchsberger, C., Tayo, B., Nalls, M., Feitosa, M.F., Isaacs, A., Dehghan, A., D'Adamo, P., Adeyemo, A., Dieffenbach, A.K., Zonderman, A.B., Nolte, I.M., Van Der Most, P.J., Wright, A.F., Shuldiner, A.R., Morrison, A.C., Hofman, A., Smith, A.V., Dreisbach, A.W., Franke, A., Uitterlinden, A.G., Metspalu, A., Tonjes, A., Lupo, A., Robino, A., Johansson, Å., Demirkan, A., Kollerits, B., Freedman, B.I., Ponte, B., Oostra, B.A., Paulweber, B., Krämer, B.K., Mitchell, B.D., Buckley, B.M., Peralta, C.A., Hayward, C., Helmer, C., Rotimi, C.N., Shaffer, C.M., Müller, C., Sala, C., Van Duijn, C.M., Saint-Pierre, A., Ackermann, D., Shriner, D., Ruggiero, D., Toniolo, D., Lu, Y., Cusi, D., Czamara, D., Ellinghaus, D., Siscovick, D.S., Ruderfer, D., Gieger, C., Grallert, H., Rochtchina, E., Atkinson, E.J., Holliday, E.G., Boerwinkle, E., Salvi, E., Bottinger, E.P., Murgia, F., Rivadeneira, F., Ernst, F., Kronenberg, F., Hu, F.B., Navis, G.J., Curhan, G.C., Ehret, G.B., Homuth, G., Coassin, S., Thun, G.-A., Pistis, G., Gambaro, G., Malerba, G., Montgomery, G.W., Eiriksdottir, G., Jacobs, G., Li, G., Wichmann, H.-E., Campbell, H., Schmidt, H., Wallaschofski, H., Völzke, H., Brenner, H., Kroemer, H.K., Kramer, H., Lin, H., Leach, I.M., Ford, I., Guessous, I., Rudan, I., Prokopenko, I., Borecki, I., Heid, I.M., Kolcic, I., Persico, I., Jukema, J.W., Wilson, J.F., Felix, J.F., Divers, J., Lambert, J.-C., Stafford, J.M., Gaspoz, J.-M., Smith, J.A., Faul, J.D., Wang, J.J., Ding, J., Hirschhorn, J.N., Attia, J., Whitfield, J.B., Chalmers, J., Viikari, J., Coresh, J., Denny, J.C., Karjalainen, J., Fernandes, J.K., Endlich, K., Butterbach, K., Keene, K.L., Lohman, K., Portas, L., Launer, L.J., Lyytikäinen, L.-P., Yengo, L., Franke, L., Ferrucci, L., Rose, L.M., Kedenko, L., Rao, M., Struchalin, M., Kleber, M.E., Cavalieri, M., Haun, M., Cornelis, M.C., Ciullo, M., Pirastu, M., De Andrade, M., McEvoy, M.A., Woodward, M., Adam, M., Cocca, M., Nauck, M., Imboden, M., Waldenberger, M., Pruijm, M., Metzger, M., Stumvoll, M., Evans, M.K., Sale, M.M., Kähönen, M., Boban, M., Bochud, M., Rheinberger, M., Verweij, N., Bouatia-Naji, N., Martin, N.G., Hastie, N., Probst-Hensch, N., Soranzo, N., Devuyst, O., Raitakari, O., Gottesman, O., Franco, O.H., Polasek, O., Gasparini, P., Munroe, P.B., Ridker, P.M., Mitchell, P., Muntner, P., Meisinger, C., Smit, J.H., Abecasis, G.R., Adair, L.S., Alexander, M., Altshuler, D., Amin, N., Arking, D.E., Arora, P., Aulchenko, Y., Bakker, S.J.L., Bandinelli, S., Barroso, I., Beckmann, J.S., Beilby, J.P., Bergman, R.N., Bergmann, S., Bis, J.C., Boehnke, M., Bonnycastle, L.L., Bornstein, S.R., Bots, M.L., Bragg-Gresham, J.L., Brand, S.-M., Brand, E., Braund, P.S., Brown, M.J., Burton, P.R., Casas, J.P., Caulfield, M.J., Chakravarti, A., Chambers, J.C., Chandak, G.R., Chang, Y.-P.C., Charchar, F.J., Chaturvedi, N., Cho, Y.S., Clarke, R., Collins, F.S., Collins, R., Connell, J.M., Cooper, J.A., Cooper, M.N., Cooper, R.S., Corsi, A.M., Dörr, M., Dahgam, S., Danesh, J., Smith, G.D., Day, I.N.M., Deloukas, P., Denniff, M., Dominiczak, A.F., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, F.G.R., Fox, E.R., Frayling, T.M., Galan, P., Ganesh, S.K., Garcia, M., Gaunt, T.R., Glazer, N.L., Go, M.J., Goel, A., Grässler, J., Grobbee, D.E., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, B.-G., Hardy, R., Hartikainen, A.-L., Heath, S., Heckbert, S.R., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, A.A., Hilton, G., Hingorani, A.D., Hoffman Bolton, J.A., Hopewell, J.C., Howard, P., Humphries, S.E., Hunt, S.C., Hveem, K., Ikram, M.A., Islam, M., Iwai, N., Jarvelin, M.-R., Jackson, A.U., Jafar, T.H., Janipalli, C.S., Johnson, T., Kathiresan, S., Khaw, K.-T., Kim, H.-L., Kinra, S., Kita, Y., Kivimaki, M., Kooner, J.S., Kumar, M.J.K., Kuh, D., Kulkarni, S.R., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, E.G., Langefeld, C.D., Larson, M.G., Lathrop, M., Lawlor, D.A., Lawrence, R.W., Lee, J.-Y., Lee, N.R., Levy, D., Longstreth, W.T., Luan, J., Lucas, G., Ludwig, B., Mangino, M., Mani, K.R., Marmot, M.G., Mattace-Raso, F.U.S., Matullo, G., McArdle, W.L., McKenzie, C.A., Meitinger, T., Melander, O., Meneton, P., Meschia, J.F., Miki, T., Milaneschi, Y., Mohlke, K.L., Mooser, V., Morken, M.A., Morris, R.W., Mosley, T.H., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, K.-D.H., Nilsson, P., Nyberg, F., O'Donnell, C.J., Ogihara, T., Ohkubo, T., Okamura, T., Ong, R.T.-H., Ongen, H., Onland-Moret, N.C., O'Reilly, P.F., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, L.J., Palmer, N.D., Parker, A.N., Peden, J.F., Peltonen, L., Perola, M., Pihur, V., Platou, C.G.P., Plump, A., Prabhakaran, D., Psaty, B.M., Raffel, L.J., Rao, D.C., Rasheed, A., Ricceri, F., Rice, K.M., Rosengren, A., Rotter, J.I., Rudock, M.E., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, N.J., Schwartz, S.M., Schwarz, P.E.H., Scott, L.J., Scott, J., Scuteri, A., Sehmi, J.S., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, N.R.G., Sijbrands, E.J.G., Sim, X., Singleton, A., Sjögren, M., Smith, N.L., Artigas, M.S., Spector, T.D., Staessen, J.A., Stancakova, A., Steinle, N.I., Strachan, D.P., Stringham, H.M., Sun, Y.V., Swift, A.J., Tabara, Y., Tai, E.-S., Talmud, P.J., Taylor, A., Terzic, J., Thelle, D.S., Tobin, M.D., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, C.S.P.M., Umemura, S., Van Der Harst, P., Van Der Schouw, Y.T., Van Gilst, W.H., Vartiainen, E., Vasan, R.S., Veldre, G., Verwoert, G.C., Viigimaa, M., Vinay, D.G., Vineis, P., Voight, B.F., Vollenweider, P., Wagenknecht, L.E., Wain, L.V., Wang, X., Wang, T.J., Wareham, N.J., Watkins, H., Weder, A.B., Whincup, P.H., Wiggins, K.L., Witteman, J.C.M., Wong, A., Wu, Y., Yajnik, C.S., Yao, J., Young, J.H., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, J.H., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, J.-Y., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, S.-C., Wong, T.-Y., Liu, J., Young, T.L., Aung, T., Teo, Y.-Y., Kim, Y.J., Kang, D., Chen, C.-H., Tsai, F.-J., Chang, L.-C., Fann, S.-J.C., Mei, H., Hixson, J.E., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, Y.-T., Tanaka, T., Reilly, M.P., Schunkert, H., Assimes, T.L., Hall, A., Hengstenberg, C., König, I.R., Laaksonen, R., McPherson, R., Thompson, J.R., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, L.A., Halperin, E., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, G.A., Holm, H., Roberts, R., Stewart, A.F.R., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, K.J., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, H.J., Perret, C., Proust, C., Münzel, T.F., Barbalic, M., Chen, I.Y.-D., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, K.D., Volcik, K., Gretarsdottir, S., Gulcher, J.R., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, A.K., Willenborg, C., Böhm, B.O., Dobnig, H., Grammer, T.B., Hoffmann, M.M., Meinitzer, A., Winkelmann, B.R., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, S.B., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, H.H., Devaney, J., Burnett, M.S., Pichard, A.D., Kent, K.M., Satler, L., Lindsay, J.M., Waksman, R., Knouff, C.W., Waterworth, D.M., Walker, M.C., Epstein, S.E., Rader, D.J., Nelson, C.P., Wright, B.J., Balmforth, A.J., Ball, S.G., Loehr, L.R., Rosamond, W.D., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, Y.A., Stricker, B.H., Chang, P.P., Willerson, J.T., Felix, S.B., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, R.J., Greiser, K.H., Deckers, J.W., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, M.M., Werdan, K., Mitchell, G.F., Arnett, D.K., Gottdiener, J.S., Blettner, M., Friedrich, N., Kovacs, P., Wild, P.S., Froguel, P., Rettig, R., Mägi, R., Biffar, R., Schmidt, R., Middelberg, R.P.S., Carroll, R.J., Penninx, B.W., Scott, R.J., Katz, R., Sedaghat, S., Wild, S.H., Kardia, S.L.R., Ulivi, S., Hwang, S.-J., Enroth, S., Kloiber, S., Trompet, S., Stengel, B., Hancock, S.J., Turner, S.T., Rosas, S.E., Stracke, S., Harris, T.B., Zeller, T., Zemunik, T., Lehtimäki, T., Illig, T., Aspelund, T., Nikopensius, T., Esko, T., Gyllensten, U., Völker, U., Emilsson, V., Vitart, V., Aalto, V., Gudnason, V., Chouraki, V., Chen, W.-M., Igl, W., März, W., Koenig, W., Lieb, W., Loos, R.J.F., Liu, Y., Snieder, H., Pramstaller, P.P., Parsa, A., O'Connell, J.R., Susztak, K., Hamet, P., Tremblay, J., De Boer, I.H., Böger, C.A., Goessling, W., Chasman, D.I., Köttgen, A., Kao, W.H.L., and Fox, C.S.

Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. © 2016, Nature Publishing Group. All rights reserved.

Published
2016

20. 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
Full Text
View/download PDF

21. Genetic overlap between diagnostic subtypes of ischemic stroke

Author

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

Abstract

Background and Purpose: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. Methods: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. Results: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10-4) and profile scores (rg=0.72; 95% confide

Published
2015
Full Text
View/download PDF

22. Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: A pharmacogenomics study from the CHARGE consortium

Author

Bis, J.C. (Joshua), Sitlani, C.M. (Colleen), Irvin, R. (Ryan), Avery, C.L., Smith, A.V. (Davey), Sun, F. (Fangui), Evans, D.S. (Daniel), Musani, S. (Solomon), Li, X. (Xiaohui), Trompet, S. (Stella), Krijthe, B.P. (Bouwe), Harris, T.B. (Tamara), Quibrera, P.M. (P. Miguel), Brody, J.A. (Jennifer A.), Demissie, S. (Serkalem), Davis, B.R. (Barry), Wiggins, K.L. (Kerri), Tranah, G.J. (Gregory), Lange, L.A. (Leslie), Sotoodehnia, N. (Nona), Stott, D.J. (David. J.), Franco, O.H. (Oscar), Launer, L.J. (Lenore), Stürmer, T., Taylor, K.D. (Kent), Cupples, L.A. (Adrienne), Eckfeldt, J.H. (John), Smith, N.L. (Nicholas), Liu, Y. (YongMei), Wilson, J.G. (James), Heckbert, S.R. (Susan), Buckley, B.M. (Brendan M.), Ikram, M.A. (Arfan), Boerwinkle, E.A. (Eric), Chen, Y.-D.I. (Yii-Der Ida), De Craen, A.J.M. (Anton J. M.), Uitterlinden, A.G. (André), Rotter, J.I. (Jerome I.), Ford, I., Hofman, A. (Albert), Sattar, N. (Naveed), Slagboom, P.E. (Eline), Westendorp, R.G.J. (Rudi), Gudnason, V. (Vilmundur), Vasan, R.S. (Ramachandran S.), Lumley, T. (Thomas), Cummings, S.R. (Steven R.), Taylor, H.A. (Herman), Post, W. (Wendy), Jukema, J.W. (Jan Wouter), Stricker, B.H.Ch. (Bruno), Whitsel, E.A. (Eric), Psaty, B.M. (Bruce), Arnett, D.K. (Donna), Bis, J.C. (Joshua), Sitlani, C.M. (Colleen), Irvin, R. (Ryan), Avery, C.L., Smith, A.V. (Davey), Sun, F. (Fangui), Evans, D.S. (Daniel), Musani, S. (Solomon), Li, X. (Xiaohui), Trompet, S. (Stella), Krijthe, B.P. (Bouwe), Harris, T.B. (Tamara), Quibrera, P.M. (P. Miguel), Brody, J.A. (Jennifer A.), Demissie, S. (Serkalem), Davis, B.R. (Barry), Wiggins, K.L. (Kerri), Tranah, G.J. (Gregory), Lange, L.A. (Leslie), Sotoodehnia, N. (Nona), Stott, D.J. (David. J.), Franco, O.H. (Oscar), Launer, L.J. (Lenore), Stürmer, T., Taylor, K.D. (Kent), Cupples, L.A. (Adrienne), Eckfeldt, J.H. (John), Smith, N.L. (Nicholas), Liu, Y. (YongMei), Wilson, J.G. (James), Heckbert, S.R. (Susan), Buckley, B.M. (Brendan M.), Ikram, M.A. (Arfan), Boerwinkle, E.A. (Eric), Chen, Y.-D.I. (Yii-Der Ida), De Craen, A.J.M. (Anton J. M.), Uitterlinden, A.G. (André), Rotter, J.I. (Jerome I.), Ford, I., Hofman, A. (Albert), Sattar, N. (Naveed), Slagboom, P.E. (Eline), Westendorp, R.G.J. (Rudi), Gudnason, V. (Vilmundur), Vasan, R.S. (Ramachandran S.), Lumley, T. (Thomas), Cummings, S.R. (Steven R.), Taylor, H.A. (Herman), Post, W. (Wendy), Jukema, J.W. (Jan Wouter), Stricker, B.H.Ch. (Bruno), Whitsel, E.A. (Eric), Psaty, B.M. (Bruce), and Arnett, D.K. (Donna)

Abstract

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk ofmajor cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regressionmodels to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from t

Published
2015
Full Text
View/download PDF

23. Novel Associations of Multiple Genetic Loci With Plasma Levels of Factor VII, Factor VIII, and von Willebrand Factor : The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium

Author

Smith, N.L., Chen, M.H., Dehghan, A., Strachan, D.P., Basu, S., Soranzo, N., Hayward, C., Rudan, Igor, Sabater-Lleal, M., Bis, J.C., de Maat, M.P., Rumley, A., Kong, X., Yang, Q., Williams, F.M., Vitart, V., Campbell, H., Mälarstig, A., Wiggins, K.L., van Duijn, C.M., McArdle, W.L., Pankow, J.S., Johnson, A.D., Silveira, A., McKnight, B., Uitterlinden, A.G., Wellcome Trust Case Control Consortium, Aleksić, N., Meigs, J.B., Peters, A., Koenig, W., Cushman, M., Kathiresan, S., Rotter, J.I., Bovill, E.G., Hofman, A., Boerwinkle, E., Tofler, G.H., Peden, J.F., Psaty, B.M., Leebeek, F., Folsom, A.R., Larson, M.G., Spector, T.D., Wright, A.F., Wilson, J.F., Hamsten, A., Lumley, T., Witteman, J.C., Tang, W., and O'Donnell, C.J.

Subjects
hemic and lymphatic diseases, genome-wide association study, plasma levels, Factor VII, Factor VIII, von Willebrand Factor, genetic loci
Abstract

Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels. The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (

Published
2010

24. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Author

Postmus, D. (Douwe), Trompet, S. (Stella), Deshmukh, H. (Harshal), Barnes, M.J. (Michael), Li, X. (Xiaohui), Warren, H. (Helen), Chasman, D.I. (Daniel), Zhou, K. (Kaixin), Arsenault, B.J. (Benoit J.), Donnelly, L.A. (Louise), Wiggins, K.L. (Kerri), Avery, C.L., Griffin, P. (Paula), Feng, Q. (Qiping), Taylor, K.D. (Kent), Li, G. (Guo), Evans, D.S. (Daniel), Smith, A.V. (Davey), Keyser, C.E. (Catherina Elisabeth) de, Johnson, A.D. (Andrew), Craen, A.J. (Anton) de, Stott, D.J. (David. J.), Buckley, B.M. (Brendan M.), Ford, I., Westendorp, R.G.J. (Rudi), Slagboom, P.E. (Eline), Sattar, N. (Naveed), Munroe, P. (Patricia), Sever, P. (Peter), Poulter, N.R. (Neil), Stanton, A. (Alice), Shields, D.C. (Denis C.), O'Brien, E. (Eoin), Shaw-Hawkins, S. (Sue), Chen, Y.-D.I. (Ida), Nickerson, D.A. (Deborah), Smith, J.D. (Joshua D.), Dubé, G.P. (Gregory), Boekholdt, S.M. (Matthijs), Hovingh, G.K. (Kees), Kastelein, J.J.P. (John), Mckeigue, P.M. (Paul), Betteridge, J. (John), Neil, A. (Andrew), Durrington, P.N. (Paul), Doney, A.S.F. (Alex), Carr, F. (Fiona), Morris, A.D. (Andrew), McCarthy, M.I. (Mark), Groop, L. (Leif), Ahlqvist, E. (Emma), Barroso, I.E. (Inês), Blackwell, K.L. (Kimberly), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panagiotis), Duncanson, A. (Audrey), Jankowski, J.A. (Janusz Antoni), Markus, H.S. (Hugh), Mathew, C.G. (Christopher G.), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Viswanathan, A.C. (Ananth), Wood, N.W. (Nicholas), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Donnelly, P. (Peter), Langford, C. (Cordelia), Hunt, S.E. (Sarah), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, M. (Matthew), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Bis, J.C. (Joshua), Rice, K.M. (Kenneth), Smith, N.L. (Nicholas), Lumley, T. (Thomas), Whitsel, E.A. (Eric), Stürmer, T., Boerwinkle, E.A. (Eric), Ngwa, J.S., O'Donnell, C.J. (Christopher J.), Vasan, R.S. (Ramachandran Srini), Wei, W.-Q. (Wei-Qi), Wilke, R.A. (Russell A.), Liu, C.-T. (Ching-Ti), Sun, F. (Fangui), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Post, W. (Wendy), Sotoodehnia, N. (Nona), Arnold, A.M. (Alice), Stafford, J.M. (Jeanette M.), Ding, J. (Jingzhong), Herrington, D.M. (David), Kritchevsky, S.B. (Stephen), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Harris, T.B. (Tamara), Chu, A.Y. (Audrey), Giulianini, F. (Franco), MacFadyen, J.G. (Jean G.), Barratt, B.J. (Bryan J.), Nyberg, F. (Fredrik), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Emilsson, V. (Valur), Franco, O.H. (Oscar), Ridker, P.M. (Paul), Gudnason, V. (Vilmundur), Liu, Y. (YongMei), Denny, J.C. (Joshua C.), Ballantyne, C. (Christie), Rotter, J.I. (Jerome I.), Cupples, L.A. (Adrienne), Psaty, B.M. (Bruce), Tardif, J.-C. (Jean-Claude), Colhoun, H.M. (H.), Hitman, G.A. (Graham), Krauss, R.M. (Ronald), Jukema, J.W. (Jan Wouter), Caulfield, M. (Mark), Postmus, D. (Douwe), Trompet, S. (Stella), Deshmukh, H. (Harshal), Barnes, M.J. (Michael), Li, X. (Xiaohui), Warren, H. (Helen), Chasman, D.I. (Daniel), Zhou, K. (Kaixin), Arsenault, B.J. (Benoit J.), Donnelly, L.A. (Louise), Wiggins, K.L. (Kerri), Avery, C.L., Griffin, P. (Paula), Feng, Q. (Qiping), Taylor, K.D. (Kent), Li, G. (Guo), Evans, D.S. (Daniel), Smith, A.V. (Davey), Keyser, C.E. (Catherina Elisabeth) de, Johnson, A.D. (Andrew), Craen, A.J. (Anton) de, Stott, D.J. (David. J.), Buckley, B.M. (Brendan M.), Ford, I., Westendorp, R.G.J. (Rudi), Slagboom, P.E. (Eline), Sattar, N. (Naveed), Munroe, P. (Patricia), Sever, P. (Peter), Poulter, N.R. (Neil), Stanton, A. (Alice), Shields, D.C. (Denis C.), O'Brien, E. (Eoin), Shaw-Hawkins, S. (Sue), Chen, Y.-D.I. (Ida), Nickerson, D.A. (Deborah), Smith, J.D. (Joshua D.), Dubé, G.P. (Gregory), Boekholdt, S.M. (Matthijs), Hovingh, G.K. (Kees), Kastelein, J.J.P. (John), Mckeigue, P.M. (Paul), Betteridge, J. (John), Neil, A. (Andrew), Durrington, P.N. (Paul), Doney, A.S.F. (Alex), Carr, F. (Fiona), Morris, A.D. (Andrew), McCarthy, M.I. (Mark), Groop, L. (Leif), Ahlqvist, E. (Emma), Barroso, I.E. (Inês), Blackwell, K.L. (Kimberly), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panagiotis), Duncanson, A. (Audrey), Jankowski, J.A. (Janusz Antoni), Markus, H.S. (Hugh), Mathew, C.G. (Christopher G.), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Viswanathan, A.C. (Ananth), Wood, N.W. (Nicholas), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Donnelly, P. (Peter), Langford, C. (Cordelia), Hunt, S.E. (Sarah), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, M. (Matthew), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Bis, J.C. (Joshua), Rice, K.M. (Kenneth), Smith, N.L. (Nicholas), Lumley, T. (Thomas), Whitsel, E.A. (Eric), Stürmer, T., Boerwinkle, E.A. (Eric), Ngwa, J.S., O'Donnell, C.J. (Christopher J.), Vasan, R.S. (Ramachandran Srini), Wei, W.-Q. (Wei-Qi), Wilke, R.A. (Russell A.), Liu, C.-T. (Ching-Ti), Sun, F. (Fangui), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Post, W. (Wendy), Sotoodehnia, N. (Nona), Arnold, A.M. (Alice), Stafford, J.M. (Jeanette M.), Ding, J. (Jingzhong), Herrington, D.M. (David), Kritchevsky, S.B. (Stephen), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Harris, T.B. (Tamara), Chu, A.Y. (Audrey), Giulianini, F. (Franco), MacFadyen, J.G. (Jean G.), Barratt, B.J. (Bryan J.), Nyberg, F. (Fredrik), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Emilsson, V. (Valur), Franco, O.H. (Oscar), Ridker, P.M. (Paul), Gudnason, V. (Vilmundur), Liu, Y. (YongMei), Denny, J.C. (Joshua C.), Ballantyne, C. (Christie), Rotter, J.I. (Jerome I.), Cupples, L.A. (Adrienne), Psaty, B.M. (Bruce), Tardif, J.-C. (Jean-Claude), Colhoun, H.M. (H.), Hitman, G.A. (Graham), Krauss, R.M. (Ronald), Jukema, J.W. (Jan Wouter), and Caulfield, M. (Mark)

Published
2014
Full Text
View/download PDF

25. Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

Author

Jensen, R.A. (Richard), Sim, X. (Xueling), Li, X. (Xiaohui), Cotch, M.F. (Mary Frances), Ikram, M.K. (Kamran), Holliday, E.G. (Elizabeth), Eiriksdottir, G. (Gudny), Harris, T.B. (Tamara), Jonasson, F. (Fridbert), Klein, B.E.K. (Barbara), Launer, L.J. (Lenore), Smith, A.V. (Albert Vernon), Boerwinkle, E.A. (Eric), Cheung, N. (Ning), Hewit, A.W. (Alex), Liew, G. (Gerald), Mitchell, P. (Paul), Wang, J.J. (Jie Jin), Attia, J. (John), Scott, R.J. (Rodney), Glazer, N.L. (Nicole), Lumley, T. (Thomas), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Taylor, K. (Kent), Hofman, A. (Albert), Jong, P.T.V.M. (Paulus) de, Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Tay, W.-T. (Wan-Ting), Teo, Y.Y. (Yik Ying), Seielstad, M. (Mark), Liu, J. (Jianjun), Cheng, C-Y. (Ching-Yu), Saw, S-M. (Seang-Mei), Aung, T. (Tin), Ganesh, S.K. (Santhi), O'Donnell, C.J. (Christopher), Nalls, M.A. (Michael), Wiggins, K.L. (Kerri), Kuo, J.Z. (Jane), Duijn, C.M. (Cornelia) van, Gudnason, V. (Vilmundur), Klein, R. (Ronald), Siscovick, D.S. (David), Rotter, J.I. (Jerome), Tai, E.S. (Shyong), Vingerling, J.R. (Hans), Wong, T.Y. (Tien Yin), Jensen, R.A. (Richard), Sim, X. (Xueling), Li, X. (Xiaohui), Cotch, M.F. (Mary Frances), Ikram, M.K. (Kamran), Holliday, E.G. (Elizabeth), Eiriksdottir, G. (Gudny), Harris, T.B. (Tamara), Jonasson, F. (Fridbert), Klein, B.E.K. (Barbara), Launer, L.J. (Lenore), Smith, A.V. (Albert Vernon), Boerwinkle, E.A. (Eric), Cheung, N. (Ning), Hewit, A.W. (Alex), Liew, G. (Gerald), Mitchell, P. (Paul), Wang, J.J. (Jie Jin), Attia, J. (John), Scott, R.J. (Rodney), Glazer, N.L. (Nicole), Lumley, T. (Thomas), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Taylor, K. (Kent), Hofman, A. (Albert), Jong, P.T.V.M. (Paulus) de, Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Tay, W.-T. (Wan-Ting), Teo, Y.Y. (Yik Ying), Seielstad, M. (Mark), Liu, J. (Jianjun), Cheng, C-Y. (Ching-Yu), Saw, S-M. (Seang-Mei), Aung, T. (Tin), Ganesh, S.K. (Santhi), O'Donnell, C.J. (Christopher), Nalls, M.A. (Michael), Wiggins, K.L. (Kerri), Kuo, J.Z. (Jane), Duijn, C.M. (Cornelia) van, Gudnason, V. (Vilmundur), Klein, R. (Ronald), Siscovick, D.S. (David), Rotter, J.I. (Jerome), Tai, E.S. (Shyong), Vingerling, J.R. (Hans), and Wong, T.Y. (Tien Yin)

Abstract

Background: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. Methods: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. Results: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, 21.360.23 (beta 6 standard error), p=6.661029. Evidence suggests this was a false positive finding. The minor allele frequency was low (,2%), the quality of the imputation was moderate (r2 ,0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. Conclusions: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

Published
2013
Full Text
View/download PDF

26. Genetic Loci for Retinal Arteriolar Microcirculation

Author

Sim, X. (Xueling), Jensen, R.A. (Richard), Ikram, M.K. (Kamran), Cotch, M.F. (Mary Frances), Li, X. (Xiaohui), MacGregor, S. (Stuart), Xie, J. (Jing), Smith, A.V. (Albert Vernon), Boerwinkle, E.A. (Eric), Mitchell, P. (Paul), Klein, R. (Ronald), Klein, B.E.K. (Barbara), Glazer, N.L. (Nicole), Lumley, T. (Thomas), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Jong, P.T.V.M. (Paulus) de, Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Aspelund, T. (Thor), Eiriksdottir, G. (Gudny), Harris, T.B. (Tamara), Jonasson, F. (Fridbert), Launer, L.J. (Lenore), Attia, J. (John), Baird, P.N. (Paul), Harrap, S. (Stephen), Holliday, E.G. (Elizabeth), Inouye, M. (Michael), Rochtchina, E. (Elena), Scott, R.J. (Rodney), Viswanathan, A.C. (Ananth), Li, G. (Guo), Smith, N.L. (Nicholas), Wiggins, K.L. (Kerri), Kuo, J.Z. (Jane), Taylor, K.D. (Kent), Hewit, A.W. (Alex), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Sun, C. (Cong), Young, T.L. (Terri), Mackey, D.A. (David), Zuydam, N.R. (Natalie) van, Doney, A.S.F. (Alex), Palmer, C.N.A. (Colin), Morris, A.D. (Andrew), Rotter, J.I. (Jerome), Tai, E.S. (Shyong), Gudnason, V. (Vilmundur), Vingerling, J.R. (Hans), Siscovick, D.S. (David), Wang, J.J. (Jie Jin), Wong, T.Y. (Tien Yin), Sim, X. (Xueling), Jensen, R.A. (Richard), Ikram, M.K. (Kamran), Cotch, M.F. (Mary Frances), Li, X. (Xiaohui), MacGregor, S. (Stuart), Xie, J. (Jing), Smith, A.V. (Albert Vernon), Boerwinkle, E.A. (Eric), Mitchell, P. (Paul), Klein, R. (Ronald), Klein, B.E.K. (Barbara), Glazer, N.L. (Nicole), Lumley, T. (Thomas), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Jong, P.T.V.M. (Paulus) de, Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Aspelund, T. (Thor), Eiriksdottir, G. (Gudny), Harris, T.B. (Tamara), Jonasson, F. (Fridbert), Launer, L.J. (Lenore), Attia, J. (John), Baird, P.N. (Paul), Harrap, S. (Stephen), Holliday, E.G. (Elizabeth), Inouye, M. (Michael), Rochtchina, E. (Elena), Scott, R.J. (Rodney), Viswanathan, A.C. (Ananth), Li, G. (Guo), Smith, N.L. (Nicholas), Wiggins, K.L. (Kerri), Kuo, J.Z. (Jane), Taylor, K.D. (Kent), Hewit, A.W. (Alex), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Sun, C. (Cong), Young, T.L. (Terri), Mackey, D.A. (David), Zuydam, N.R. (Natalie) van, Doney, A.S.F. (Alex), Palmer, C.N.A. (Colin), Morris, A.D. (Andrew), Rotter, J.I. (Jerome), Tai, E.S. (Shyong), Gudnason, V. (Vilmundur), Vingerling, J.R. (Hans), Siscovick, D.S. (David), Wang, J.J. (Jie Jin), and Wong, T.Y. (Tien Yin)

Abstract

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value < 5 x 10(-8) This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value= 2.11 x 10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myoca

Published
2013
Full Text
View/download PDF

27. 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
Full Text
View/download PDF

28. Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

Author

Holliday, E.G., Maguire, J.M., Evans, T-J, Koblar, S.A., Jannes, J., Sturm, J.W., Hankey, G.J., Baker, R., Golledge, J., Parsons, M.W., Malik, R., McEvoy, M., Biros, E., Lewis, M.D., Lincz, L.F., Peel, R., Oldmeadow, C., Smith, W., Moscato, P., Barlera, S., Bevan, S., Bis, J.C., Boerwinkle, E., Boncoraglio, G.B., Brott, T.G., Brown, R.D., Cheng, Y-C, Cole, J.W., Cotlarciuc, I., Devan, W.J., Fornage, M., Furie, K.L., Grétarsdóttir, S., Gschwendtner, A., Ikram, M.A., Longstreth, W.T., Meschia, J.F., Mitchell, B.D., Mosley, T.H., Nalls, M.A., Parati, E.A., Psaty, B.M., Sharma, P., Stefansson, K., Thorleifsson, G., Thorsteinsdottir, U., Traylor, M., Verhaaren, B.F.J., Wiggins, K.L., Worrall, B.B., Sudlow, C., Rothwell, P.M., Farrall, M., Dichgans, M., Rosand, J., Markus, H.S., Scott, R.J., Levi, C., Attia, J., Holliday, E.G., Maguire, J.M., Evans, T-J, Koblar, S.A., Jannes, J., Sturm, J.W., Hankey, G.J., Baker, R., Golledge, J., Parsons, M.W., Malik, R., McEvoy, M., Biros, E., Lewis, M.D., Lincz, L.F., Peel, R., Oldmeadow, C., Smith, W., Moscato, P., Barlera, S., Bevan, S., Bis, J.C., Boerwinkle, E., Boncoraglio, G.B., Brott, T.G., Brown, R.D., Cheng, Y-C, Cole, J.W., Cotlarciuc, I., Devan, W.J., Fornage, M., Furie, K.L., Grétarsdóttir, S., Gschwendtner, A., Ikram, M.A., Longstreth, W.T., Meschia, J.F., Mitchell, B.D., Mosley, T.H., Nalls, M.A., Parati, E.A., Psaty, B.M., Sharma, P., Stefansson, K., Thorleifsson, G., Thorsteinsdottir, U., Traylor, M., Verhaaren, B.F.J., Wiggins, K.L., Worrall, B.B., Sudlow, C., Rothwell, P.M., Farrall, M., Dichgans, M., Rosand, J., Markus, H.S., Scott, R.J., Levi, C., and Attia, J.

Abstract

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10 -8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10 -4; discovery and replication combined OR = 1.21, P = 4.7 × 10 -8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

Published
2012

30. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Author

International Consortium for Blood Pressure Genome-Wide Association Studies, CARDIoGRAM consortium, CKDGen Consortium, KidneyGen Consortium, EchoGen consortium, CHARGE-HF consortium, Ehret, G.B., Munroe, P.B., Rice, K.M., Bochud, M., Johnson, A.D., Chasman, D.I., Smith, A.V., Tobin, M.D., Verwoert, G.C., Hwang, S.J., Pihur, V., Vollenweider, P., O'Reilly, P.F., Amin, N., Bragg-Gresham, J.L., Teumer, A., Glazer, N.L., Launer, L., Zhao, J.H., Aulchenko, Y., Heath, S., Sõber, S., Parsa, A., Luan, J., Arora, P., Dehghan, A., Zhang, F., Lucas, G., Hicks, A.A., Jackson, A.U., Peden, J.F., Tanaka, T., Wild, S.H., Rudan, I., Igl, W., Milaneschi, Y., Parker, A.N., Fava, C., Chambers, J.C., Fox, E.R., Kumari, M., Go, M.J., van der Harst, P., Kao, W.H., Sjögren, M., Vinay, D.G., Alexander, M., Tabara, Y., Shaw-Hawkins, S., Whincup, P.H., Liu, Y., Shi, G., Kuusisto, J., Tayo, B., Seielstad, M., Sim, X., Nguyen, K.D., Lehtimäki, T., Matullo, G., Wu, Y., Gaunt, T.R., Onland-Moret, N.C., Cooper, M.N., Platou, C.G., Org, E., Hardy, R., Dahgam, S., Palmen, J., Vitart, V., Braund, P.S., Kuznetsova, T., Uiterwaal, C.S., Adeyemo, A., Palmas, W., Campbell, H., Ludwig, B., Tomaszewski, M., Tzoulaki, I., Palmer, N.D., Aspelund, T., Garcia, M., Chang, Y.P., O'Connell, J.R., Steinle, N.I., Grobbee, D.E., Arking, D.E., Kardia, S.L., Morrison, A.C., Hernandez, D., Najjar, S., McArdle, W.L., Hadley, D., Brown, M.J., Connell, J.M., Hingorani, A.D., Day, I.N., Lawlor, D.A., Beilby, J.P., Lawrence, R.W., Clarke, R., Hopewell, J.C., Ongen, H., Dreisbach, A.W., Li, Y., Young, J.H., Bis, J.C., Kähönen, M., Viikari, J., Adair, L.S., Lee, N.R., Chen, M.H., Olden, M., Pattaro, C., Bolton, J.A., Köttgen, A., Bergmann, S., Mooser, V., Chaturvedi, N., Frayling, T.M., Islam, M., Jafar, T.H., Erdmann, J., Kulkarni, S.R., Bornstein, S.R., Grässler, J., Groop, L., Voight, B.F., Kettunen, J., Howard, P., Taylor, A., Guarrera, S., Ricceri, F., Emilsson, V., Plump, A., Barroso, I., Khaw, K.T., Weder, A.B., Hunt, S.C., Sun, Y.V., Bergman, R.N., Collins, F.S., Bonnycastle, L.L., Scott, L.J., Stringham, H.M., Peltonen, L., Perola, M., Vartiainen, E., Brand, S.M., Staessen, J.A., Wang, T.J., Burton, P.R., Artigas, M.S., Dong, Y., Snieder, H., Wang, X., Zhu, H., Lohman, K.K., Rudock, M.E., Heckbert, S.R., Smith, N.L., Wiggins, K.L., Doumatey, A., Shriner, D., Veldre, G., Viigimaa, M., Kinra, S., Prabhakaran, D., Tripathy, V., Langefeld, C.D., Rosengren, A., Thelle, D.S., Corsi, A.M., Singleton, A., Forrester, T., Hilton, G., McKenzie, C.A., Salako, T., Iwai, N., Kita, Y., Ogihara, T., Ohkubo, T., Okamura, T., Ueshima, H., Umemura, S., Eyheramendy, S., Meitinger, T., Wichmann, H.E., Cho, Y.S., Kim, H.L., Lee, J.Y., Scott, J., Sehmi, J.S., Zhang, W., Hedblad, B., Nilsson, P., Smith, G.D., Wong, A., Narisu, N., Stančáková, A., Raffel, L.J., Yao, J., Kathiresan, S., O'Donnell, C.J., Schwartz, S.M., Ikram, M.A., Longstreth, W.T., Mosley, T.H., Seshadri, S., Shrine, N.R., Wain, L.V., Morken, M.A., Swift, A.J., Laitinen, J., Prokopenko, I., Zitting, P., Cooper, J.A., Humphries, S.E., Danesh, J., Rasheed, A., Goel, A., Hamsten, A., Watkins, H., Bakker, S.J., van Gilst, W.H., Janipalli, C.S., Mani, K.R., Yajnik, C.S., Hofman, A., Mattace-Raso, F.U., Oostra, B.A., Demirkan, A., Isaacs, A., Rivadeneira, F., Lakatta, E.G., Orru, M., Scuteri, A., Ala-Korpela, M., Kangas, A.J., Lyytikäinen, L.P., Soininen, P., Tukiainen, T., Würtz, P., Ong, R.T., Dörr, M., Kroemer, H.K., Völker, U., Völzke, H., Galan, P., Hercberg, S., Lathrop, M., Zelenika, D., Deloukas, P., Mangino, M., Spector, T.D., Zhai, G., Meschia, J.F., Nalls, M.A., Sharma, P., Terzic, J., Kumar, M.V., Denniff, M., Zukowska-Szczechowska, E., Wagenknecht, L.E., Fowkes, F.G., Charchar, F.J., Schwarz, P.E., Hayward, C., Guo, X., Rotimi, C., Bots, M.L., Brand, E., Samani, N.J., Polasek, O., Talmud, P.J., Nyberg, F., Kuh, D., Laan, M., Hveem, K., Palmer, L.J., van der Schouw, Y.T., Casas, J.P., Mohlke, K.L., Vineis, P., Raitakari, O., Ganesh, S.K., Wong, T.Y., Tai, E.S., Cooper, R.S., Laakso, M., Rao, D.C., Harris, T.B., Morris, R.W., Dominiczak, A.F., Kivimaki, M., Marmot, M.G., Miki, T., Saleheen, D., Chandak, G.R., Coresh, J., Navis, G., Salomaa, V., Han, B.G., Zhu, X., Kooner, J.S., Melander, O., Ridker, P.M., Bandinelli, S., Gyllensten, U.B., Wright, A.F., Wilson, J.F., Ferrucci, L., Farrall, M., Tuomilehto, J., Pramstaller, P.P., Elosua, R., Soranzo, N., Sijbrands, E.J., Altshuler, D., Loos, R.J., Shuldiner, A.R., Gieger, C., Meneton, P., Uitterlinden, A.G., Wareham, N.J., Gudnason, V., Rotter, J.I., Rettig, R., Uda, M., Strachan, D.P., Witteman, J.C., Hartikainen, A.L., Beckmann, J.S., Boerwinkle, E., Vasan, R.S., Boehnke, M., Larson, M.G., Järvelin, M.R., Psaty, B.M., Abecasis, G.R., Chakravarti, A., Elliott, P., van Duijn, C.M., Newton-Cheh, C., Levy, D., Caulfield, M.J., Johnson, T., Tang, H., Knowles, J., Hlatky, M., Fortmann, S., Assimes, T.L., Quertermous, T., Go, A., Iribarren, C., Absher, D., Risch, N., Myers, R., Sidney, S., Ziegler, A., Schillert, A., Bickel, C., Sinning, C., Rupprecht, H.J., Lackner, K., Wild, P., Schnabel, R., Blankenberg, S., Zeller, T., Münzel, T., Perret, C., Cambien, F., Tiret, L., Nicaud, V., Proust, C., Uitterlinden, A., van Duijn, C., Whitteman, J., Cupples, L.A., Demissie-Banjaw, S., Ramachandran, V., Smith, A., Folsom, A., Morrison, A., Chen, I.Y., Bis, J., Volcik, K., Rice, K., Taylor, K.D., Marciante, K., Smith, N., Glazer, N., Heckbert, S., Harris, T., Lumley, T., Kong, A., Thorleifsson, G., Thorgeirsson, G., Holm, H., Gulcher, J.R., Stefansson, K., Andersen, K., Gretarsdottir, S., Thorsteinsdottir, U., Preuss, M., Schreiber, S., König, I.R., Lieb, W., Hengstenberg, C., Schunkert, H., Fischer, M., Grosshennig, A., Medack, A., Stark, K., Linsel-Nitschke, P., Bruse, P., Aherrahrou, Z., Peters, A., Loley, C., Willenborg, C., Nahrstedt, J., Freyer, J., Gulde, S., Doering, A., Meisinger, C., Klopp, N., Illig, T., Meinitzer, A., Tomaschitz, A., Halperin, E., Dobnig, H., Scharnagl, H., Kleber, M., Laaksonen, R., Pilz, S., Grammer, T.B., Stojakovic, T., Renner, W., März, W., Böhm, B.O., Winkelmann, B.R., Winkler, K., Hoffmann, M.M., Siscovick, D.S., Musunuru, K., Barbalic, M., Guiducci, C., Burtt, N., Gabriel, S.B., Stewart, A.F., Wells, G.A., Chen, L., Jarinova, O., Roberts, R., McPherson, R., Dandona, S., Pichard, A.D., Rader, D.J., Devaney, J., Lindsay, J.M., Kent, K.M., Qu, L., Satler, L., Burnett, M.S., Li, M., Reilly, M.P., Wilensky, R., Waksman, R., Epstein, S., Matthai, W., Knouff, C.W., Waterworth, D.M., Hakonarson, H.H., Walker, M.C., Hall, A.S., Balmforth, A.J., Wright, B.J., Nelson, C., Thompson, J.R., Ball, S.G., Felix, J.F., Demissie, S., Loehr, L.R., Rosamond, W.D., Folsom, A.R., Benjamin, E., Aulchenko, Y.S., Haritunians, T., Couper, D., Murabito, J., Wang, Y.A., Stricker, B.H., Gottdiener, J.S., Chang, P.P., Willerson, J.T., Böger, C.A., Fuchsberger, C., Gao, X., Yang, Q., Schmidt, H., Ketkar, S., Paré, G., Atkinson, E.J., Lohman, K., Cornelis, M.C., Probst-Hensch, N.M., Kronenberg, F., Tönjes, A., Eiriksdottir, G., Launer, L.J., Rampersaud, E., Mitchell, B.D., Struchalin, M., Cavalieri, M., Giallauria, F., Metter, J., de Boer, J., Siscovick, D., Zillikens, M.C., Feitosa, M., Province, M., de Andrade, M., Turner, S.T., Wild, P.S., Schnabel, R.B., Wilde, S., Munzel, T.F., Leak, T.S., Koenig, W., Zgaga, L., Zemunik, T., Kolcic, I., Minelli, C., Hu, F.B., Johansson, A., Zaboli, G., Ellinghaus, D., Imboden, M., Nitsch, D., Brandstätter, A., Kollerits, B., Kedenko, L., Mägi, R., Stumvoll, M., Kovacs, P., Boban, M., Campbell, S., Endlich, K., Nauck, M., Badola, S., Curhan, G.C., Franke, A., Rochat, T., Paulweber, B., Wang, W., Schmidt, R., Shlipak, M.G., Borecki, I., Krämer, B.K., Gyllensten, U., Hastie, N., Heid, I.M., Fox, C.S., Felix, S.B., Watzinger, N., Homuth, G., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, R.J., Greiser, K.H., Deckers, J.W., Stritzke, J., Lackner, K.J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, M.M., Werdan, K., Mitchell, G.F., Arnett, D.K., Blettner, M., Friedrich, N., Benjamin, E.J., Lord, G.M., Gale, D.P., Wass, M.N., Ahmadi, K.R., Beckmann, J., Bilo, H.J., Cook, H.T., Cotlarciuc, I., Davey Smith, G., de Silva, R., Deng, G., Devuyst, O., Dikkeschei, L.D., Dimkovic, N., Dockrell, M., Dominiczak, A., Ebrahim, S., Eggermann, T., Floege, J., Forouhi, N.G., Gansevoort, R.T., Han, X., Homan van der Heide, J.J., Hepkema, B.G., Hernandez-Fuentes, M., Hypponen, E., de Jong, P.E., Kleefstra, N., Lagou, V., Lapsley, M., Luttropp, K., Maréchal, C., Nordfors, L., Penninx, B.W., Perucha, E., Pouta, A., Roderick, P.J., Ruokonen, A., Sanna, S., Schalling, M., Schlessinger, D., Schlieper, G., Seelen, M.A., Smit, J.H., Stenvinkel, P., Sternberg, M.J., Swaminathan, R., Ubink-Veltmaat, L.J., Wallace, C., Waterworth, D., Zerres, K., Waeber, G., Maxwell, P.H., McCarthy, M.I., Jarvelin, M.R., Lightstone, L., International Consortium for Blood Pressure Genome-Wide Association Studies, CARDIoGRAM consortium, CKDGen Consortium, KidneyGen Consortium, EchoGen consortium, CHARGE-HF consortium, Ehret, G.B., Munroe, P.B., Rice, K.M., Bochud, M., Johnson, A.D., Chasman, D.I., Smith, A.V., Tobin, M.D., Verwoert, G.C., Hwang, S.J., Pihur, V., Vollenweider, P., O'Reilly, P.F., Amin, N., Bragg-Gresham, J.L., Teumer, A., Glazer, N.L., Launer, L., Zhao, J.H., Aulchenko, Y., Heath, S., Sõber, S., Parsa, A., Luan, J., Arora, P., Dehghan, A., Zhang, F., Lucas, G., Hicks, A.A., Jackson, A.U., Peden, J.F., Tanaka, T., Wild, S.H., Rudan, I., Igl, W., Milaneschi, Y., Parker, A.N., Fava, C., Chambers, J.C., Fox, E.R., Kumari, M., Go, M.J., van der Harst, P., Kao, W.H., Sjögren, M., Vinay, D.G., Alexander, M., Tabara, Y., Shaw-Hawkins, S., Whincup, P.H., Liu, Y., Shi, G., Kuusisto, J., Tayo, B., Seielstad, M., Sim, X., Nguyen, K.D., Lehtimäki, T., Matullo, G., Wu, Y., Gaunt, T.R., Onland-Moret, N.C., Cooper, M.N., Platou, C.G., Org, E., Hardy, R., Dahgam, S., Palmen, J., Vitart, V., Braund, P.S., Kuznetsova, T., Uiterwaal, C.S., Adeyemo, A., Palmas, W., Campbell, H., Ludwig, B., Tomaszewski, M., Tzoulaki, I., Palmer, N.D., Aspelund, T., Garcia, M., Chang, Y.P., O'Connell, J.R., Steinle, N.I., Grobbee, D.E., Arking, D.E., Kardia, S.L., Morrison, A.C., Hernandez, D., Najjar, S., McArdle, W.L., Hadley, D., Brown, M.J., Connell, J.M., Hingorani, A.D., Day, I.N., Lawlor, D.A., Beilby, J.P., Lawrence, R.W., Clarke, R., Hopewell, J.C., Ongen, H., Dreisbach, A.W., Li, Y., Young, J.H., Bis, J.C., Kähönen, M., Viikari, J., Adair, L.S., Lee, N.R., Chen, M.H., Olden, M., Pattaro, C., Bolton, J.A., Köttgen, A., Bergmann, S., Mooser, V., Chaturvedi, N., Frayling, T.M., Islam, M., Jafar, T.H., Erdmann, J., Kulkarni, S.R., Bornstein, S.R., Grässler, J., Groop, L., Voight, B.F., Kettunen, J., Howard, P., Taylor, A., Guarrera, S., Ricceri, F., Emilsson, V., Plump, A., Barroso, I., Khaw, K.T., Weder, A.B., Hunt, S.C., Sun, Y.V., Bergman, R.N., Collins, F.S., Bonnycastle, L.L., Scott, L.J., Stringham, H.M., Peltonen, L., Perola, M., Vartiainen, E., Brand, S.M., Staessen, J.A., Wang, T.J., Burton, P.R., Artigas, M.S., Dong, Y., Snieder, H., Wang, X., Zhu, H., Lohman, K.K., Rudock, M.E., Heckbert, S.R., Smith, N.L., Wiggins, K.L., Doumatey, A., Shriner, D., Veldre, G., Viigimaa, M., Kinra, S., Prabhakaran, D., Tripathy, V., Langefeld, C.D., Rosengren, A., Thelle, D.S., Corsi, A.M., Singleton, A., Forrester, T., Hilton, G., McKenzie, C.A., Salako, T., Iwai, N., Kita, Y., Ogihara, T., Ohkubo, T., Okamura, T., Ueshima, H., Umemura, S., Eyheramendy, S., Meitinger, T., Wichmann, H.E., Cho, Y.S., Kim, H.L., Lee, J.Y., Scott, J., Sehmi, J.S., Zhang, W., Hedblad, B., Nilsson, P., Smith, G.D., Wong, A., Narisu, N., Stančáková, A., Raffel, L.J., Yao, J., Kathiresan, S., O'Donnell, C.J., Schwartz, S.M., Ikram, M.A., Longstreth, W.T., Mosley, T.H., Seshadri, S., Shrine, N.R., Wain, L.V., Morken, M.A., Swift, A.J., Laitinen, J., Prokopenko, I., Zitting, P., Cooper, J.A., Humphries, S.E., Danesh, J., Rasheed, A., Goel, A., Hamsten, A., Watkins, H., Bakker, S.J., van Gilst, W.H., Janipalli, C.S., Mani, K.R., Yajnik, C.S., Hofman, A., Mattace-Raso, F.U., Oostra, B.A., Demirkan, A., Isaacs, A., Rivadeneira, F., Lakatta, E.G., Orru, M., Scuteri, A., Ala-Korpela, M., Kangas, A.J., Lyytikäinen, L.P., Soininen, P., Tukiainen, T., Würtz, P., Ong, R.T., Dörr, M., Kroemer, H.K., Völker, U., Völzke, H., Galan, P., Hercberg, S., Lathrop, M., Zelenika, D., Deloukas, P., Mangino, M., Spector, T.D., Zhai, G., Meschia, J.F., Nalls, M.A., Sharma, P., Terzic, J., Kumar, M.V., Denniff, M., Zukowska-Szczechowska, E., Wagenknecht, L.E., Fowkes, F.G., Charchar, F.J., Schwarz, P.E., Hayward, C., Guo, X., Rotimi, C., Bots, M.L., Brand, E., Samani, N.J., Polasek, O., Talmud, P.J., Nyberg, F., Kuh, D., Laan, M., Hveem, K., Palmer, L.J., van der Schouw, Y.T., Casas, J.P., Mohlke, K.L., Vineis, P., Raitakari, O., Ganesh, S.K., Wong, T.Y., Tai, E.S., Cooper, R.S., Laakso, M., Rao, D.C., Harris, T.B., Morris, R.W., Dominiczak, A.F., Kivimaki, M., Marmot, M.G., Miki, T., Saleheen, D., Chandak, G.R., Coresh, J., Navis, G., Salomaa, V., Han, B.G., Zhu, X., Kooner, J.S., Melander, O., Ridker, P.M., Bandinelli, S., Gyllensten, U.B., Wright, A.F., Wilson, J.F., Ferrucci, L., Farrall, M., Tuomilehto, J., Pramstaller, P.P., Elosua, R., Soranzo, N., Sijbrands, E.J., Altshuler, D., Loos, R.J., Shuldiner, A.R., Gieger, C., Meneton, P., Uitterlinden, A.G., Wareham, N.J., Gudnason, V., Rotter, J.I., Rettig, R., Uda, M., Strachan, D.P., Witteman, J.C., Hartikainen, A.L., Beckmann, J.S., Boerwinkle, E., Vasan, R.S., Boehnke, M., Larson, M.G., Järvelin, M.R., Psaty, B.M., Abecasis, G.R., Chakravarti, A., Elliott, P., van Duijn, C.M., Newton-Cheh, C., Levy, D., Caulfield, M.J., Johnson, T., Tang, H., Knowles, J., Hlatky, M., Fortmann, S., Assimes, T.L., Quertermous, T., Go, A., Iribarren, C., Absher, D., Risch, N., Myers, R., Sidney, S., Ziegler, A., Schillert, A., Bickel, C., Sinning, C., Rupprecht, H.J., Lackner, K., Wild, P., Schnabel, R., Blankenberg, S., Zeller, T., Münzel, T., Perret, C., Cambien, F., Tiret, L., Nicaud, V., Proust, C., Uitterlinden, A., van Duijn, C., Whitteman, J., Cupples, L.A., Demissie-Banjaw, S., Ramachandran, V., Smith, A., Folsom, A., Morrison, A., Chen, I.Y., Bis, J., Volcik, K., Rice, K., Taylor, K.D., Marciante, K., Smith, N., Glazer, N., Heckbert, S., Harris, T., Lumley, T., Kong, A., Thorleifsson, G., Thorgeirsson, G., Holm, H., Gulcher, J.R., Stefansson, K., Andersen, K., Gretarsdottir, S., Thorsteinsdottir, U., Preuss, M., Schreiber, S., König, I.R., Lieb, W., Hengstenberg, C., Schunkert, H., Fischer, M., Grosshennig, A., Medack, A., Stark, K., Linsel-Nitschke, P., Bruse, P., Aherrahrou, Z., Peters, A., Loley, C., Willenborg, C., Nahrstedt, J., Freyer, J., Gulde, S., Doering, A., Meisinger, C., Klopp, N., Illig, T., Meinitzer, A., Tomaschitz, A., Halperin, E., Dobnig, H., Scharnagl, H., Kleber, M., Laaksonen, R., Pilz, S., Grammer, T.B., Stojakovic, T., Renner, W., März, W., Böhm, B.O., Winkelmann, B.R., Winkler, K., Hoffmann, M.M., Siscovick, D.S., Musunuru, K., Barbalic, M., Guiducci, C., Burtt, N., Gabriel, S.B., Stewart, A.F., Wells, G.A., Chen, L., Jarinova, O., Roberts, R., McPherson, R., Dandona, S., Pichard, A.D., Rader, D.J., Devaney, J., Lindsay, J.M., Kent, K.M., Qu, L., Satler, L., Burnett, M.S., Li, M., Reilly, M.P., Wilensky, R., Waksman, R., Epstein, S., Matthai, W., Knouff, C.W., Waterworth, D.M., Hakonarson, H.H., Walker, M.C., Hall, A.S., Balmforth, A.J., Wright, B.J., Nelson, C., Thompson, J.R., Ball, S.G., Felix, J.F., Demissie, S., Loehr, L.R., Rosamond, W.D., Folsom, A.R., Benjamin, E., Aulchenko, Y.S., Haritunians, T., Couper, D., Murabito, J., Wang, Y.A., Stricker, B.H., Gottdiener, J.S., Chang, P.P., Willerson, J.T., Böger, C.A., Fuchsberger, C., Gao, X., Yang, Q., Schmidt, H., Ketkar, S., Paré, G., Atkinson, E.J., Lohman, K., Cornelis, M.C., Probst-Hensch, N.M., Kronenberg, F., Tönjes, A., Eiriksdottir, G., Launer, L.J., Rampersaud, E., Mitchell, B.D., Struchalin, M., Cavalieri, M., Giallauria, F., Metter, J., de Boer, J., Siscovick, D., Zillikens, M.C., Feitosa, M., Province, M., de Andrade, M., Turner, S.T., Wild, P.S., Schnabel, R.B., Wilde, S., Munzel, T.F., Leak, T.S., Koenig, W., Zgaga, L., Zemunik, T., Kolcic, I., Minelli, C., Hu, F.B., Johansson, A., Zaboli, G., Ellinghaus, D., Imboden, M., Nitsch, D., Brandstätter, A., Kollerits, B., Kedenko, L., Mägi, R., Stumvoll, M., Kovacs, P., Boban, M., Campbell, S., Endlich, K., Nauck, M., Badola, S., Curhan, G.C., Franke, A., Rochat, T., Paulweber, B., Wang, W., Schmidt, R., Shlipak, M.G., Borecki, I., Krämer, B.K., Gyllensten, U., Hastie, N., Heid, I.M., Fox, C.S., Felix, S.B., Watzinger, N., Homuth, G., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, R.J., Greiser, K.H., Deckers, J.W., Stritzke, J., Lackner, K.J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, M.M., Werdan, K., Mitchell, G.F., Arnett, D.K., Blettner, M., Friedrich, N., Benjamin, E.J., Lord, G.M., Gale, D.P., Wass, M.N., Ahmadi, K.R., Beckmann, J., Bilo, H.J., Cook, H.T., Cotlarciuc, I., Davey Smith, G., de Silva, R., Deng, G., Devuyst, O., Dikkeschei, L.D., Dimkovic, N., Dockrell, M., Dominiczak, A., Ebrahim, S., Eggermann, T., Floege, J., Forouhi, N.G., Gansevoort, R.T., Han, X., Homan van der Heide, J.J., Hepkema, B.G., Hernandez-Fuentes, M., Hypponen, E., de Jong, P.E., Kleefstra, N., Lagou, V., Lapsley, M., Luttropp, K., Maréchal, C., Nordfors, L., Penninx, B.W., Perucha, E., Pouta, A., Roderick, P.J., Ruokonen, A., Sanna, S., Schalling, M., Schlessinger, D., Schlieper, G., Seelen, M.A., Smit, J.H., Stenvinkel, P., Sternberg, M.J., Swaminathan, R., Ubink-Veltmaat, L.J., Wallace, C., Waterworth, D., Zerres, K., Waeber, G., Maxwell, P.H., McCarthy, M.I., Jarvelin, M.R., and Lightstone, L.

Abstract

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Published
2011

31. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Author

Ehret, G.B. (Georg), Munroe, P. (Patricia), Rice, K.M. (Kenneth), Bochud, M. (Murielle), Johnson, A.D. (Andrew), Chasman, D.I. (Daniel), Smith, A.V. (Albert Vernon), Tobin, M.D. (Martin), Verwoert, G.C. (Germaine), Hwang, S.J., Pihur, V. (Vasyl), Vollenweider, P. (Peter), O'Reilly, P.F. (Paul), Amin, N. (Najaf), Bragg-Gresham, J.L. (Jennifer L.), Teumer, A. (Alexander), Glazer, N.L. (Nicole), Launer, L.J. (Lenore), Zhao, J.H. (Jing Hua), Aulchenko, Y.S. (Yurii), Heath, S.C. (Simon), Sõber, S. (Siim), Parsa, A. (Afshin), Luan, J., Arora, P. (Pankaj), Dehghan, A. (Abbas), Zhang, F. (Feng), Lucas, G. (Gavin), Hicks, A.A. (Andrew), Jackson, A.U. (Anne), Peden, J. (John), Tanaka, T. (Toshiko), Wild, S.H. (Sarah), Rudan, I. (Igor), Igl, W. (Wilmar), Milaneschi, Y. (Yuri), Parker, A.N. (Alex), Fava, C. (Cristiano), Chambers, J.C. (John), Fox, E.R. (Ervin), Kumari, M. (Meena), Jin Go, M. (Min), Harst, P. (Pim) van der, Kao, W.-H.L. (Wen-Hong Linda), Sjögren, M. (Marketa), Vinay, D.G., Alexander, M. (Myriam), Tabara, Y. (Yasuharu), Shaw-Hawkins, S. (Sue), Whincup, P.H. (Peter), Liu, Y. (YongMei), Shi, G. (Gang), Kuusisto, J. (Johanna), Tayo, B. (Bamidele), Seielstad, M. (Mark), Sim, X. (Xueling), Hoang Nguyen, K.-D., Lehtimäki, T. (Terho), Matullo, G. (Giuseppe), Wu, Y. (Ying), Gaunt, T.R. (Tom), Onland-Moret, N.C. (Charlotte), Cooper, M.N. (Matthew), Platou, C. (Carl), Org, E. (Elin), Hardy, R. (Rebecca), Dahgam, S. (Santosh), Palmen, J. (Jutta), Vitart, V. (Veronique), Braund, P.S. (Peter), Kuznetsova, T. (Tatiana), Uiterwaal, C.S.P.M. (Cuno), Adeyemo, A. (Adebowale), Palmas, W. (Walter), Campbell, H. (Harry), Ludwig, B. (Barbara), Tomaszewski, M., Tzoulaki, I., Palmer, N.D. (Nicholette), Aspelund, T. (Thor), Garcia, M. (Melissa), Chang, Y.-P.C. (Yen-Pei), O´Connell, J.R., Steinle, N.I. (Nanette), Grobbee, D.E. (Diederick), Arking, D.E. (Dan), Kardia, S.L. (Sharon), Morrison, A.C. (Alanna), Hernandez, D.G. (Dena), Najjar, S.S. (Samer), McArdle, W.L. (Wendy), Hadley, D. (David), Brown, M.J. (Morris), Connell, J. (John), Hingorani, A. (Aroon), Day, I.N.M. (Ian), Lawlor, D.A. (Debbie), Beilby, J.P. (John), Lawrence, R.W. (Robert), Clarke, R., Hopewell, J., Ongen, H. (Halit), Dreisbach, A.W. (Albert), Li, Y. (Yali), Hunter Young, J., Bis, J.C. (Joshua), Kähönen, M. (Mika), Viikari, J. (Jorma), Lee, N.R. (Nanette), Chen, M-H. (Ming-Huei), Olden, M. (Matthias), Pattaro, C. (Cristian), Hoffman Bolton, J.A. (Judith), Köttgen, A. (Anna), Bergmann, S.M. (Sven), Mooser, V. (Vincent), Chaturvedi, N. (Nish), Frayling, T.M. (Timothy), Islam, M. (Muhammad), Jafar, T.H. (Tazeen), Kulkarni, S.R. (Smita), Bornstein, S.R. (Stefan), Gräßler, J. (Jürgen), Groop, L. (Leif), Voight, B.F. (Benjamin), Kettunen, J. (Johannes), Howard, P. (Philip), Taylor, A. (Andrew), Guarrera, S. (Simonetta), Ricceri, F. (Fulvio), Emilsson, V. (Valur), Plump, A.S. (Andrew), Khaw, K-T. (Kay-Tee), Weder, A.B. (Alan), Hunt, S.C. (Steven), Sun, Y.V. (Yan), Bergman, R.N. (Richard), Collins, F.S. (Francis), Bonnycastle, L.L. (Lori), Scott, L.J. (Laura), Stringham, H.M. (Heather), Peltonen, L. (Leena Johanna), Perola, M. (Markus), Vartiainen, E. (Erkki), Brand, S.-M., Staessen, J.A. (Jan), Wang, Y.A. (Ying), Burton, P.R. (Paul), Soler Artigas, M. (Maria), Dong, Y. (Yanbin), Snieder, H. (Harold), Zhu, H. (Haidong), Lohman, K. (Kurt), Rudock, M.E. (Megan), Heckbert, S.R. (Susan), Wiggins, K.L. (Kerri), Doumatey, A. (Ayo), Shriner, D. (Daniel), Veldre, G. (Gudrun), Viigimaa, M. (Margus), Kinra, S. (Sanjay), Prabhakaran, D. (Dorairaj), Tripathy, V. (Vikal), Langefeld, C.D. (Carl), Rosengren, A. (Annika), Thelle, D.S. (Dag), Corsi, A.M. (Anna Maria), Singleton, A. (Andrew), Forrester, T. (Terrence), Hilton, G. (Gina), McKenzie, C.A. (Colin), Salako, T. (Tunde), Iwai, N. (Naoharu), Kita, Y. (Yoshikuni), Ogihara, T. (Toshio), Ohkubo, T. (Takayoshi), Okamura, T. (Tomonori), Ueshima, H. (Hirotsugu), Umemura, S. (Satoshi), Eyheramendy, S. (Susana), Meitinger, T. (Thomas), Wichmann, H.E. (Heinz Erich), Shin Cho, Y. (Yoon), Kim, H.-L., Sehmi, J.S. (Joban), Hedblad, B. (Bo), Nilsson, P. (Peter), Davey-Smith, G. (George), Wong, A. (Andrew), Narisu, N. (Narisu), Stancáková, A. (Alena), Raffel, L.J. (Leslie), Yao, J. (Jie), Kathiresan, S. (Sekar), O'Donnell, C.J. (Christopher), Schwartz, S.M. (Stephen), Ikram, M.A. (Arfan), Longstreth Jr, W.T., Mosley, T.H. (Thomas), Seshadri, S. (Sudha), Shrine, N.R.G. (Nick), Wain, L.V. (Louise), Morken, M.A. (Mario), Swift, A.J. (Amy), Laitinen, J. (Jaana), Prokopenko, I. (Inga), Zitting, P. (Paavo), Humphries, S.E. (Steve), Danesh, J. (John), Rasheed, A. (Asif), Goel, A. (Anuj), Hamsten, A. (Anders), Watkins, H. (Hugh), Gilst, W.H. (Wiek) van, Janipalli, C.S. (Charles), Radha Mani, K., Yajnik, C. (Chittaranjan), Hofman, A. (Albert), Mattace Raso, F.U.S. (Francesco), Oostra, B.A. (Ben), Demirkan, A. (Ayşe), Isaacs, A.J. (Aaron), Rivadeneira Ramirez, F. (Fernando), Lakatta, E. (Edward), Orrù, M. (Marco), Scuteri, A. (Angelo), Ala-Korpela, M. (Mika), Kangas, A.J. (Antti), Lyytikäinen, L.-P. (Leo-Pekka), Soininen, P. (Pasi), Tukiainen, T. (Taru), Würtz, P. (Peter), Twee-Hee Ong, R. (Rick), Dörr, M. (Marcus), Kroemer, H.K. (Heyo), Völker, U. (Uwe), Völzke, H. (Henry), Galan, P. (Pilar), Hercberg, S. (Serge), Lathrop, G.M. (Mark), Zelenika, D. (Diana), Deloukas, P. (Panagiotis), Mangino, M. (Massimo), Spector, T.D. (Timothy), Zhai, G. (Guangju), Meschia, J.F. (James F.), Nalls, M.A. (Michael), Sharma, P. (Pankaj), Terzic, J. (Janos), Kranthi Kumar, M.V., Denniff, M. (Matthew), Zukowska-Szczechowska, E. (Ewa), Wagenknecht, L.E. (Lynne), Fowkes, F.G.R. (Gerald), Charchar, F.J. (Fadi), Schwarz, P.E.H. (Peter), Hayward, C. (Caroline), Guo, X. (Xiuqing), Rotimi, C. (Charles), Bots, M.L. (Michiel), Samani, N.J. (Nilesh), Polasek, O. (Ozren), Talmud, P.J. (Philippa), Nyberg, F. (Fredrik), Kuh, D. (Diana), Laan, M. (Maris), Hveem, K. (Kristian), Schouw, Y.T. (Yvonne) van der, Casas, J.P. (Juan), Mohlke, K.L. (Karen), Vineis, P. (Paolo), Raitakari, O. (Olli), Ganesh, S.K. (Santhi), Shyong Tai, E., Laakso, M. (Markku), Rao, D.C. (Dabeeru C.), Harris, T.B. (Tamara), Morris, R.W. (Richard), Dominiczak, A. (Anna), Kivimaki, M. (Mika), Marmot, M. (Michael), Miki, T. (Tetsuro), Saleheen, D., Chandak, G.R. (Giriraj), Coresh, J. (Josef), Navis, G. (Gerjan), Salomaa, V. (Veikko), Han, B.-G., Kooner, J.S. (Jaspal), Melander, O. (Olle), Ridker, P.M. (Paul), Bandinelli, S. (Stefania), Gyllensten, U. (Ulf), Wright, A.F. (Alan), Wilson, J.F. (James), Ferrucci, L. (Luigi), Farrall, M. (Martin), Tuomilehto, J. (Jaakko), Pramstaller, P.P. (Peter Paul), Elosua, R. (Roberto), Soranzo, N. (Nicole), Sijbrands, E.J.G. (Eric), Altshuler, D. (David), Loos, R.J.F. (Ruth), Shuldiner, A.R. (Alan), Gieger, C. (Christian), Meneton, P. (Pierre), Uitterlinden, A.G. (André), Wareham, N.J. (Nick), Gudnason, V. (Vilmundur), Rotter, J.I. (Jerome), Rettig, R. (Rainer), Uda, M. (Manuela), Strachan, D.P. (David), Witteman, J.C.M. (Jacqueline), Hartikainen, A.L., Beckmann, J.S. (Jacques), Boerwinkle, E.A. (Eric), Erdmann, J. (Jeanette), Vasan, R.S. (Ramachandran Srini), Boehnke, M. (Michael), Larson, M.G. (Martin), Järvelin, M.R., Psaty, B.M. (Bruce), Tikka-Kleemola, P. (Päivi), Newton-Cheh, C. (Christopher), Elliott, P. (Paul), Levy, D. (Daniel), Caulfield, M. (Mark), Abecasis, G.R. (Gonçalo), Adair, L.S. (Linda), Bakker, S.J.L. (Stephan), Barroso, I.E. (Inês), Ehret, G.B. (Georg), Munroe, P. (Patricia), Rice, K.M. (Kenneth), Bochud, M. (Murielle), Johnson, A.D. (Andrew), Chasman, D.I. (Daniel), Smith, A.V. (Albert Vernon), Tobin, M.D. (Martin), Verwoert, G.C. (Germaine), Hwang, S.J., Pihur, V. (Vasyl), Vollenweider, P. (Peter), O'Reilly, P.F. (Paul), Amin, N. (Najaf), Bragg-Gresham, J.L. (Jennifer L.), Teumer, A. (Alexander), Glazer, N.L. (Nicole), Launer, L.J. (Lenore), Zhao, J.H. (Jing Hua), Aulchenko, Y.S. (Yurii), Heath, S.C. (Simon), Sõber, S. (Siim), Parsa, A. (Afshin), Luan, J., Arora, P. (Pankaj), Dehghan, A. (Abbas), Zhang, F. (Feng), Lucas, G. (Gavin), Hicks, A.A. (Andrew), Jackson, A.U. (Anne), Peden, J. (John), Tanaka, T. (Toshiko), Wild, S.H. (Sarah), Rudan, I. (Igor), Igl, W. (Wilmar), Milaneschi, Y. (Yuri), Parker, A.N. (Alex), Fava, C. (Cristiano), Chambers, J.C. (John), Fox, E.R. (Ervin), Kumari, M. (Meena), Jin Go, M. (Min), Harst, P. (Pim) van der, Kao, W.-H.L. (Wen-Hong Linda), Sjögren, M. (Marketa), Vinay, D.G., Alexander, M. (Myriam), Tabara, Y. (Yasuharu), Shaw-Hawkins, S. (Sue), Whincup, P.H. (Peter), Liu, Y. (YongMei), Shi, G. (Gang), Kuusisto, J. (Johanna), Tayo, B. (Bamidele), Seielstad, M. (Mark), Sim, X. (Xueling), Hoang Nguyen, K.-D., Lehtimäki, T. (Terho), Matullo, G. (Giuseppe), Wu, Y. (Ying), Gaunt, T.R. (Tom), Onland-Moret, N.C. (Charlotte), Cooper, M.N. (Matthew), Platou, C. (Carl), Org, E. (Elin), Hardy, R. (Rebecca), Dahgam, S. (Santosh), Palmen, J. (Jutta), Vitart, V. (Veronique), Braund, P.S. (Peter), Kuznetsova, T. (Tatiana), Uiterwaal, C.S.P.M. (Cuno), Adeyemo, A. (Adebowale), Palmas, W. (Walter), Campbell, H. (Harry), Ludwig, B. (Barbara), Tomaszewski, M., Tzoulaki, I., Palmer, N.D. (Nicholette), Aspelund, T. (Thor), Garcia, M. (Melissa), Chang, Y.-P.C. (Yen-Pei), O´Connell, J.R., Steinle, N.I. (Nanette), Grobbee, D.E. (Diederick), Arking, D.E. (Dan), Kardia, S.L. (Sharon), Morrison, A.C. (Alanna), Hernandez, D.G. (Dena), Najjar, S.S. (Samer), McArdle, W.L. (Wendy), Hadley, D. (David), Brown, M.J. (Morris), Connell, J. (John), Hingorani, A. (Aroon), Day, I.N.M. (Ian), Lawlor, D.A. (Debbie), Beilby, J.P. (John), Lawrence, R.W. (Robert), Clarke, R., Hopewell, J., Ongen, H. (Halit), Dreisbach, A.W. (Albert), Li, Y. (Yali), Hunter Young, J., Bis, J.C. (Joshua), Kähönen, M. (Mika), Viikari, J. (Jorma), Lee, N.R. (Nanette), Chen, M-H. (Ming-Huei), Olden, M. (Matthias), Pattaro, C. (Cristian), Hoffman Bolton, J.A. (Judith), Köttgen, A. (Anna), Bergmann, S.M. (Sven), Mooser, V. (Vincent), Chaturvedi, N. (Nish), Frayling, T.M. (Timothy), Islam, M. (Muhammad), Jafar, T.H. (Tazeen), Kulkarni, S.R. (Smita), Bornstein, S.R. (Stefan), Gräßler, J. (Jürgen), Groop, L. (Leif), Voight, B.F. (Benjamin), Kettunen, J. (Johannes), Howard, P. (Philip), Taylor, A. (Andrew), Guarrera, S. (Simonetta), Ricceri, F. (Fulvio), Emilsson, V. (Valur), Plump, A.S. (Andrew), Khaw, K-T. (Kay-Tee), Weder, A.B. (Alan), Hunt, S.C. (Steven), Sun, Y.V. (Yan), Bergman, R.N. (Richard), Collins, F.S. (Francis), Bonnycastle, L.L. (Lori), Scott, L.J. (Laura), Stringham, H.M. (Heather), Peltonen, L. (Leena Johanna), Perola, M. (Markus), Vartiainen, E. (Erkki), Brand, S.-M., Staessen, J.A. (Jan), Wang, Y.A. (Ying), Burton, P.R. (Paul), Soler Artigas, M. (Maria), Dong, Y. (Yanbin), Snieder, H. (Harold), Zhu, H. (Haidong), Lohman, K. (Kurt), Rudock, M.E. (Megan), Heckbert, S.R. (Susan), Wiggins, K.L. (Kerri), Doumatey, A. (Ayo), Shriner, D. (Daniel), Veldre, G. (Gudrun), Viigimaa, M. (Margus), Kinra, S. (Sanjay), Prabhakaran, D. (Dorairaj), Tripathy, V. (Vikal), Langefeld, C.D. (Carl), Rosengren, A. (Annika), Thelle, D.S. (Dag), Corsi, A.M. (Anna Maria), Singleton, A. (Andrew), Forrester, T. (Terrence), Hilton, G. (Gina), McKenzie, C.A. (Colin), Salako, T. (Tunde), Iwai, N. (Naoharu), Kita, Y. (Yoshikuni), Ogihara, T. (Toshio), Ohkubo, T. (Takayoshi), Okamura, T. (Tomonori), Ueshima, H. (Hirotsugu), Umemura, S. (Satoshi), Eyheramendy, S. (Susana), Meitinger, T. (Thomas), Wichmann, H.E. (Heinz Erich), Shin Cho, Y. (Yoon), Kim, H.-L., Sehmi, J.S. (Joban), Hedblad, B. (Bo), Nilsson, P. (Peter), Davey-Smith, G. (George), Wong, A. (Andrew), Narisu, N. (Narisu), Stancáková, A. (Alena), Raffel, L.J. (Leslie), Yao, J. (Jie), Kathiresan, S. (Sekar), O'Donnell, C.J. (Christopher), Schwartz, S.M. (Stephen), Ikram, M.A. (Arfan), Longstreth Jr, W.T., Mosley, T.H. (Thomas), Seshadri, S. (Sudha), Shrine, N.R.G. (Nick), Wain, L.V. (Louise), Morken, M.A. (Mario), Swift, A.J. (Amy), Laitinen, J. (Jaana), Prokopenko, I. (Inga), Zitting, P. (Paavo), Humphries, S.E. (Steve), Danesh, J. (John), Rasheed, A. (Asif), Goel, A. (Anuj), Hamsten, A. (Anders), Watkins, H. (Hugh), Gilst, W.H. (Wiek) van, Janipalli, C.S. (Charles), Radha Mani, K., Yajnik, C. (Chittaranjan), Hofman, A. (Albert), Mattace Raso, F.U.S. (Francesco), Oostra, B.A. (Ben), Demirkan, A. (Ayşe), Isaacs, A.J. (Aaron), Rivadeneira Ramirez, F. (Fernando), Lakatta, E. (Edward), Orrù, M. (Marco), Scuteri, A. (Angelo), Ala-Korpela, M. (Mika), Kangas, A.J. (Antti), Lyytikäinen, L.-P. (Leo-Pekka), Soininen, P. (Pasi), Tukiainen, T. (Taru), Würtz, P. (Peter), Twee-Hee Ong, R. (Rick), Dörr, M. (Marcus), Kroemer, H.K. (Heyo), Völker, U. (Uwe), Völzke, H. (Henry), Galan, P. (Pilar), Hercberg, S. (Serge), Lathrop, G.M. (Mark), Zelenika, D. (Diana), Deloukas, P. (Panagiotis), Mangino, M. (Massimo), Spector, T.D. (Timothy), Zhai, G. (Guangju), Meschia, J.F. (James F.), Nalls, M.A. (Michael), Sharma, P. (Pankaj), Terzic, J. (Janos), Kranthi Kumar, M.V., Denniff, M. (Matthew), Zukowska-Szczechowska, E. (Ewa), Wagenknecht, L.E. (Lynne), Fowkes, F.G.R. (Gerald), Charchar, F.J. (Fadi), Schwarz, P.E.H. (Peter), Hayward, C. (Caroline), Guo, X. (Xiuqing), Rotimi, C. (Charles), Bots, M.L. (Michiel), Samani, N.J. (Nilesh), Polasek, O. (Ozren), Talmud, P.J. (Philippa), Nyberg, F. (Fredrik), Kuh, D. (Diana), Laan, M. (Maris), Hveem, K. (Kristian), Schouw, Y.T. (Yvonne) van der, Casas, J.P. (Juan), Mohlke, K.L. (Karen), Vineis, P. (Paolo), Raitakari, O. (Olli), Ganesh, S.K. (Santhi), Shyong Tai, E., Laakso, M. (Markku), Rao, D.C. (Dabeeru C.), Harris, T.B. (Tamara), Morris, R.W. (Richard), Dominiczak, A. (Anna), Kivimaki, M. (Mika), Marmot, M. (Michael), Miki, T. (Tetsuro), Saleheen, D., Chandak, G.R. (Giriraj), Coresh, J. (Josef), Navis, G. (Gerjan), Salomaa, V. (Veikko), Han, B.-G., Kooner, J.S. (Jaspal), Melander, O. (Olle), Ridker, P.M. (Paul), Bandinelli, S. (Stefania), Gyllensten, U. (Ulf), Wright, A.F. (Alan), Wilson, J.F. (James), Ferrucci, L. (Luigi), Farrall, M. (Martin), Tuomilehto, J. (Jaakko), Pramstaller, P.P. (Peter Paul), Elosua, R. (Roberto), Soranzo, N. (Nicole), Sijbrands, E.J.G. (Eric), Altshuler, D. (David), Loos, R.J.F. (Ruth), Shuldiner, A.R. (Alan), Gieger, C. (Christian), Meneton, P. (Pierre), Uitterlinden, A.G. (André), Wareham, N.J. (Nick), Gudnason, V. (Vilmundur), Rotter, J.I. (Jerome), Rettig, R. (Rainer), Uda, M. (Manuela), Strachan, D.P. (David), Witteman, J.C.M. (Jacqueline), Hartikainen, A.L., Beckmann, J.S. (Jacques), Boerwinkle, E.A. (Eric), Erdmann, J. (Jeanette), Vasan, R.S. (Ramachandran Srini), Boehnke, M. (Michael), Larson, M.G. (Martin), Järvelin, M.R., Psaty, B.M. (Bruce), Tikka-Kleemola, P. (Päivi), Newton-Cheh, C. (Christopher), Elliott, P. (Paul), Levy, D. (Daniel), Caulfield, M. (Mark), Abecasis, G.R. (Gonçalo), Adair, L.S. (Linda), Bakker, S.J.L. (Stephan), and Barroso, I.E. (Inês)

Abstract

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140mmg Hg systolic blood pressure ≥90mmg Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3 GUCY1B3, NPR3 C5orf23, ADM, FURIN FES, GOSR2, GNAS EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 geno

Published
2011
Full Text
View/download PDF

32. Multiple loci are associated with white blood cell phenotypes

Author

Nalls, M.A. (Michael), Couper, D. (David), Tanaka, T. (Toshiko), Rooij, F.J.A. (Frank) van, Chen, M-H. (Ming-Huei), Smith, A.V. (Albert Vernon), Toniolo, D. (Daniela), Zakai, N.A. (Neil), Yang, Q. (Qiong Fang), Greinacher, A. (Andreas), Wood, A.R. (Andrew), Garcia, M. (Melissa), Gasparini, P. (Paolo), Liu, Y. (YongMei), Lumley, T. (Thomas), Folsom, A.R. (Aaron), Reiner, A.P. (Alex), Gieger, C. (Christian), Lagou, V. (Vasiliki), Felix, J.F. (Janine), Völzke, H. (Henry), Gouskova, N.A. (Natalia), Biffi, A. (Alessandro), Döring, A. (Angela), Völker, U. (Uwe), Chong, S. (Sean), Wiggins, K.L. (Kerri), Rendon, A. (Augusto), Dehghan, A. (Abbas), Moore, M. (Matt), Taylor, K.D. (Kent), Wilson, J.G. (James), Lettre, G. (Guillaume), Hofman, A. (Albert), Bis, J.C. (Joshua), Pirastu, N. (Nicola), Fox, C.S. (Caroline), Meisinger, C. (Christa), Sambrook, J.G. (Jennifer), Arepalli, S. (Sampath), Nauck, M. (Matthias), Prokisch, H. (Holger), Stephens, J. (Jonathan), Glazer, N.L. (Nicole), Cupples, L.A. (Adrienne), Okada, Y. (Yukinori), Takahashi, A. (Atsushi), Kamatani, Y. (Yoichiro), Matsuda, K. (Koichi), Tsunoda, T. (Tatsuhiko), Kubo, M. (Michiaki), Nakamura, Y. (Yusuke), Yamamoto, K. (Kazuhiko), Stumvoll, M. (Michael), Tönjes, A. (Anke), Prokopenko, I. (Inga), Illig, T. (Thomas), Patel, K.V. (Kushang), Garner, S.F. (Stephen), Kuhnel, B. (Brigitte), Mangino, M. (Massimo), Oostra, B.A. (Ben), Thein, S.L., Coresh, J. (Josef), Wichmann, H.E. (Heinz Erich), Menzel, S. (Stephan), Lin, J., Pistis, G. (Giorgio), Uitterlinden, A.G. (André), Spector, T.D. (Timothy), Teumer, A. (Alexander), Eiriksdottir, G. (Gudny), Gudnason, V. (Vilmundur), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Chakravarti, A. (Aravinda), Tikka-Kleemola, P. (Päivi), Melzer, D. (David), Ouwehand, W.H. (Willem), Levy, D. (Daniel), Boerwinkle, E.A. (Eric), Singleton, A. (Andrew), Hernandez, D.G. (Dena), Longo, D.L. (Dan), Soranzo, N. (Nicole), Witteman, J.C.M. (Jacqueline), Psaty, B.M. (Bruce), Ferrucci, L. (Luigi), Harris, T.B. (Tamara), O'Donnell, C.J. (Christopher), Ganesh, S.K. (Santhi), Nalls, M.A. (Michael), Couper, D. (David), Tanaka, T. (Toshiko), Rooij, F.J.A. (Frank) van, Chen, M-H. (Ming-Huei), Smith, A.V. (Albert Vernon), Toniolo, D. (Daniela), Zakai, N.A. (Neil), Yang, Q. (Qiong Fang), Greinacher, A. (Andreas), Wood, A.R. (Andrew), Garcia, M. (Melissa), Gasparini, P. (Paolo), Liu, Y. (YongMei), Lumley, T. (Thomas), Folsom, A.R. (Aaron), Reiner, A.P. (Alex), Gieger, C. (Christian), Lagou, V. (Vasiliki), Felix, J.F. (Janine), Völzke, H. (Henry), Gouskova, N.A. (Natalia), Biffi, A. (Alessandro), Döring, A. (Angela), Völker, U. (Uwe), Chong, S. (Sean), Wiggins, K.L. (Kerri), Rendon, A. (Augusto), Dehghan, A. (Abbas), Moore, M. (Matt), Taylor, K.D. (Kent), Wilson, J.G. (James), Lettre, G. (Guillaume), Hofman, A. (Albert), Bis, J.C. (Joshua), Pirastu, N. (Nicola), Fox, C.S. (Caroline), Meisinger, C. (Christa), Sambrook, J.G. (Jennifer), Arepalli, S. (Sampath), Nauck, M. (Matthias), Prokisch, H. (Holger), Stephens, J. (Jonathan), Glazer, N.L. (Nicole), Cupples, L.A. (Adrienne), Okada, Y. (Yukinori), Takahashi, A. (Atsushi), Kamatani, Y. (Yoichiro), Matsuda, K. (Koichi), Tsunoda, T. (Tatsuhiko), Kubo, M. (Michiaki), Nakamura, Y. (Yusuke), Yamamoto, K. (Kazuhiko), Stumvoll, M. (Michael), Tönjes, A. (Anke), Prokopenko, I. (Inga), Illig, T. (Thomas), Patel, K.V. (Kushang), Garner, S.F. (Stephen), Kuhnel, B. (Brigitte), Mangino, M. (Massimo), Oostra, B.A. (Ben), Thein, S.L., Coresh, J. (Josef), Wichmann, H.E. (Heinz Erich), Menzel, S. (Stephan), Lin, J., Pistis, G. (Giorgio), Uitterlinden, A.G. (André), Spector, T.D. (Timothy), Teumer, A. (Alexander), Eiriksdottir, G. (Gudny), Gudnason, V. (Vilmundur), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Chakravarti, A. (Aravinda), Tikka-Kleemola, P. (Päivi), Melzer, D. (David), Ouwehand, W.H. (Willem), Levy, D. (Daniel), Boerwinkle, E.A. (Eric), Singleton, A. (Andrew), Hernandez, D.G. (Dena), Longo, D.L. (Dan), Soranzo, N. (Nicole), Witteman, J.C.M. (Jacqueline), Psaty, B.M. (Bruce), Ferrucci, L. (Luigi), Harris, T.B. (Tamara), O'Donnell, C.J. (Christopher), and Ganesh, S.K. (Santhi)

Abstract

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse

Published
2011
Full Text
View/download PDF

33. Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo

Author

Ikram, M.K. (Kamran), Xueling, S. (Sim), Jensen, R.A. (Richard), Cotch, M.F. (Mary Frances), Hewit, A.W. (Alex), Ikram, M.A. (Arfan), Wang, J.J. (Jie Jin), Klein, B.E.K. (Barbara), Breteler, M.M.B. (Monique), Cheung, N. (Ning), Liew, G. (Gerald), Mitchell, P. (Paul), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Jong, P.T.V.M. (Paulus) de, Duijn, C.M. (Cornelia) van, Kao, L. (Linda), Cheng, C-Y. (Ching-Yu), Smith, A.V. (Albert Vernon), Glazer, N.L. (Nicole), Lumley, T. (Thomas), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Jonasson, F. (Fridbert), Eiriksdottir, G. (Gudny), Aspelund, T. (Thor), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Taylor, K.D. (Kent), Li, X. (Xiaohui), Sivakumaran, T.A. (Theru), Mackey, D.A. (David), MacGregor, S. (Stuart), Martin, N.G. (Nicholas), Young, T.L. (Terry), Bis, J.C. (Joshua), Wiggins, K.L. (Kerri), Heckbert, S.R. (Susan), Hammond, C.J. (Christopher), Andrew, T. (Toby), Fahy, S. (Samantha), Attia, J. (John), Holliday, E.G. (Elizabeth), Scott, R.J. (Rodney), Islam, F.M.A. (Amirul), Rotter, J.I. (Jerome), McAuley, A.K. (Annie), Boerwinkle, E.A. (Eric), Tai, E.S. (Shyong), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Vingerling, J.R. (Hans), Wong, T.Y. (Tien Yin), Ikram, M.K. (Kamran), Xueling, S. (Sim), Jensen, R.A. (Richard), Cotch, M.F. (Mary Frances), Hewit, A.W. (Alex), Ikram, M.A. (Arfan), Wang, J.J. (Jie Jin), Klein, B.E.K. (Barbara), Breteler, M.M.B. (Monique), Cheung, N. (Ning), Liew, G. (Gerald), Mitchell, P. (Paul), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Jong, P.T.V.M. (Paulus) de, Duijn, C.M. (Cornelia) van, Kao, L. (Linda), Cheng, C-Y. (Ching-Yu), Smith, A.V. (Albert Vernon), Glazer, N.L. (Nicole), Lumley, T. (Thomas), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Jonasson, F. (Fridbert), Eiriksdottir, G. (Gudny), Aspelund, T. (Thor), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Taylor, K.D. (Kent), Li, X. (Xiaohui), Sivakumaran, T.A. (Theru), Mackey, D.A. (David), MacGregor, S. (Stuart), Martin, N.G. (Nicholas), Young, T.L. (Terry), Bis, J.C. (Joshua), Wiggins, K.L. (Kerri), Heckbert, S.R. (Susan), Hammond, C.J. (Christopher), Andrew, T. (Toby), Fahy, S. (Samantha), Attia, J. (John), Holliday, E.G. (Elizabeth), Scott, R.J. (Rodney), Islam, F.M.A. (Amirul), Rotter, J.I. (Jerome), McAuley, A.K. (Annie), Boerwinkle, E.A. (Eric), Tai, E.S. (Shyong), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Vingerling, J.R. (Hans), and Wong, T.Y. (Tien Yin)

Abstract

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10-8) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10-25, within the RASIP1 locus), rs225717 (6q24; p = 1.25×10-16, adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10-13, in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10-16, adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

Published
2010
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results