@article {1087, title = {Common variants at ten loci influence QT interval duration in the QTGEN Study.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Apr}, pages = {399-406}, abstract = {

QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5\% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, Aged, Arrhythmias, Cardiac, Chromosome Mapping, Death, Sudden, Cardiac, Electroencephalography, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, European Continental Ancestry Group, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, KCNQ1 Potassium Channel, Meta-Analysis as Topic, Muscle Proteins, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Potassium Channels, Voltage-Gated, Risk Factors, Sodium Channels}, issn = {1546-1718}, doi = {10.1038/ng.364}, author = {Newton-Cheh, Christopher and Eijgelsheim, Mark and Rice, Kenneth M and de Bakker, Paul I W and Yin, Xiaoyan and Estrada, Karol and Bis, Joshua C and Marciante, Kristin and Rivadeneira, Fernando and Noseworthy, Peter A and Sotoodehnia, Nona and Smith, Nicholas L and Rotter, Jerome I and Kors, Jan A and Witteman, Jacqueline C M and Hofman, Albert and Heckbert, Susan R and O{\textquoteright}Donnell, Christopher J and Uitterlinden, Andr{\'e} G and Psaty, Bruce M and Lumley, Thomas and Larson, Martin G and Stricker, Bruno H Ch} } @article {1170, title = {Common variants in KCNN3 are associated with lone atrial fibrillation.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Mar}, pages = {240-4}, abstract = {

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95\% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

}, keywords = {Adolescent, Adult, Aged, Atrial Fibrillation, Case-Control Studies, Cohort Studies, Female, Genome-Wide Association Study, Humans, Introns, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Small-Conductance Calcium-Activated Potassium Channels, Young Adult}, issn = {1546-1718}, doi = {10.1038/ng.537}, author = {Ellinor, Patrick T and Lunetta, Kathryn L and Glazer, Nicole L and Pfeufer, Arne and Alonso, Alvaro and Chung, Mina K and Sinner, Moritz F and de Bakker, Paul I W and Mueller, Martina and Lubitz, Steven A and Fox, Ervin and Darbar, Dawood and Smith, Nicholas L and Smith, Jonathan D and Schnabel, Renate B and Soliman, Elsayed Z and Rice, Kenneth M and Van Wagoner, David R and Beckmann, Britt-M and van Noord, Charlotte and Wang, Ke and Ehret, Georg B and Rotter, Jerome I and Hazen, Stanley L and Steinbeck, Gerhard and Smith, Albert V and Launer, Lenore J and Harris, Tamara B and Makino, Seiko and Nelis, Mari and Milan, David J and Perz, Siegfried and Esko, T{\~o}nu and K{\"o}ttgen, Anna and Moebus, Susanne and Newton-Cheh, Christopher and Li, Man and M{\"o}hlenkamp, Stefan and Wang, Thomas J and Kao, W H Linda and Vasan, Ramachandran S and N{\"o}then, Markus M and MacRae, Calum A and Stricker, Bruno H Ch and Hofman, Albert and Uitterlinden, Andr{\'e} G and Levy, Daniel and Boerwinkle, Eric and Metspalu, Andres and Topol, Eric J and Chakravarti, Aravinda and Gudnason, Vilmundur and Psaty, Bruce M and Roden, Dan M and Meitinger, Thomas and Wichmann, H-Erich and Witteman, Jacqueline C M and Barnard, John and Arking, Dan E and Benjamin, Emelia J and Heckbert, Susan R and K{\"a}{\"a}b, Stefan} } @article {1217, title = {Genome-wide association analysis identifies multiple loci related to resting heart rate.}, journal = {Hum Mol Genet}, volume = {19}, year = {2010}, month = {2010 Oct 01}, pages = {3885-94}, abstract = {

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 {\texttimes} 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7\% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6\%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

}, keywords = {Adult, Aged, Base Pairing, Cohort Studies, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Heart Rate, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Rest}, issn = {1460-2083}, doi = {10.1093/hmg/ddq303}, author = {Eijgelsheim, Mark and Newton-Cheh, Christopher and Sotoodehnia, Nona and de Bakker, Paul I W and M{\"u}ller, Martina and Morrison, Alanna C and Smith, Albert V and Isaacs, Aaron and Sanna, Serena and D{\"o}rr, Marcus and Navarro, Pau and Fuchsberger, Christian and Nolte, Ilja M and de Geus, Eco J C and Estrada, Karol and Hwang, Shih-Jen and Bis, Joshua C and R{\"u}ckert, Ina-Maria and Alonso, Alvaro and Launer, Lenore J and Hottenga, Jouke Jan and Rivadeneira, Fernando and Noseworthy, Peter A and Rice, Kenneth M and Perz, Siegfried and Arking, Dan E and Spector, Tim D and Kors, Jan A and Aulchenko, Yurii S and Tarasov, Kirill V and Homuth, Georg and Wild, Sarah H and Marroni, Fabio and Gieger, Christian and Licht, Carmilla M and Prineas, Ronald J and Hofman, Albert and Rotter, Jerome I and Hicks, Andrew A and Ernst, Florian and Najjar, Samer S and Wright, Alan F and Peters, Annette and Fox, Ervin R and Oostra, Ben A and Kroemer, Heyo K and Couper, David and V{\"o}lzke, Henry and Campbell, Harry and Meitinger, Thomas and Uda, Manuela and Witteman, Jacqueline C M and Psaty, Bruce M and Wichmann, H-Erich and Harris, Tamara B and K{\"a}{\"a}b, Stefan and Siscovick, David S and Jamshidi, Yalda and Uitterlinden, Andr{\'e} G and Folsom, Aaron R and Larson, Martin G and Wilson, James F and Penninx, Brenda W and Snieder, Harold and Pramstaller, Peter P and van Duijn, Cornelia M and Lakatta, Edward G and Felix, Stephan B and Gudnason, Vilmundur and Pfeufer, Arne and Heckbert, Susan R and Stricker, Bruno H Ch and Boerwinkle, Eric and O{\textquoteright}Donnell, Christopher J} } @article {6569, title = {Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.}, journal = {BMJ}, volume = {349}, year = {2014}, month = {2014 Jul 10}, pages = {g4164}, abstract = {

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.

DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.

PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.

MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.

RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2\% fewer units of alcohol per week (95\% confidence interval 15.6\% to 18.9\%), had a lower prevalence of binge drinking (odds ratio 0.78 (95\% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2\% (-7.8 to -2.4\%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).

CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

}, keywords = {Adult, Aged, Alcohol Dehydrogenase, Alcohol Drinking, Biomarkers, Coronary Disease, Female, Genetic Markers, Genotype, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Models, Statistical, Polymorphism, Single Nucleotide, Stroke}, issn = {1756-1833}, doi = {10.1136/bmj.g4164}, author = {Holmes, Michael V and Dale, Caroline E and Zuccolo, Luisa and Silverwood, Richard J and Guo, Yiran and Ye, Zheng and Prieto-Merino, David and Dehghan, Abbas and Trompet, Stella and Wong, Andrew and Cavadino, Alana and Drogan, Dagmar and Padmanabhan, Sandosh and Li, Shanshan and Yesupriya, Ajay and Leusink, Maarten and Sundstr{\"o}m, Johan and Hubacek, Jaroslav A and Pikhart, Hynek and Swerdlow, Daniel I and Panayiotou, Andrie G and Borinskaya, Svetlana A and Finan, Chris and Shah, Sonia and Kuchenbaecker, Karoline B and Shah, Tina and Engmann, Jorgen and Folkersen, Lasse and Eriksson, Per and Ricceri, Fulvio and Melander, Olle and Sacerdote, Carlotta and Gamble, Dale M and Rayaprolu, Sruti and Ross, Owen A and McLachlan, Stela and Vikhireva, Olga and Sluijs, Ivonne and Scott, Robert A and Adamkova, Vera and Flicker, Leon and Bockxmeer, Frank M van and Power, Christine and Marques-Vidal, Pedro and Meade, Tom and Marmot, Michael G and Ferro, Jose M and Paulos-Pinheiro, Sofia and Humphries, Steve E and Talmud, Philippa J and Mateo Leach, Irene and Verweij, Niek and Linneberg, Allan and Skaaby, Tea and Doevendans, Pieter A and Cramer, Maarten J and van der Harst, Pim and Klungel, Olaf H and Dowling, Nicole F and Dominiczak, Anna F and Kumari, Meena and Nicolaides, Andrew N and Weikert, Cornelia and Boeing, Heiner and Ebrahim, Shah and Gaunt, Tom R and Price, Jackie F and Lannfelt, Lars and Peasey, Anne and Kubinova, Ruzena and Pajak, Andrzej and Malyutina, Sofia and Voevoda, Mikhail I and Tamosiunas, Abdonas and Maitland-van der Zee, Anke H and Norman, Paul E and Hankey, Graeme J and Bergmann, Manuela M and Hofman, Albert and Franco, Oscar H and Cooper, Jackie and Palmen, Jutta and Spiering, Wilko and de Jong, Pim A and Kuh, Diana and Hardy, Rebecca and Uitterlinden, Andr{\'e} G and Ikram, M Arfan and Ford, Ian and Hypp{\"o}nen, Elina and Almeida, Osvaldo P and Wareham, Nicholas J and Khaw, Kay-Tee and Hamsten, Anders and Husemoen, Lise Lotte N and Tj{\o}nneland, Anne and Tolstrup, Janne S and Rimm, Eric and Beulens, Joline W J and Verschuren, W M Monique and Onland-Moret, N Charlotte and Hofker, Marten H and Wannamethee, S Goya and Whincup, Peter H and Morris, Richard and Vicente, Astrid M and Watkins, Hugh and Farrall, Martin and Jukema, J Wouter and Meschia, James and Cupples, L Adrienne and Sharp, Stephen J and Fornage, Myriam and Kooperberg, Charles and LaCroix, Andrea Z and Dai, James Y and Lanktree, Matthew B and Siscovick, David S and Jorgenson, Eric and Spring, Bonnie and Coresh, Josef and Li, Yun R and Buxbaum, Sarah G and Schreiner, Pamela J and Ellison, R Curtis and Tsai, Michael Y and Patel, Sanjay R and Redline, Susan and Johnson, Andrew D and Hoogeveen, Ron C and Hakonarson, Hakon and Rotter, Jerome I and Boerwinkle, Eric and de Bakker, Paul I W and Kivimaki, Mika and Asselbergs, Folkert W and Sattar, Naveed and Lawlor, Debbie A and Whittaker, John and Davey Smith, George and Mukamal, Kenneth and Psaty, Bruce M and Wilson, James G and Lange, Leslie A and Hamidovic, Ajna and Hingorani, Aroon D and Nordestgaard, B{\o}rge G and Bobak, Martin and Leon, David A and Langenberg, Claudia and Palmer, Tom M and Reiner, Alex P and Keating, Brendan J and Dudbridge, Frank and Casas, Juan P} } @article {6544, title = {Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Aug}, pages = {826-36}, abstract = {

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.

}, keywords = {Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.3014}, author = {Arking, Dan E and Pulit, Sara L and Crotti, Lia and van der Harst, Pim and Munroe, Patricia B and Koopmann, Tamara T and Sotoodehnia, Nona and Rossin, Elizabeth J and Morley, Michael and Wang, Xinchen and Johnson, Andrew D and Lundby, Alicia and Gudbjartsson, Daniel F and Noseworthy, Peter A and Eijgelsheim, Mark and Bradford, Yuki and Tarasov, Kirill V and D{\"o}rr, Marcus and M{\"u}ller-Nurasyid, Martina and Lahtinen, Annukka M and Nolte, Ilja M and Smith, Albert Vernon and Bis, Joshua C and Isaacs, Aaron and Newhouse, Stephen J and Evans, Daniel S and Post, Wendy S and Waggott, Daryl and Lyytik{\"a}inen, Leo-Pekka and Hicks, Andrew A and Eisele, Lewin and Ellinghaus, David and Hayward, Caroline and Navarro, Pau and Ulivi, Sheila and Tanaka, Toshiko and Tester, David J and Chatel, St{\'e}phanie and Gustafsson, Stefan and Kumari, Meena and Morris, Richard W and Naluai, {\r A}sa T and Padmanabhan, Sandosh and Kluttig, Alexander and Strohmer, Bernhard and Panayiotou, Andrie G and Torres, Maria and Knoflach, Michael and Hubacek, Jaroslav A and Slowikowski, Kamil and Raychaudhuri, Soumya and Kumar, Runjun D and Harris, Tamara B and Launer, Lenore J and Shuldiner, Alan R and Alonso, Alvaro and Bader, Joel S and Ehret, Georg and Huang, Hailiang and Kao, W H Linda and Strait, James B and Macfarlane, Peter W and Brown, Morris and Caulfield, Mark J and Samani, Nilesh J and Kronenberg, Florian and Willeit, Johann and Smith, J Gustav and Greiser, Karin H and Meyer Zu Schwabedissen, Henriette and Werdan, Karl and Carella, Massimo and Zelante, Leopoldo and Heckbert, Susan R and Psaty, Bruce M and Rotter, Jerome I and Kolcic, Ivana and Polasek, Ozren and Wright, Alan F and Griffin, Maura and Daly, Mark J and Arnar, David O and Holm, Hilma and Thorsteinsdottir, Unnur and Denny, Joshua C and Roden, Dan M and Zuvich, Rebecca L and Emilsson, Valur and Plump, Andrew S and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Yin, Xiaoyan and Bobbo, Marco and D{\textquoteright}Adamo, Adamo P and Iorio, Annamaria and Sinagra, Gianfranco and Carracedo, Angel and Cummings, Steven R and Nalls, Michael A and Jula, Antti and Kontula, Kimmo K and Marjamaa, Annukka and Oikarinen, Lasse and Perola, Markus and Porthan, Kimmo and Erbel, Raimund and Hoffmann, Per and J{\"o}ckel, Karl-Heinz and K{\"a}lsch, Hagen and N{\"o}then, Markus M and den Hoed, Marcel and Loos, Ruth J F and Thelle, Dag S and Gieger, Christian and Meitinger, Thomas and Perz, Siegfried and Peters, Annette and Prucha, Hanna and Sinner, Moritz F and Waldenberger, Melanie and de Boer, Rudolf A and Franke, Lude and van der Vleuten, Pieter A and Beckmann, Britt Maria and Martens, Eimo and Bardai, Abdennasser and Hofman, Nynke and Wilde, Arthur A M and Behr, Elijah R and Dalageorgou, Chrysoula and Giudicessi, John R and Medeiros-Domingo, Argelia and Barc, Julien and Kyndt, Florence and Probst, Vincent and Ghidoni, Alice and Insolia, Roberto and Hamilton, Robert M and Scherer, Stephen W and Brandimarto, Jeffrey and Margulies, Kenneth and Moravec, Christine E and del Greco M, Fabiola and Fuchsberger, Christian and O{\textquoteright}Connell, Jeffrey R and Lee, Wai K and Watt, Graham C M and Campbell, Harry and Wild, Sarah H and El Mokhtari, Nour E and Frey, Norbert and Asselbergs, Folkert W and Mateo Leach, Irene and Navis, Gerjan and van den Berg, Maarten P and van Veldhuisen, Dirk J and Kellis, Manolis and Krijthe, Bouwe P and Franco, Oscar H and Hofman, Albert and Kors, Jan A and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Kedenko, Lyudmyla and Lamina, Claudia and Oostra, Ben A and Abecasis, Goncalo R and Lakatta, Edward G and Mulas, Antonella and Orr{\`u}, Marco and Schlessinger, David and Uda, Manuela and Markus, Marcello R P and V{\"o}lker, Uwe and Snieder, Harold and Spector, Timothy D and Arnl{\"o}v, Johan and Lind, Lars and Sundstr{\"o}m, Johan and Syv{\"a}nen, Ann-Christine and Kivimaki, Mika and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Raitakari, Olli T and Viikari, Jorma S and Adamkova, Vera and Kiechl, Stefan and Brion, Maria and Nicolaides, Andrew N and Paulweber, Bernhard and Haerting, Johannes and Dominiczak, Anna F and Nyberg, Fredrik and Whincup, Peter H and Hingorani, Aroon D and Schott, Jean-Jacques and Bezzina, Connie R and Ingelsson, Erik and Ferrucci, Luigi and Gasparini, Paolo and Wilson, James F and Rudan, Igor and Franke, Andre and M{\"u}hleisen, Thomas W and Pramstaller, Peter P and Lehtim{\"a}ki, Terho J and Paterson, Andrew D and Parsa, Afshin and Liu, Yongmei and van Duijn, Cornelia M and Siscovick, David S and Gudnason, Vilmundur and Jamshidi, Yalda and Salomaa, Veikko and Felix, Stephan B and Sanna, Serena and Ritchie, Marylyn D and Stricker, Bruno H and Stefansson, Kari and Boyer, Laurie A and Cappola, Thomas P and Olsen, Jesper V and Lage, Kasper and Schwartz, Peter J and K{\"a}{\"a}b, Stefan and Chakravarti, Aravinda and Ackerman, Michael J and Pfeufer, Arne and de Bakker, Paul I W and Newton-Cheh, Christopher} }