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Find video protocols related to scientific articles indexed in Pubmed.
Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
Dan E Arking, Sara L Pulit, Lia Crotti, Pim van der Harst, Patricia B Munroe, Tamara T Koopmann, Nona Sotoodehnia, Elizabeth J Rossin, Michael Morley, Xinchen Wang, Andrew D Johnson, Alicia Lundby, Daniel F Gudbjartsson, Peter A Noseworthy, Mark Eijgelsheim, Yuki Bradford, Kirill V Tarasov, Marcus Dörr, Martina Müller-Nurasyid, Annukka M Lahtinen, Ilja M Nolte, Albert Vernon Smith, Joshua C Bis, Aaron Isaacs, Stephen J Newhouse, Daniel S Evans, Wendy S Post, Daryl Waggott, Leo-Pekka Lyytikäinen, Andrew A Hicks, Lewin Eisele, David Ellinghaus, Caroline Hayward, Pau Navarro, Sheila Ulivi, Toshiko Tanaka, David J Tester, Stéphanie Chatel, Stefan Gustafsson, Meena Kumari, Richard W Morris, Asa T Naluai, Sandosh Padmanabhan, Alexander Kluttig, Bernhard Strohmer, Andrie G Panayiotou, Maria Torres, Michael Knoflach, Jaroslav A Hubacek, Kamil Slowikowski, Soumya Raychaudhuri, Runjun D Kumar, Tamara B Harris, Lenore J Launer, Alan R Shuldiner, Alvaro Alonso, Joel S Bader, Georg Ehret, Hailiang Huang, W H Linda Kao, James B Strait, Peter W Macfarlane, Morris Brown, Mark J Caulfield, Nilesh J Samani, Florian Kronenberg, Johann Willeit, , J Gustav Smith, Karin H Greiser, Henriette Meyer zu Schwabedissen, Karl Werdan, Massimo Carella, Leopoldo Zelante, Susan R Heckbert, Bruce M Psaty, Jerome I Rotter, Ivana Kolčić, Ozren Polašek, Alan F Wright, Maura Griffin, Mark J Daly, David O Arnar, Hilma Holm, Unnur Thorsteinsdottir, Joshua C Denny, Dan M Roden, Rebecca L Zuvich, Valur Emilsson, Andrew S Plump, Martin G Larson, Christopher J O'Donnell, Xiaoyan Yin, Marco Bobbo, Adamo P d'Adamo, AnnaMaria Iorio, Gianfranco Sinagra, Angel Carracedo, Steven R Cummings, Michael A Nalls, Antti Jula, Kimmo K Kontula, Annukka Marjamaa, Lasse Oikarinen, Markus Perola, Kimmo Porthan, Raimund Erbel, Per Hoffmann, Karl-Heinz Jöckel, Hagen Kälsch, Markus M Nöthen, Marcel den Hoed, Ruth J F Loos, Dag S Thelle, Christian Gieger, Thomas Meitinger, Siegfried Perz, Annette Peters, Hanna Prucha, Moritz F Sinner, Melanie Waldenberger, Rudolf A de Boer, Lude Franke, Pieter A van der Vleuten, Britt Maria Beckmann, Eimo Martens, Abdennasser Bardai, Nynke Hofman, Arthur A M Wilde, Elijah R Behr, Chrysoula Dalageorgou, John R Giudicessi, Argelia Medeiros-Domingo, Julien Barc, Florence Kyndt, Vincent Probst, Alice Ghidoni, Roberto Insolia, Robert M Hamilton, Stephen W Scherer, Jeffrey Brandimarto, Kenneth Margulies, Christine E Moravec, Fabiola Del Greco M, Christian Fuchsberger, Jeffrey R O'Connell, Wai K Lee, Graham C M Watt, Harry Campbell, Sarah H Wild, Nour E El Mokhtari, Norbert Frey, Folkert W Asselbergs, Irene Mateo Leach, Gerjan Navis, Maarten P van den Berg, Dirk J van Veldhuisen, Manolis Kellis, Bouwe P Krijthe, Oscar H Franco, Albert Hofman, Jan A Kors, André G Uitterlinden, Jacqueline C M Witteman, Lyudmyla Kedenko, Claudia Lamina, Ben A Oostra, Gonçalo R Abecasis, Edward G Lakatta, Antonella Mulas, Marco Orrù, David Schlessinger, Manuela Uda, Marcello R P Markus, Uwe Völker, Harold Snieder, Timothy D Spector, Johan Arnlöv, Lars Lind, Johan Sundström, Ann-Christine Syvänen, Mika Kivimäki, Mika Kähönen, Nina Mononen, Olli T Raitakari, Jorma S Viikari, Vera Adamkova, Stefan Kiechl, María Brión, Andrew N Nicolaides, Bernhard Paulweber, Johannes Haerting, Anna F Dominiczak, Fredrik Nyberg, Peter H Whincup, Aroon D Hingorani, Jean-Jacques Schott, Connie R Bezzina, Erik Ingelsson, Luigi Ferrucci, Paolo Gasparini, James F Wilson, Igor Rudan, Andre Franke, Thomas W Mühleisen, Peter P Pramstaller, Terho J Lehtimäki, Andrew D Paterson, Afshin Parsa, Yongmei Liu, Cornelia M van Duijn, David S Siscovick, Vilmundur Gudnason, Yalda Jamshidi, Veikko Salomaa, Stephan B Felix, Serena Sanna, Marylyn D Ritchie, Bruno H Stricker, Kari Stefansson, Laurie A Boyer, Thomas P Cappola, Jesper V Olsen, Kasper Lage, Peter J Schwartz, Stefan Kääb, Aravinda Chakravarti, Michael J Ackerman, Arne Pfeufer, Paul I W de Bakker, Christopher Newton-Cheh.
Nat. Genet.
PUBLISHED: 05-29-2014
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The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ?8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
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Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.
Alireza Moayyeri, Yi-Hsiang Hsu, David Karasik, Karol Estrada, Su-Mei Xiao, Carrie Nielson, Priya Srikanth, Sylvie Giroux, Scott G Wilson, Hou-Feng Zheng, Albert V Smith, Stephen R Pye, Paul J Leo, Alexander Teumer, Joo-Yeon Hwang, Claes Ohlsson, Fiona McGuigan, Ryan L Minster, Caroline Hayward, José M Olmos, Leo-Pekka Lyytikäinen, Joshua R Lewis, Karin M A Swart, Laura Masi, Chris Oldmeadow, Elizabeth G Holliday, Sulin Cheng, Natasja M van Schoor, Nicholas C Harvey, Marcin Kruk, Fabiola Del Greco M, Wilmar Igl, Olivia Trummer, Efi Grigoriou, Robert Luben, Ching-Ti Liu, Yanhua Zhou, Ling Oei, Carolina Medina-Gomez, Joseph Zmuda, Greg Tranah, Suzanne J Brown, Frances M Williams, Nicole Soranzo, Johanna Jakobsdottir, Kristin Siggeirsdottir, Kate L Holliday, Anke Hannemann, Min Jin Go, Melissa Garcia, Ozren Polašek, Marika Laaksonen, Kun Zhu, Anke W Enneman, Mark McEvoy, Roseanne Peel, Pak Chung Sham, Maciej Jaworski, Asa Johansson, Andrew A Hicks, Pawel Pludowski, Rodney Scott, Rosalie A M Dhonukshe-Rutten, Nathalie van der Velde, Mika Kähönen, Jorma S Viikari, Harri Sievänen, Olli T Raitakari, Jesús González-Macías, José L Hernández, Dan Mellström, Osten Ljunggren, Yoon Shin Cho, Uwe Völker, Matthias Nauck, Georg Homuth, Henry Völzke, Robin Haring, Matthew A Brown, Eugene McCloskey, Geoffrey C Nicholson, Richard Eastell, John A Eisman, Graeme Jones, Ian R Reid, Elaine M Dennison, John Wark, Steven Boonen, Dirk Vanderschueren, Frederick C W Wu, Thor Aspelund, J Brent Richards, Doug Bauer, Albert Hofman, Kay-Tee Khaw, George Dedoussis, Barbara Obermayer-Pietsch, Ulf Gyllensten, Peter P Pramstaller, Roman S Lorenc, Cyrus Cooper, Annie Wai Chee Kung, Paul Lips, Markku Alen, John Attia, Maria Luisa Brandi, Lisette C P G M de Groot, Terho Lehtimäki, José A Riancho, Harry Campbell, Yongmei Liu, Tamara B Harris, Kristina Akesson, Magnus Karlsson, Jong-Young Lee, Henri Wallaschofski, Emma L Duncan, Terence W O'Neill, Vilmundur Gudnason, Timothy D Spector, François Rousseau, Eric Orwoll, Steven R Cummings, Nick J Wareham, Fernando Rivadeneira, André G Uitterlinden, Richard L Prince, Douglas P Kiel, Jonathan Reeve, Stephen K Kaptoge.
Hum. Mol. Genet.
PUBLISHED: 01-14-2014
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Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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Serum iron levels and the risk of Parkinson disease: a mendelian randomization study.
PLoS Med.
PUBLISHED: 06-01-2013
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Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.
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Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
Louise V Wain, Germaine C Verwoert, Paul F O'Reilly, Gang Shi, Toby Johnson, Andrew D Johnson, Murielle Bochud, Kenneth M Rice, Peter Henneman, Albert V Smith, Georg B Ehret, Najaf Amin, Martin G Larson, Vincent Mooser, David Hadley, Marcus Dörr, Joshua C Bis, Thor Aspelund, Tonu Esko, A Cecile J W Janssens, Jing Hua Zhao, Simon Heath, Maris Laan, Jingyuan Fu, Giorgio Pistis, Jian'an Luan, Pankaj Arora, Gavin Lucas, Nicola Pirastu, Irene Pichler, Anne U Jackson, Rebecca J Webster, Feng Zhang, John F Peden, Helena Schmidt, Toshiko Tanaka, Harry Campbell, Wilmar Igl, Yuri Milaneschi, Jouke-Jan Hottenga, Veronique Vitart, Daniel I Chasman, Stella Trompet, Jennifer L Bragg-Gresham, Behrooz Z Alizadeh, John C Chambers, Xiuqing Guo, Terho Lehtimäki, Brigitte Kühnel, Lorna M Lopez, Ozren Polašek, Mladen Boban, Christopher P Nelson, Alanna C Morrison, Vasyl Pihur, Santhi K Ganesh, Albert Hofman, Suman Kundu, Francesco U S Mattace-Raso, Fernando Rivadeneira, Eric J G Sijbrands, André G Uitterlinden, Shih-Jen Hwang, Ramachandran S Vasan, Thomas J Wang, Sven Bergmann, Peter Vollenweider, Gérard Waeber, Jaana Laitinen, Anneli Pouta, Paavo Zitting, Wendy L McArdle, Heyo K Kroemer, Uwe Völker, Henry Völzke, Nicole L Glazer, Kent D Taylor, Tamara B Harris, Helene Alavere, Toomas Haller, Aime Keis, Mari-Liis Tammesoo, Yurii Aulchenko, Inês Barroso, Kay-Tee Khaw, Pilar Galán, Serge Hercberg, Mark Lathrop, Susana Eyheramendy, Elin Org, Siim Sõber, Xiaowen Lu, Ilja M Nolte, Brenda W Penninx, Tanguy Corre, Corrado Masciullo, Cinzia Sala, Leif Groop, Benjamin F Voight, Olle Melander, Christopher J O'Donnell, Veikko Salomaa, Adamo Pio D'adamo, Antonella Fabretto, Flavio Faletra, Sheila Ulivi, Fabiola M Del Greco, Maurizio Facheris, Francis S Collins, Richard N Bergman, John P Beilby, Joseph Hung, A William Musk, Massimo Mangino, So-Youn Shin, Nicole Soranzo, Hugh Watkins, Anuj Goel, Anders Hamsten, Pierre Gider, Marisa Loitfelder, Marion Zeginigg, Dena Hernandez, Samer S Najjar, Pau Navarro, Sarah H Wild, Anna Maria Corsi, Andrew Singleton, Eco J C de Geus, Gonneke Willemsen, Alex N Parker, Lynda M Rose, Brendan Buckley, David Stott, Marco Orrù, Manuela Uda, , Melanie M van der Klauw, Weihua Zhang, Xinzhong Li, James Scott, Yii-Der Ida Chen, Gregory L Burke, Mika Kähönen, Jorma Viikari, Angela Döring, Thomas Meitinger, Gail Davies, John M Starr, Valur Emilsson, Andrew Plump, Jan H Lindeman, Peter A C 't Hoen, Inke R König, Janine F Felix, Robert Clarke, Jemma C Hopewell, Halit Ongen, Monique Breteler, Stéphanie Debette, Anita L Destefano, Myriam Fornage, Gary F Mitchell, Nicholas L Smith, Hilma Holm, Kari Stefansson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Nilesh J Samani, Michael Preuss, Igor Rudan, Caroline Hayward, Ian J Deary, H-Erich Wichmann, Olli T Raitakari, Walter Palmas, Jaspal S Kooner, Ronald P Stolk, J Wouter Jukema, Alan F Wright, Dorret I Boomsma, Stefania Bandinelli, Ulf B Gyllensten, James F Wilson, Luigi Ferrucci, Reinhold Schmidt, Martin Farrall, Tim D Spector, Lyle J Palmer, Jaakko Tuomilehto, Arne Pfeufer, Paolo Gasparini, David Siscovick, David Altshuler, Ruth J F Loos, Daniela Toniolo, Harold Snieder, Christian Gieger, Pierre Meneton, Nicholas J Wareham, Ben A Oostra, Andres Metspalu, Lenore Launer, Rainer Rettig, David P Strachan, Jacques S Beckmann, Jacqueline C M Witteman, Jeanette Erdmann, Ko Willems van Dijk, Eric Boerwinkle, Michael Boehnke, Paul M Ridker, Marjo-Riitta Järvelin, Aravinda Chakravarti, Gonçalo R Abecasis, Vilmundur Gudnason, Christopher Newton-Cheh, Daniel Levy, Patricia B Munroe, Bruce M Psaty, Mark J Caulfield, Dabeeru C Rao, Martin D Tobin, Paul Elliott, Cornelia M van Duijn.
Nat. Genet.
PUBLISHED: 02-10-2011
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Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
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Genome-wide association analysis and fine mapping of NT-proBNP level provide novel insight into the role of the MTHFR-CLCN6-NPPA-NPPB gene cluster.
Hum. Mol. Genet.
PUBLISHED: 01-27-2011
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High blood concentration of the N-terminal cleavage product of the B-type natriuretic peptide (NT-proBNP) is strongly associated with cardiac dysfunction and is increasingly used for heart failure diagnosis. To identify genetic variants associated with NT-proBNP level, we performed a genome-wide association analysis in 1325 individuals from South Tyrol, Italy, and followed up the most significant results in 1746 individuals from two German population-based studies. A genome-wide significant signal in the MTHFR-CLCN6-NPPA-NPPB gene cluster was replicated, after correction for multiple testing (replication one-sided P-value = 8.4 × 10(-10)). A conditional regression analysis of 128 single-nucleotide polymorphisms in the region of interest identified novel variants in the CLCN6 gene as independently associated with NT-proBNP. In this locus, four haplotypes were associated with increased NT-proBNP levels (haplotype-specific combined P-values from 8.3 × 10(-03) to 9.3 × 10(-11)). The observed increase in the NT-proBNP level was proportional to the number of haplotype copies present (i.e. dosage effect), with an increase associated with two copies that varied between 20 and 100 pg/ml across populations. The identification of novel variants in the MTHFR-CLCN6-NPPA-NPPB cluster provides new insights into the biological mechanisms of cardiac dysfunction.
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Discovery and fine mapping of serum protein loci through transethnic meta-analysis.
Nora Franceschini, Frank J A van Rooij, Bram P Prins, Mary F Feitosa, Mahir Karakas, John H Eckfeldt, Aaron R Folsom, Jeffrey Kopp, Ahmad Vaez, Jeanette S Andrews, Jens Baumert, Vesna Boraska, Linda Broer, Caroline Hayward, Julius S Ngwa, Yukinori Okada, Ozren Polašek, Harm-Jan Westra, Ying A Wang, Fabiola Del Greco M, Nicole L Glazer, Karen Kapur, Ido P Kema, Lorna M Lopez, Arne Schillert, Albert V Smith, Cheryl A Winkler, Lina Zgaga, , Stefania Bandinelli, Sven Bergmann, Mladen Boban, Murielle Bochud, Y D Chen, Gail Davies, Abbas Dehghan, Jingzhong Ding, Angela Doering, J Peter Durda, Luigi Ferrucci, Oscar H Franco, Lude Franke, Grog Gunjaca, Albert Hofman, Fang-Chi Hsu, Ivana Kolčić, Aldi Kraja, Michiaki Kubo, Karl J Lackner, Lenore Launer, Laura R Loehr, Guo Li, Christa Meisinger, Yusuke Nakamura, Christine Schwienbacher, John M Starr, Atsushi Takahashi, Vesela Torlak, André G Uitterlinden, Veronique Vitart, Melanie Waldenberger, Philipp S Wild, Mirna Kirin, Tanja Zeller, Tatijana Zemunik, Qunyuan Zhang, Andreas Ziegler, Stefan Blankenberg, Eric Boerwinkle, Ingrid B Borecki, Harry Campbell, Ian J Deary, Timothy M Frayling, Christian Gieger, Tamara B Harris, Andrew A Hicks, Wolfgang Koenig, Christopher J O' Donnell, Caroline S Fox, Peter P Pramstaller, Bruce M Psaty, Alex P Reiner, Jerome I Rotter, Igor Rudan, Harold Snieder, Toshihiro Tanaka, Cornelia M van Duijn, Peter Vollenweider, Gérard Waeber, James F Wilson, Jacqueline C M Witteman, Bruce H R Wolffenbuttel, Alan F Wright, Qingyu Wu, Yongmei Liu, Nancy S Jenny, Kari E North, Janine F Felix, Behrooz Z Alizadeh, L Adrienne Cupples, John R B Perry, Andrew P Morris.
Am. J. Hum. Genet.
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Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.
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