TY - JOUR T1 - Common variants at ten loci influence QT interval duration in the QTGEN Study. JF - Nat Genet Y1 - 2009 A1 - Newton-Cheh, Christopher A1 - Eijgelsheim, Mark A1 - Rice, Kenneth M A1 - de Bakker, Paul I W A1 - Yin, Xiaoyan A1 - Estrada, Karol A1 - Bis, Joshua C A1 - Marciante, Kristin A1 - Rivadeneira, Fernando A1 - Noseworthy, Peter A A1 - Sotoodehnia, Nona A1 - Smith, Nicholas L A1 - Rotter, Jerome I A1 - Kors, Jan A A1 - Witteman, Jacqueline C M A1 - Hofman, Albert A1 - Heckbert, Susan R A1 - O'Donnell, Christopher J A1 - Uitterlinden, André G A1 - Psaty, Bruce M A1 - Lumley, Thomas A1 - Larson, Martin G A1 - Stricker, Bruno H Ch KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Aged KW - Arrhythmias, Cardiac KW - Chromosome Mapping KW - Death, Sudden, Cardiac KW - Electroencephalography KW - ERG1 Potassium Channel KW - Ether-A-Go-Go Potassium Channels KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome, Human KW - Humans KW - KCNQ1 Potassium Channel KW - Meta-Analysis as Topic KW - Muscle Proteins KW - NAV1.5 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Voltage-Gated KW - Risk Factors KW - Sodium Channels AB -

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.

VL - 41 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19305408?dopt=Abstract ER - TY - JOUR T1 - Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. JF - Nat Genet Y1 - 2010 A1 - Sotoodehnia, Nona A1 - Isaacs, Aaron A1 - de Bakker, Paul I W A1 - Dörr, Marcus A1 - Newton-Cheh, Christopher A1 - Nolte, Ilja M A1 - van der Harst, Pim A1 - Müller, Martina A1 - Eijgelsheim, Mark A1 - Alonso, Alvaro A1 - Hicks, Andrew A A1 - Padmanabhan, Sandosh A1 - Hayward, Caroline A1 - Smith, Albert Vernon A1 - Polasek, Ozren A1 - Giovannone, Steven A1 - Fu, Jingyuan A1 - Magnani, Jared W A1 - Marciante, Kristin D A1 - Pfeufer, Arne A1 - Gharib, Sina A A1 - Teumer, Alexander A1 - Li, Man A1 - Bis, Joshua C A1 - Rivadeneira, Fernando A1 - Aspelund, Thor A1 - Köttgen, Anna A1 - Johnson, Toby A1 - Rice, Kenneth A1 - Sie, Mark P S A1 - Wang, Ying A A1 - Klopp, Norman A1 - Fuchsberger, Christian A1 - Wild, Sarah H A1 - Mateo Leach, Irene A1 - Estrada, Karol A1 - Völker, Uwe A1 - Wright, Alan F A1 - Asselbergs, Folkert W A1 - Qu, Jiaxiang A1 - Chakravarti, Aravinda A1 - Sinner, Moritz F A1 - Kors, Jan A A1 - Petersmann, Astrid A1 - Harris, Tamara B A1 - Soliman, Elsayed Z A1 - Munroe, Patricia B A1 - Psaty, Bruce M A1 - Oostra, Ben A A1 - Cupples, L Adrienne A1 - Perz, Siegfried A1 - de Boer, Rudolf A A1 - Uitterlinden, André G A1 - Völzke, Henry A1 - Spector, Timothy D A1 - Liu, Fang-Yu A1 - Boerwinkle, Eric A1 - Dominiczak, Anna F A1 - Rotter, Jerome I A1 - van Herpen, Gé A1 - Levy, Daniel A1 - Wichmann, H-Erich A1 - van Gilst, Wiek H A1 - Witteman, Jacqueline C M A1 - Kroemer, Heyo K A1 - Kao, W H Linda A1 - Heckbert, Susan R A1 - Meitinger, Thomas A1 - Hofman, Albert A1 - Campbell, Harry A1 - Folsom, Aaron R A1 - van Veldhuisen, Dirk J A1 - Schwienbacher, Christine A1 - O'Donnell, Christopher J A1 - Volpato, Claudia Beu A1 - Caulfield, Mark J A1 - Connell, John M A1 - Launer, Lenore A1 - Lu, Xiaowen A1 - Franke, Lude A1 - Fehrmann, Rudolf S N A1 - te Meerman, Gerard A1 - Groen, Harry J M A1 - Weersma, Rinse K A1 - van den Berg, Leonard H A1 - Wijmenga, Cisca A1 - Ophoff, Roel A A1 - Navis, Gerjan A1 - Rudan, Igor A1 - Snieder, Harold A1 - Wilson, James F A1 - Pramstaller, Peter P A1 - Siscovick, David S A1 - Wang, Thomas J A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M A1 - Felix, Stephan B A1 - Fishman, Glenn I A1 - Jamshidi, Yalda A1 - Stricker, Bruno H Ch A1 - Samani, Nilesh J A1 - Kääb, Stefan A1 - Arking, Dan E KW - Animals KW - Animals, Newborn KW - Chromosomes, Human KW - Computational Biology KW - Electrocardiography KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Mice KW - Mice, Transgenic KW - Models, Animal KW - Myocytes, Cardiac KW - NAV1.8 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Sodium Channels AB -

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

VL - 42 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21076409?dopt=Abstract ER - TY - JOUR T1 - Common variants in KCNN3 are associated with lone atrial fibrillation. JF - Nat Genet Y1 - 2010 A1 - Ellinor, Patrick T A1 - Lunetta, Kathryn L A1 - Glazer, Nicole L A1 - Pfeufer, Arne A1 - Alonso, Alvaro A1 - Chung, Mina K A1 - Sinner, Moritz F A1 - de Bakker, Paul I W A1 - Mueller, Martina A1 - Lubitz, Steven A A1 - Fox, Ervin A1 - Darbar, Dawood A1 - Smith, Nicholas L A1 - Smith, Jonathan D A1 - Schnabel, Renate B A1 - Soliman, Elsayed Z A1 - Rice, Kenneth M A1 - Van Wagoner, David R A1 - Beckmann, Britt-M A1 - van Noord, Charlotte A1 - Wang, Ke A1 - Ehret, Georg B A1 - Rotter, Jerome I A1 - Hazen, Stanley L A1 - Steinbeck, Gerhard A1 - Smith, Albert V A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Makino, Seiko A1 - Nelis, Mari A1 - Milan, David J A1 - Perz, Siegfried A1 - Esko, Tõnu A1 - Köttgen, Anna A1 - Moebus, Susanne A1 - Newton-Cheh, Christopher A1 - Li, Man A1 - Möhlenkamp, Stefan A1 - Wang, Thomas J A1 - Kao, W H Linda A1 - Vasan, Ramachandran S A1 - Nöthen, Markus M A1 - MacRae, Calum A A1 - Stricker, Bruno H Ch A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Levy, Daniel A1 - Boerwinkle, Eric A1 - Metspalu, Andres A1 - Topol, Eric J A1 - Chakravarti, Aravinda A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Roden, Dan M A1 - Meitinger, Thomas A1 - Wichmann, H-Erich A1 - Witteman, Jacqueline C M A1 - Barnard, John A1 - Arking, Dan E A1 - Benjamin, Emelia J A1 - Heckbert, Susan R A1 - Kääb, Stefan KW - Adolescent KW - Adult KW - Aged KW - Atrial Fibrillation KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Humans KW - Introns KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Small-Conductance Calcium-Activated Potassium Channels KW - Young Adult AB -

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.

VL - 42 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20173747?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies multiple loci related to resting heart rate. JF - Hum Mol Genet Y1 - 2010 A1 - Eijgelsheim, Mark A1 - Newton-Cheh, Christopher A1 - Sotoodehnia, Nona A1 - de Bakker, Paul I W A1 - Müller, Martina A1 - Morrison, Alanna C A1 - Smith, Albert V A1 - Isaacs, Aaron A1 - Sanna, Serena A1 - Dörr, Marcus A1 - Navarro, Pau A1 - Fuchsberger, Christian A1 - Nolte, Ilja M A1 - de Geus, Eco J C A1 - Estrada, Karol A1 - Hwang, Shih-Jen A1 - Bis, Joshua C A1 - Rückert, Ina-Maria A1 - Alonso, Alvaro A1 - Launer, Lenore J A1 - Hottenga, Jouke Jan A1 - Rivadeneira, Fernando A1 - Noseworthy, Peter A A1 - Rice, Kenneth M A1 - Perz, Siegfried A1 - Arking, Dan E A1 - Spector, Tim D A1 - Kors, Jan A A1 - Aulchenko, Yurii S A1 - Tarasov, Kirill V A1 - Homuth, Georg A1 - Wild, Sarah H A1 - Marroni, Fabio A1 - Gieger, Christian A1 - Licht, Carmilla M A1 - Prineas, Ronald J A1 - Hofman, Albert A1 - Rotter, Jerome I A1 - Hicks, Andrew A A1 - Ernst, Florian A1 - Najjar, Samer S A1 - Wright, Alan F A1 - Peters, Annette A1 - Fox, Ervin R A1 - Oostra, Ben A A1 - Kroemer, Heyo K A1 - Couper, David A1 - Völzke, Henry A1 - Campbell, Harry A1 - Meitinger, Thomas A1 - Uda, Manuela A1 - Witteman, Jacqueline C M A1 - Psaty, Bruce M A1 - Wichmann, H-Erich A1 - Harris, Tamara B A1 - Kääb, Stefan A1 - Siscovick, David S A1 - Jamshidi, Yalda A1 - Uitterlinden, André G A1 - Folsom, Aaron R A1 - Larson, Martin G A1 - Wilson, James F A1 - Penninx, Brenda W A1 - Snieder, Harold A1 - Pramstaller, Peter P A1 - van Duijn, Cornelia M A1 - Lakatta, Edward G A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Pfeufer, Arne A1 - Heckbert, Susan R A1 - Stricker, Bruno H Ch A1 - Boerwinkle, Eric A1 - O'Donnell, Christopher J KW - Adult KW - Aged KW - Base Pairing KW - Cohort Studies KW - Female KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Heart Rate KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Rest AB -

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 × 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.

VL - 19 IS - 19 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20639392?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. JF - Lancet Neurol Y1 - 2012 A1 - Traylor, Matthew A1 - Farrall, Martin A1 - Holliday, Elizabeth G A1 - Sudlow, Cathie A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Malik, Rainer A1 - Bevan, Steve A1 - Thorsteinsdottir, Unnur A1 - Nalls, Mike A A1 - Longstreth, Wt A1 - Wiggins, Kerri L A1 - Yadav, Sunaina A1 - Parati, Eugenio A A1 - DeStefano, Anita L A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Khan, Muhammad Saleem A1 - Reiner, Alex P A1 - Helgadottir, Anna A1 - Achterberg, Sefanja A1 - Fernandez-Cadenas, Israel A1 - Abboud, Sherine A1 - Schmidt, Reinhold A1 - Walters, Matthew A1 - Chen, Wei-Min A1 - Ringelstein, E Bernd A1 - O'Donnell, Martin A1 - Ho, Weang Kee A1 - Pera, Joanna A1 - Lemmens, Robin A1 - Norrving, Bo A1 - Higgins, Peter A1 - Benn, Marianne A1 - Sale, Michele A1 - Kuhlenbäumer, Gregor A1 - Doney, Alexander S F A1 - Vicente, Astrid M A1 - Delavaran, Hossein A1 - Algra, Ale A1 - Davies, Gail A1 - Oliveira, Sofia A A1 - Palmer, Colin N A A1 - Deary, Ian A1 - Schmidt, Helena A1 - Pandolfo, Massimo A1 - Montaner, Joan A1 - Carty, Cara A1 - de Bakker, Paul I W A1 - Kostulas, Konstantinos A1 - Ferro, Jose M A1 - van Zuydam, Natalie R A1 - Valdimarsson, Einar A1 - Nordestgaard, Børge G A1 - Lindgren, Arne A1 - Thijs, Vincent A1 - Slowik, Agnieszka A1 - Saleheen, Danish A1 - Paré, Guillaume A1 - Berger, Klaus A1 - Thorleifsson, Gudmar A1 - Hofman, Albert A1 - Mosley, Thomas H A1 - Mitchell, Braxton D A1 - Furie, Karen A1 - Clarke, Robert A1 - Levi, Christopher A1 - Seshadri, Sudha A1 - Gschwendtner, Andreas A1 - Boncoraglio, Giorgio B A1 - Sharma, Pankaj A1 - Bis, Joshua C A1 - Gretarsdottir, Solveig A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Stefansson, Kari A1 - Dichgans, Martin A1 - Markus, Hugh S KW - Brain Ischemia KW - Databases, Genetic KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Stroke AB -

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 Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

VL - 11 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23041239?dopt=Abstract ER - TY - JOUR T1 - Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. JF - Nat Genet Y1 - 2013 A1 - den Hoed, Marcel A1 - Eijgelsheim, Mark A1 - Esko, Tõnu A1 - Brundel, Bianca J J M A1 - Peal, David S A1 - Evans, David M A1 - Nolte, Ilja M A1 - Segrè, Ayellet V A1 - Holm, Hilma A1 - Handsaker, Robert E A1 - Westra, Harm-Jan A1 - Johnson, Toby A1 - Isaacs, Aaron A1 - Yang, Jian A1 - Lundby, Alicia A1 - Zhao, Jing Hua A1 - Kim, Young Jin A1 - Go, Min Jin A1 - Almgren, Peter A1 - Bochud, Murielle A1 - Boucher, Gabrielle A1 - Cornelis, Marilyn C A1 - Gudbjartsson, Daniel A1 - Hadley, David A1 - van der Harst, Pim A1 - Hayward, Caroline A1 - den Heijer, Martin A1 - Igl, Wilmar A1 - Jackson, Anne U A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Kemp, John P A1 - Kristiansson, Kati A1 - Ladenvall, Claes A1 - Lorentzon, Mattias A1 - Montasser, May E A1 - Njajou, Omer T A1 - O'Reilly, Paul F A1 - Padmanabhan, Sandosh A1 - St Pourcain, Beate A1 - Rankinen, Tuomo A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - Timpson, Nicholas J A1 - Vitart, Veronique A1 - Waite, Lindsay A1 - Wheeler, William A1 - Zhang, Weihua A1 - Draisma, Harmen H M A1 - Feitosa, Mary F A1 - Kerr, Kathleen F A1 - Lind, Penelope A A1 - Mihailov, Evelin A1 - Onland-Moret, N Charlotte A1 - Song, Ci A1 - Weedon, Michael N A1 - Xie, Weijia A1 - Yengo, Loic A1 - Absher, Devin A1 - Albert, Christine M A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - de Bakker, Paul I W A1 - Balkau, Beverley A1 - Barlassina, Cristina A1 - Benaglio, Paola A1 - Bis, Joshua C A1 - Bouatia-Naji, Nabila A1 - Brage, Søren A1 - Chanock, Stephen J A1 - Chines, Peter S A1 - Chung, Mina A1 - Darbar, Dawood A1 - Dina, Christian A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Felix, Stephan B A1 - Fischer, Krista A1 - Fuchsberger, Christian A1 - de Geus, Eco J C A1 - Goyette, Philippe A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartikainen, Anna-Liisa A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Hicks, Andrew A A1 - Hofman, Albert A1 - Holewijn, Suzanne A1 - Hoogstra-Berends, Femke A1 - Hottenga, Jouke-Jan A1 - Jensen, Majken K A1 - Johansson, Asa A1 - Junttila, Juhani A1 - Kääb, Stefan A1 - Kanon, Bart A1 - Ketkar, Shamika A1 - Khaw, Kay-Tee A1 - Knowles, Joshua W A1 - Kooner, Angrad S A1 - Kors, Jan A A1 - Kumari, Meena A1 - Milani, Lili A1 - Laiho, Päivi A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Leusink, Maarten A1 - Liu, Yongmei A1 - Luben, Robert N A1 - Lunetta, Kathryn L A1 - Lynch, Stacey N A1 - Markus, Marcello R P A1 - Marques-Vidal, Pedro A1 - Mateo Leach, Irene A1 - McArdle, Wendy L A1 - McCarroll, Steven A A1 - Medland, Sarah E A1 - Miller, Kathryn A A1 - Montgomery, Grant W A1 - Morrison, Alanna C A1 - Müller-Nurasyid, Martina A1 - Navarro, Pau A1 - Nelis, Mari A1 - O'Connell, Jeffrey R A1 - O'Donnell, Christopher J A1 - Ong, Ken K A1 - Newman, Anne B A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Rao, Dabeeru C A1 - Ring, Susan M A1 - Rossin, Elizabeth J A1 - Rudan, Diana A1 - Sanna, Serena A1 - Scott, Robert A A1 - Sehmi, Jaban S A1 - Sharp, Stephen A1 - Shin, Jordan T A1 - Singleton, Andrew B A1 - Smith, Albert V A1 - Soranzo, Nicole A1 - Spector, Tim D A1 - Stewart, Chip A1 - Stringham, Heather M A1 - Tarasov, Kirill V A1 - Uitterlinden, André G A1 - Vandenput, Liesbeth A1 - Hwang, Shih-Jen A1 - Whitfield, John B A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Witteman, Jacqueline C M A1 - Wong, Andrew A1 - Wong, Quenna A1 - Jamshidi, Yalda A1 - Zitting, Paavo A1 - Boer, Jolanda M A A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Ekelund, Ulf A1 - Forouhi, Nita G A1 - Froguel, Philippe A1 - Hingorani, Aroon A1 - Ingelsson, Erik A1 - Kivimaki, Mika A1 - Kronmal, Richard A A1 - Kuh, Diana A1 - Lind, Lars A1 - Martin, Nicholas G A1 - Oostra, Ben A A1 - Pedersen, Nancy L A1 - Quertermous, Thomas A1 - Rotter, Jerome I A1 - van der Schouw, Yvonne T A1 - Verschuren, W M Monique A1 - Walker, Mark A1 - Albanes, Demetrius A1 - Arnar, David O A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Boehnke, Michael A1 - de Boer, Rudolf A A1 - Bouchard, Claude A1 - Caulfield, W L Mark A1 - Chambers, John C A1 - Curhan, Gary A1 - Cusi, Daniele A1 - Eriksson, Johan A1 - Ferrucci, Luigi A1 - van Gilst, Wiek H A1 - Glorioso, Nicola A1 - de Graaf, Jacqueline A1 - Groop, Leif A1 - Gyllensten, Ulf A1 - Hsueh, Wen-Chi A1 - Hu, Frank B A1 - Huikuri, Heikki V A1 - Hunter, David J A1 - Iribarren, Carlos A1 - Isomaa, Bo A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kiemeney, Lambertus A A1 - van der Klauw, Melanie M A1 - Kooner, Jaspal S A1 - Kraft, Peter A1 - Iacoviello, Licia A1 - Lehtimäki, Terho A1 - Lokki, Marja-Liisa L A1 - Mitchell, Braxton D A1 - Navis, Gerjan A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Poulter, Neil R A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Rimm, Eric B A1 - Rioux, John D A1 - Rizzi, Federica A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Sever, Peter S A1 - Shields, Denis C A1 - Shuldiner, Alan R A1 - Sinisalo, Juha A1 - Stanton, Alice V A1 - Stolk, Ronald P A1 - Strachan, David P A1 - Tardif, Jean-Claude A1 - Thorsteinsdottir, Unnur A1 - Tuomilehto, Jaako A1 - van Veldhuisen, Dirk J A1 - Virtamo, Jarmo A1 - Viikari, Jorma A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Widen, Elisabeth A1 - Cho, Yoon Shin A1 - Olsen, Jesper V A1 - Visscher, Peter M A1 - Willer, Cristen A1 - Franke, Lude A1 - Erdmann, Jeanette A1 - Thompson, John R A1 - Pfeufer, Arne A1 - Sotoodehnia, Nona A1 - Newton-Cheh, Christopher A1 - Ellinor, Patrick T A1 - Stricker, Bruno H Ch A1 - Metspalu, Andres A1 - Perola, Markus A1 - Beckmann, Jacques S A1 - Smith, George Davey A1 - Stefansson, Kari A1 - Wareham, Nicholas J A1 - Munroe, Patricia B A1 - Sibon, Ody C M A1 - Milan, David J A1 - Snieder, Harold A1 - Samani, Nilesh J A1 - Loos, Ruth J F KW - Animals KW - Arrhythmias, Cardiac KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Heart Rate KW - Humans KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

VL - 45 IS - 6 ER - TY - JOUR T1 - Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. JF - BMJ Y1 - 2014 A1 - Holmes, Michael V A1 - Dale, Caroline E A1 - Zuccolo, Luisa A1 - Silverwood, Richard J A1 - Guo, Yiran A1 - Ye, Zheng A1 - Prieto-Merino, David A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Wong, Andrew A1 - Cavadino, Alana A1 - Drogan, Dagmar A1 - Padmanabhan, Sandosh A1 - Li, Shanshan A1 - Yesupriya, Ajay A1 - Leusink, Maarten A1 - Sundström, Johan A1 - Hubacek, Jaroslav A A1 - Pikhart, Hynek A1 - Swerdlow, Daniel I A1 - Panayiotou, Andrie G A1 - Borinskaya, Svetlana A A1 - Finan, Chris A1 - Shah, Sonia A1 - Kuchenbaecker, Karoline B A1 - Shah, Tina A1 - Engmann, Jorgen A1 - Folkersen, Lasse A1 - Eriksson, Per A1 - Ricceri, Fulvio A1 - Melander, Olle A1 - Sacerdote, Carlotta A1 - Gamble, Dale M A1 - Rayaprolu, Sruti A1 - Ross, Owen A A1 - McLachlan, Stela A1 - Vikhireva, Olga A1 - Sluijs, Ivonne A1 - Scott, Robert A A1 - Adamkova, Vera A1 - Flicker, Leon A1 - Bockxmeer, Frank M van A1 - Power, Christine A1 - Marques-Vidal, Pedro A1 - Meade, Tom A1 - Marmot, Michael G A1 - Ferro, Jose M A1 - Paulos-Pinheiro, Sofia A1 - Humphries, Steve E A1 - Talmud, Philippa J A1 - Mateo Leach, Irene A1 - Verweij, Niek A1 - Linneberg, Allan A1 - Skaaby, Tea A1 - Doevendans, Pieter A A1 - Cramer, Maarten J A1 - van der Harst, Pim A1 - Klungel, Olaf H A1 - Dowling, Nicole F A1 - Dominiczak, Anna F A1 - Kumari, Meena A1 - Nicolaides, Andrew N A1 - Weikert, Cornelia A1 - Boeing, Heiner A1 - Ebrahim, Shah A1 - Gaunt, Tom R A1 - Price, Jackie F A1 - Lannfelt, Lars A1 - Peasey, Anne A1 - Kubinova, Ruzena A1 - Pajak, Andrzej A1 - Malyutina, Sofia A1 - Voevoda, Mikhail I A1 - Tamosiunas, Abdonas A1 - Maitland-van der Zee, Anke H A1 - Norman, Paul E A1 - Hankey, Graeme J A1 - Bergmann, Manuela M A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Cooper, Jackie A1 - Palmen, Jutta A1 - Spiering, Wilko A1 - de Jong, Pim A A1 - Kuh, Diana A1 - Hardy, Rebecca A1 - Uitterlinden, André G A1 - Ikram, M Arfan A1 - Ford, Ian A1 - Hyppönen, Elina A1 - Almeida, Osvaldo P A1 - Wareham, Nicholas J A1 - Khaw, Kay-Tee A1 - Hamsten, Anders A1 - Husemoen, Lise Lotte N A1 - Tjønneland, Anne A1 - Tolstrup, Janne S A1 - Rimm, Eric A1 - Beulens, Joline W J A1 - Verschuren, W M Monique A1 - Onland-Moret, N Charlotte A1 - Hofker, Marten H A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Morris, Richard A1 - Vicente, Astrid M A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Jukema, J Wouter A1 - Meschia, James A1 - Cupples, L Adrienne A1 - Sharp, Stephen J A1 - Fornage, Myriam A1 - Kooperberg, Charles A1 - LaCroix, Andrea Z A1 - Dai, James Y A1 - Lanktree, Matthew B A1 - Siscovick, David S A1 - Jorgenson, Eric A1 - Spring, Bonnie A1 - Coresh, Josef A1 - Li, Yun R A1 - Buxbaum, Sarah G A1 - Schreiner, Pamela J A1 - Ellison, R Curtis A1 - Tsai, Michael Y A1 - Patel, Sanjay R A1 - Redline, Susan A1 - Johnson, Andrew D A1 - Hoogeveen, Ron C A1 - Hakonarson, Hakon A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - de Bakker, Paul I W A1 - Kivimaki, Mika A1 - Asselbergs, Folkert W A1 - Sattar, Naveed A1 - Lawlor, Debbie A A1 - Whittaker, John A1 - Davey Smith, George A1 - Mukamal, Kenneth A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Lange, Leslie A A1 - Hamidovic, Ajna A1 - Hingorani, Aroon D A1 - Nordestgaard, Børge G A1 - Bobak, Martin A1 - Leon, David A A1 - Langenberg, Claudia A1 - Palmer, Tom M A1 - Reiner, Alex P A1 - Keating, Brendan J A1 - Dudbridge, Frank A1 - Casas, Juan P KW - Adult KW - Aged KW - Alcohol Dehydrogenase KW - Alcohol Drinking KW - Biomarkers KW - Coronary Disease KW - Female KW - Genetic Markers KW - Genotype KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Models, Statistical KW - Polymorphism, Single Nucleotide KW - Stroke AB -

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.

VL - 349 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25011450?dopt=Abstract ER - TY - JOUR T1 - Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. JF - Nat Genet Y1 - 2014 A1 - Arking, Dan E A1 - Pulit, Sara L A1 - Crotti, Lia A1 - van der Harst, Pim A1 - Munroe, Patricia B A1 - Koopmann, Tamara T A1 - Sotoodehnia, Nona A1 - Rossin, Elizabeth J A1 - Morley, Michael A1 - Wang, Xinchen A1 - Johnson, Andrew D A1 - Lundby, Alicia A1 - Gudbjartsson, Daniel F A1 - Noseworthy, Peter A A1 - Eijgelsheim, Mark A1 - Bradford, Yuki A1 - Tarasov, Kirill V A1 - Dörr, Marcus A1 - Müller-Nurasyid, Martina A1 - Lahtinen, Annukka M A1 - Nolte, Ilja M A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Isaacs, Aaron A1 - Newhouse, Stephen J A1 - Evans, Daniel S A1 - Post, Wendy S A1 - Waggott, Daryl A1 - Lyytikäinen, Leo-Pekka A1 - Hicks, Andrew A A1 - Eisele, Lewin A1 - Ellinghaus, David A1 - Hayward, Caroline A1 - Navarro, Pau A1 - Ulivi, Sheila A1 - Tanaka, Toshiko A1 - Tester, David J A1 - Chatel, Stéphanie A1 - Gustafsson, Stefan A1 - Kumari, Meena A1 - Morris, Richard W A1 - Naluai, Åsa T A1 - Padmanabhan, Sandosh A1 - Kluttig, Alexander A1 - Strohmer, Bernhard A1 - Panayiotou, Andrie G A1 - Torres, Maria A1 - Knoflach, Michael A1 - Hubacek, Jaroslav A A1 - Slowikowski, Kamil A1 - Raychaudhuri, Soumya A1 - Kumar, Runjun D A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shuldiner, Alan R A1 - Alonso, Alvaro A1 - Bader, Joel S A1 - Ehret, Georg A1 - Huang, Hailiang A1 - Kao, W H Linda A1 - Strait, James B A1 - Macfarlane, Peter W A1 - Brown, Morris A1 - Caulfield, Mark J A1 - Samani, Nilesh J A1 - Kronenberg, Florian A1 - Willeit, Johann A1 - Smith, J Gustav A1 - Greiser, Karin H A1 - Meyer Zu Schwabedissen, Henriette A1 - Werdan, Karl A1 - Carella, Massimo A1 - Zelante, Leopoldo A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wright, Alan F A1 - Griffin, Maura A1 - Daly, Mark J A1 - Arnar, David O A1 - Holm, Hilma A1 - Thorsteinsdottir, Unnur A1 - Denny, Joshua C A1 - Roden, Dan M A1 - Zuvich, Rebecca L A1 - Emilsson, Valur A1 - Plump, Andrew S A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Yin, Xiaoyan A1 - Bobbo, Marco A1 - D'Adamo, Adamo P A1 - Iorio, Annamaria A1 - Sinagra, Gianfranco A1 - Carracedo, Angel A1 - Cummings, Steven R A1 - Nalls, Michael A A1 - Jula, Antti A1 - Kontula, Kimmo K A1 - Marjamaa, Annukka A1 - Oikarinen, Lasse A1 - Perola, Markus A1 - Porthan, Kimmo A1 - Erbel, Raimund A1 - Hoffmann, Per A1 - Jöckel, Karl-Heinz A1 - Kälsch, Hagen A1 - Nöthen, Markus M A1 - den Hoed, Marcel A1 - Loos, Ruth J F A1 - Thelle, Dag S A1 - Gieger, Christian A1 - Meitinger, Thomas A1 - Perz, Siegfried A1 - Peters, Annette A1 - Prucha, Hanna A1 - Sinner, Moritz F A1 - Waldenberger, Melanie A1 - de Boer, Rudolf A A1 - Franke, Lude A1 - van der Vleuten, Pieter A A1 - Beckmann, Britt Maria A1 - Martens, Eimo A1 - Bardai, Abdennasser A1 - Hofman, Nynke A1 - Wilde, Arthur A M A1 - Behr, Elijah R A1 - Dalageorgou, Chrysoula A1 - Giudicessi, John R A1 - Medeiros-Domingo, Argelia A1 - Barc, Julien A1 - Kyndt, Florence A1 - Probst, Vincent A1 - Ghidoni, Alice A1 - Insolia, Roberto A1 - Hamilton, Robert M A1 - Scherer, Stephen W A1 - Brandimarto, Jeffrey A1 - Margulies, Kenneth A1 - Moravec, Christine E A1 - del Greco M, Fabiola A1 - Fuchsberger, Christian A1 - O'Connell, Jeffrey R A1 - Lee, Wai K A1 - Watt, Graham C M A1 - Campbell, Harry A1 - Wild, Sarah H A1 - El Mokhtari, Nour E A1 - Frey, Norbert A1 - Asselbergs, Folkert W A1 - Mateo Leach, Irene A1 - Navis, Gerjan A1 - van den Berg, Maarten P A1 - van Veldhuisen, Dirk J A1 - Kellis, Manolis A1 - Krijthe, Bouwe P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Kors, Jan A A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Kedenko, Lyudmyla A1 - Lamina, Claudia A1 - Oostra, Ben A A1 - Abecasis, Goncalo R A1 - Lakatta, Edward G A1 - Mulas, Antonella A1 - Orrù, Marco A1 - Schlessinger, David A1 - Uda, Manuela A1 - Markus, Marcello R P A1 - Völker, Uwe A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Arnlöv, Johan A1 - Lind, Lars A1 - Sundström, Johan A1 - Syvänen, Ann-Christine A1 - Kivimaki, Mika A1 - Kähönen, Mika A1 - Mononen, Nina A1 - Raitakari, Olli T A1 - Viikari, Jorma S A1 - Adamkova, Vera A1 - Kiechl, Stefan A1 - Brion, Maria A1 - Nicolaides, Andrew N A1 - Paulweber, Bernhard A1 - Haerting, Johannes A1 - Dominiczak, Anna F A1 - Nyberg, Fredrik A1 - Whincup, Peter H A1 - Hingorani, Aroon D A1 - Schott, Jean-Jacques A1 - Bezzina, Connie R A1 - Ingelsson, Erik A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Wilson, James F A1 - Rudan, Igor A1 - Franke, Andre A1 - Mühleisen, Thomas W A1 - Pramstaller, Peter P A1 - Lehtimäki, Terho J A1 - Paterson, Andrew D A1 - Parsa, Afshin A1 - Liu, Yongmei A1 - van Duijn, Cornelia M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Jamshidi, Yalda A1 - Salomaa, Veikko A1 - Felix, Stephan B A1 - Sanna, Serena A1 - Ritchie, Marylyn D A1 - Stricker, Bruno H A1 - Stefansson, Kari A1 - Boyer, Laurie A A1 - Cappola, Thomas P A1 - Olsen, Jesper V A1 - Lage, Kasper A1 - Schwartz, Peter J A1 - Kääb, Stefan A1 - Chakravarti, Aravinda A1 - Ackerman, Michael J A1 - Pfeufer, Arne A1 - de Bakker, Paul I W A1 - Newton-Cheh, Christopher KW - Adult KW - Aged KW - Arrhythmias, Cardiac KW - Calcium Signaling KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Heart Ventricles KW - Humans KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Myocardium KW - Polymorphism, Single Nucleotide AB -

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.

VL - 46 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12. JF - Neurology Y1 - 2014 A1 - Kilarski, Laura L A1 - Achterberg, Sefanja A1 - Devan, William J A1 - Traylor, Matthew A1 - Malik, Rainer A1 - Lindgren, Arne A1 - Pare, Guillame A1 - Sharma, Pankaj A1 - Slowik, Agniesczka A1 - Thijs, Vincent A1 - Walters, Matthew A1 - Worrall, Bradford B A1 - Sale, Michèle M A1 - Algra, Ale A1 - Kappelle, L Jaap A1 - Wijmenga, Cisca A1 - Norrving, Bo A1 - Sandling, Johanna K A1 - Rönnblom, Lars A1 - Goris, An A1 - Franke, Andre A1 - Sudlow, Cathie A1 - Rothwell, Peter M A1 - Levi, Christopher A1 - Holliday, Elizabeth G A1 - Fornage, Myriam A1 - Psaty, Bruce A1 - Gretarsdottir, Solveig A1 - Thorsteinsdottir, Unnar A1 - Seshadri, Sudha A1 - Mitchell, Braxton D A1 - Kittner, Steven A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Bis, Joshua C A1 - Boncoraglio, Giorgio B A1 - Meschia, James A1 - Ikram, M Arfan A1 - Hansen, Bjorn M A1 - Montaner, Joan A1 - Thorleifsson, Gudmar A1 - Stefanson, Kari A1 - Rosand, Jonathan A1 - de Bakker, Paul I W A1 - Farrall, Martin A1 - Dichgans, Martin A1 - Markus, Hugh S A1 - Bevan, Steve KW - Brain Ischemia KW - Cerebral Hemorrhage KW - Chromosomes, Human, Pair 12 KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk KW - Stroke AB -

OBJECTIVES: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.

METHODS: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.

RESULTS: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 × 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695).

CONCLUSION: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.

VL - 83 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25031287?dopt=Abstract ER - TY - JOUR T1 - Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels. JF - Nat Commun Y1 - 2015 A1 - van Leeuwen, Elisabeth M A1 - Karssen, Lennart C A1 - Deelen, Joris A1 - Isaacs, Aaron A1 - Medina-Gómez, Carolina A1 - Mbarek, Hamdi A1 - Kanterakis, Alexandros A1 - Trompet, Stella A1 - Postmus, Iris A1 - Verweij, Niek A1 - van Enckevort, David J A1 - Huffman, Jennifer E A1 - White, Charles C A1 - Feitosa, Mary F A1 - Bartz, Traci M A1 - Manichaikul, Ani A1 - Joshi, Peter K A1 - Peloso, Gina M A1 - Deelen, Patrick A1 - van Dijk, Freerk A1 - Willemsen, Gonneke A1 - de Geus, Eco J A1 - Milaneschi, Yuri A1 - Penninx, Brenda W J H A1 - Francioli, Laurent C A1 - Menelaou, Androniki A1 - Pulit, Sara L A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Oostra, Ben A A1 - Franco, Oscar H A1 - Mateo Leach, Irene A1 - Beekman, Marian A1 - de Craen, Anton J M A1 - Uh, Hae-Won A1 - Trochet, Holly A1 - Hocking, Lynne J A1 - Porteous, David J A1 - Sattar, Naveed A1 - Packard, Chris J A1 - Buckley, Brendan M A1 - Brody, Jennifer A A1 - Bis, Joshua C A1 - Rotter, Jerome I A1 - Mychaleckyj, Josyf C A1 - Campbell, Harry A1 - Duan, Qing A1 - Lange, Leslie A A1 - Wilson, James F A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Vitart, Veronique A1 - Rudan, Igor A1 - Wright, Alan F A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Borecki, Ingrid B A1 - Kearney, Patricia M A1 - Stott, David J A1 - Adrienne Cupples, L A1 - Jukema, J Wouter A1 - van der Harst, Pim A1 - Sijbrands, Eric J A1 - Hottenga, Jouke-Jan A1 - Uitterlinden, André G A1 - Swertz, Morris A A1 - van Ommen, Gert-Jan B A1 - de Bakker, Paul I W A1 - Eline Slagboom, P A1 - Boomsma, Dorret I A1 - Wijmenga, Cisca A1 - van Duijn, Cornelia M KW - ATP-Binding Cassette Transporters KW - Cholesterol KW - Gene Frequency KW - Genetic Association Studies KW - Humans KW - Mutation, Missense KW - Netherlands AB -

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25751400?dopt=Abstract ER - TY - JOUR T1 - Mendelian randomization of blood lipids for coronary heart disease. JF - Eur Heart J Y1 - 2015 A1 - Holmes, Michael V A1 - Asselbergs, Folkert W A1 - Palmer, Tom M A1 - Drenos, Fotios A1 - Lanktree, Matthew B A1 - Nelson, Christopher P A1 - Dale, Caroline E A1 - Padmanabhan, Sandosh A1 - Finan, Chris A1 - Swerdlow, Daniel I A1 - Tragante, Vinicius A1 - van Iperen, Erik P A A1 - Sivapalaratnam, Suthesh A1 - Shah, Sonia A1 - Elbers, Clara C A1 - Shah, Tina A1 - Engmann, Jorgen A1 - Giambartolomei, Claudia A1 - White, Jon A1 - Zabaneh, Delilah A1 - Sofat, Reecha A1 - McLachlan, Stela A1 - Doevendans, Pieter A A1 - Balmforth, Anthony J A1 - Hall, Alistair S A1 - North, Kari E A1 - Almoguera, Berta A1 - Hoogeveen, Ron C A1 - Cushman, Mary A1 - Fornage, Myriam A1 - Patel, Sanjay R A1 - Redline, Susan A1 - Siscovick, David S A1 - Tsai, Michael Y A1 - Karczewski, Konrad J A1 - Hofker, Marten H A1 - Verschuren, W Monique A1 - Bots, Michiel L A1 - van der Schouw, Yvonne T A1 - Melander, Olle A1 - Dominiczak, Anna F A1 - Morris, Richard A1 - Ben-Shlomo, Yoav A1 - Price, Jackie A1 - Kumari, Meena A1 - Baumert, Jens A1 - Peters, Annette A1 - Thorand, Barbara A1 - Koenig, Wolfgang A1 - Gaunt, Tom R A1 - Humphries, Steve E A1 - Clarke, Robert A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Wilson, James G A1 - Rich, Stephen S A1 - de Bakker, Paul I W A1 - Lange, Leslie A A1 - Davey Smith, George A1 - Reiner, Alex P A1 - Talmud, Philippa J A1 - Kivimaki, Mika A1 - Lawlor, Debbie A A1 - Dudbridge, Frank A1 - Samani, Nilesh J A1 - Keating, Brendan J A1 - Hingorani, Aroon D A1 - Casas, Juan P KW - Case-Control Studies KW - Cholesterol, HDL KW - Coronary Artery Disease KW - Female KW - Gene Frequency KW - Genotype KW - Genotyping Techniques KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Assessment KW - Triglycerides AB -

AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.

METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).

CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

VL - 36 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24474739?dopt=Abstract ER - TY - JOUR T1 - 52 Genetic Loci Influencing Myocardial Mass. JF - J Am Coll Cardiol Y1 - 2016 A1 - van der Harst, Pim A1 - van Setten, Jessica A1 - Verweij, Niek A1 - Vogler, Georg A1 - Franke, Lude A1 - Maurano, Matthew T A1 - Wang, Xinchen A1 - Mateo Leach, Irene A1 - Eijgelsheim, Mark A1 - Sotoodehnia, Nona A1 - Hayward, Caroline A1 - Sorice, Rossella A1 - Meirelles, Osorio A1 - Lyytikäinen, Leo-Pekka A1 - Polasek, Ozren A1 - Tanaka, Toshiko A1 - Arking, Dan E A1 - Ulivi, Sheila A1 - Trompet, Stella A1 - Müller-Nurasyid, Martina A1 - Smith, Albert V A1 - Dörr, Marcus A1 - Kerr, Kathleen F A1 - Magnani, Jared W A1 - del Greco M, Fabiola A1 - Zhang, Weihua A1 - Nolte, Ilja M A1 - Silva, Claudia T A1 - Padmanabhan, Sandosh A1 - Tragante, Vinicius A1 - Esko, Tõnu A1 - Abecasis, Goncalo R A1 - Adriaens, Michiel E A1 - Andersen, Karl A1 - Barnett, Phil A1 - Bis, Joshua C A1 - Bodmer, Rolf A1 - Buckley, Brendan M A1 - Campbell, Harry A1 - Cannon, Megan V A1 - Chakravarti, Aravinda A1 - Chen, Lin Y A1 - Delitala, Alessandro A1 - Devereux, Richard B A1 - Doevendans, Pieter A A1 - Dominiczak, Anna F A1 - Ferrucci, Luigi A1 - Ford, Ian A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Haugen, Eric A1 - Heinig, Matthias A1 - Hernandez, Dena G A1 - Hillege, Hans L A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hubner, Norbert A1 - Hwang, Shih-Jen A1 - Iorio, Annamaria A1 - Kähönen, Mika A1 - Kellis, Manolis A1 - Kolcic, Ivana A1 - Kooner, Ishminder K A1 - Kooner, Jaspal S A1 - Kors, Jan A A1 - Lakatta, Edward G A1 - Lage, Kasper A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Lundby, Alicia A1 - Macfarlane, Peter W A1 - May, Dalit A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Nappo, Stefania A1 - Naitza, Silvia A1 - Neph, Shane A1 - Nord, Alex S A1 - Nutile, Teresa A1 - Okin, Peter M A1 - Olsen, Jesper V A1 - Oostra, Ben A A1 - Penninger, Josef M A1 - Pennacchio, Len A A1 - Pers, Tune H A1 - Perz, Siegfried A1 - Peters, Annette A1 - Pinto, Yigal M A1 - Pfeufer, Arne A1 - Pilia, Maria Grazia A1 - Pramstaller, Peter P A1 - Prins, Bram P A1 - Raitakari, Olli T A1 - Raychaudhuri, Soumya A1 - Rice, Ken M A1 - Rossin, Elizabeth J A1 - Rotter, Jerome I A1 - Schafer, Sebastian A1 - Schlessinger, David A1 - Schmidt, Carsten O A1 - Sehmi, Jobanpreet A1 - Silljé, Herman H W A1 - Sinagra, Gianfranco A1 - Sinner, Moritz F A1 - Slowikowski, Kamil A1 - Soliman, Elsayed Z A1 - Spector, Timothy D A1 - Spiering, Wilko A1 - Stamatoyannopoulos, John A A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Tan, Sian-Tsung A1 - Tarasov, Kirill V A1 - Trinh, Bosco A1 - Uitterlinden, André G A1 - van den Boogaard, Malou A1 - van Duijn, Cornelia M A1 - van Gilst, Wiek H A1 - Viikari, Jorma S A1 - Visscher, Peter M A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Weichenberger, Christian X A1 - Westra, Harm-Jan A1 - Wijmenga, Cisca A1 - Wolffenbuttel, Bruce H A1 - Yang, Jian A1 - Bezzina, Connie R A1 - Munroe, Patricia B A1 - Snieder, Harold A1 - Wright, Alan F A1 - Rudan, Igor A1 - Boyer, Laurie A A1 - Asselbergs, Folkert W A1 - van Veldhuisen, Dirk J A1 - Stricker, Bruno H A1 - Psaty, Bruce M A1 - Ciullo, Marina A1 - Sanna, Serena A1 - Lehtimäki, Terho A1 - Wilson, James F A1 - Bandinelli, Stefania A1 - Alonso, Alvaro A1 - Gasparini, Paolo A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Gudnason, Vilmundur A1 - Felix, Stephan B A1 - Heckbert, Susan R A1 - de Boer, Rudolf A A1 - Newton-Cheh, Christopher A1 - Hicks, Andrew A A1 - Chambers, John C A1 - Jamshidi, Yalda A1 - Visel, Axel A1 - Christoffels, Vincent M A1 - Isaacs, Aaron A1 - Samani, Nilesh J A1 - de Bakker, Paul I W AB -

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.

OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.

METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.

RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.

CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

VL - 68 IS - 13 ER - TY - JOUR T1 - Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram. JF - Hum Mol Genet Y1 - 2016 A1 - Verweij, Niek A1 - Mateo Leach, Irene A1 - Isaacs, Aaron A1 - Arking, Dan E A1 - Bis, Joshua C A1 - Pers, Tune H A1 - van den Berg, Marten E A1 - Lyytikäinen, Leo-Pekka A1 - Barnett, Phil A1 - Wang, Xinchen A1 - Soliman, Elsayed Z A1 - van Duijn, Cornelia M A1 - Kähönen, Mika A1 - van Veldhuisen, Dirk J A1 - Kors, Jan A A1 - Raitakari, Olli T A1 - Silva, Claudia T A1 - Lehtimäki, Terho A1 - Hillege, Hans L A1 - Hirschhorn, Joel N A1 - Boyer, Laurie A A1 - van Gilst, Wiek H A1 - Alonso, Alvaro A1 - Sotoodehnia, Nona A1 - Eijgelsheim, Mark A1 - de Boer, Rudolf A A1 - de Bakker, Paul I W A1 - Franke, Lude A1 - van der Harst, Pim KW - Adaptor Proteins, Signal Transducing KW - Arrhythmias, Cardiac KW - Basic Helix-Loop-Helix Transcription Factors KW - Brugada Syndrome KW - Cardiac Conduction System Disease KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Male KW - NAV1.5 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Repressor Proteins KW - Shab Potassium Channels KW - Shal Potassium Channels AB -

The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.

VL - 25 IS - 10 ER - TY - JOUR T1 - Genetic loci associated with heart rate variability and their effects on cardiac disease risk. JF - Nat Commun Y1 - 2017 A1 - Nolte, Ilja M A1 - Munoz, M Loretto A1 - Tragante, Vinicius A1 - Amare, Azmeraw T A1 - Jansen, Rick A1 - Vaez, Ahmad A1 - von der Heyde, Benedikt A1 - Avery, Christy L A1 - Bis, Joshua C A1 - Dierckx, Bram A1 - van Dongen, Jenny A1 - Gogarten, Stephanie M A1 - Goyette, Philippe A1 - Hernesniemi, Jussi A1 - Huikari, Ville A1 - Hwang, Shih-Jen A1 - Jaju, Deepali A1 - Kerr, Kathleen F A1 - Kluttig, Alexander A1 - Krijthe, Bouwe P A1 - Kumar, Jitender A1 - van der Laan, Sander W A1 - Lyytikäinen, Leo-Pekka A1 - Maihofer, Adam X A1 - Minassian, Arpi A1 - van der Most, Peter J A1 - Müller-Nurasyid, Martina A1 - Nivard, Michel A1 - Salvi, Erika A1 - Stewart, James D A1 - Thayer, Julian F A1 - Verweij, Niek A1 - Wong, Andrew A1 - Zabaneh, Delilah A1 - Zafarmand, Mohammad H A1 - Abdellaoui, Abdel A1 - Albarwani, Sulayma A1 - Albert, Christine A1 - Alonso, Alvaro A1 - Ashar, Foram A1 - Auvinen, Juha A1 - Axelsson, Tomas A1 - Baker, Dewleen G A1 - de Bakker, Paul I W A1 - Barcella, Matteo A1 - Bayoumi, Riad A1 - Bieringa, Rob J A1 - Boomsma, Dorret A1 - Boucher, Gabrielle A1 - Britton, Annie R A1 - Christophersen, Ingrid A1 - Dietrich, Andrea A1 - Ehret, George B A1 - Ellinor, Patrick T A1 - Eskola, Markku A1 - Felix, Janine F A1 - Floras, John S A1 - Franco, Oscar H A1 - Friberg, Peter A1 - Gademan, Maaike G J A1 - Geyer, Mark A A1 - Giedraitis, Vilmantas A1 - Hartman, Catharina A A1 - Hemerich, Daiane A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huikuri, Heikki A1 - Hutri-Kähönen, Nina A1 - Jouven, Xavier A1 - Junttila, Juhani A1 - Juonala, Markus A1 - Kiviniemi, Antti M A1 - Kors, Jan A A1 - Kumari, Meena A1 - Kuznetsova, Tatiana A1 - Laurie, Cathy C A1 - Lefrandt, Joop D A1 - Li, Yong A1 - Li, Yun A1 - Liao, Duanping A1 - Limacher, Marian C A1 - Lin, Henry J A1 - Lindgren, Cecilia M A1 - Lubitz, Steven A A1 - Mahajan, Anubha A1 - McKnight, Barbara A1 - Zu Schwabedissen, Henriette Meyer A1 - Milaneschi, Yuri A1 - Mononen, Nina A1 - Morris, Andrew P A1 - Nalls, Mike A A1 - Navis, Gerjan A1 - Neijts, Melanie A1 - Nikus, Kjell A1 - North, Kari E A1 - O'Connor, Daniel T A1 - Ormel, Johan A1 - Perz, Siegfried A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Risbrough, Victoria B A1 - Sinner, Moritz F A1 - Siscovick, David A1 - Smit, Johannes H A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Staessen, Jan A A1 - Stein, Phyllis K A1 - Stilp, Adrienne M A1 - Stolarz-Skrzypek, Katarzyna A1 - Strauch, Konstantin A1 - Sundström, Johan A1 - Swenne, Cees A A1 - Syvänen, Ann-Christine A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thornton, Timothy A A1 - Tinker, Lesley E A1 - Uitterlinden, André G A1 - van Setten, Jessica A1 - Voss, Andreas A1 - Waldenberger, Melanie A1 - Wilhelmsen, Kirk C A1 - Willemsen, Gonneke A1 - Wong, Quenna A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Cusi, Daniele A1 - Evans, Michele K A1 - Greiser, Halina K A1 - van der Harst, Pim A1 - Hassan, Mohammad A1 - Ingelsson, Erik A1 - Jarvelin, Marjo-Riitta A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kivimaki, Mika A1 - Kooperberg, Charles A1 - Kuh, Diana A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Nievergelt, Caroline M A1 - O'Donnell, Chris J A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda A1 - Reiner, Alexander P A1 - Riese, Harriëtte A1 - van Roon, Arie M A1 - Rioux, John D A1 - Rotter, Jerome I A1 - Sofer, Tamar A1 - Stricker, Bruno H A1 - Tiemeier, Henning A1 - Vrijkotte, Tanja G M A1 - Asselbergs, Folkert W A1 - Brundel, Bianca J J M A1 - Heckbert, Susan R A1 - Whitsel, Eric A A1 - den Hoed, Marcel A1 - Snieder, Harold A1 - de Geus, Eco J C AB -

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 VL - 8 ER - TY - JOUR T1 - A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. JF - Eur Heart J Y1 - 2018 A1 - Ashar, Foram N A1 - Mitchell, Rebecca N A1 - Albert, Christine M A1 - Newton-Cheh, Christopher A1 - Brody, Jennifer A A1 - Müller-Nurasyid, Martina A1 - Moes, Anna A1 - Meitinger, Thomas A1 - Mak, Angel A1 - Huikuri, Heikki A1 - Junttila, M Juhani A1 - Goyette, Philippe A1 - Pulit, Sara L A1 - Pazoki, Raha A1 - Tanck, Michael W A1 - Blom, Marieke T A1 - Zhao, XiaoQing A1 - Havulinna, Aki S A1 - Jabbari, Reza A1 - Glinge, Charlotte A1 - Tragante, Vinicius A1 - Escher, Stefan A A1 - Chakravarti, Aravinda A1 - Ehret, Georg A1 - Coresh, Josef A1 - Li, Man A1 - Prineas, Ronald J A1 - Franco, Oscar H A1 - Kwok, Pui-Yan A1 - Lumley, Thomas A1 - Dumas, Florence A1 - McKnight, Barbara A1 - Rotter, Jerome I A1 - Lemaitre, Rozenn N A1 - Heckbert, Susan R A1 - O'Donnell, Christopher J A1 - Hwang, Shih-Jen A1 - Tardif, Jean-Claude A1 - VanDenburgh, Martin A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Stricker, Bruno H C A1 - de Bakker, Paul I W A1 - Franks, Paul W A1 - Jansson, Jan-Håkan A1 - Asselbergs, Folkert W A1 - Halushka, Marc K A1 - Maleszewski, Joseph J A1 - Tfelt-Hansen, Jacob A1 - Engstrøm, Thomas A1 - Salomaa, Veikko A1 - Virmani, Renu A1 - Kolodgie, Frank A1 - Wilde, Arthur A M A1 - Tan, Hanno L A1 - Bezzina, Connie R A1 - Eijgelsheim, Mark A1 - Rioux, John D A1 - Jouven, Xavier A1 - Kääb, Stefan A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Arking, Dan E A1 - Sotoodehnia, Nona AB -

Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.

Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.

Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

ER - TY - JOUR T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. JF - Nat Genet Y1 - 2018 A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - den Hoed, Marcel A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Bis, Joshua C A1 - Pastinen, Tomi A1 - Ruusalepp, Arno A1 - Schadt, Eric E A1 - Koplev, Simon A1 - Björkegren, Johan L M A1 - Codoni, Veronica A1 - Civelek, Mete A1 - Smith, Nicholas L A1 - Trégouët, David A A1 - Christophersen, Ingrid E A1 - Roselli, Carolina A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Tai, E Shyong A1 - Kooner, Jaspal S A1 - Kato, Norihiro A1 - He, Jiang A1 - van der Harst, Pim A1 - Elliott, Paul A1 - Chambers, John C A1 - Takeuchi, Fumihiko A1 - Johnson, Andrew D A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - Hoed, Marcel den A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Amin, Najaf A1 - Aparicio, Hugo S A1 - Arnett, Donna K A1 - Attia, John A1 - Beiser, Alexa S A1 - Berr, Claudine A1 - Buring, Julie E A1 - Bustamante, Mariana A1 - Caso, Valeria A1 - Cheng, Yu-Ching A1 - Choi, Seung Hoan A1 - Chowhan, Ayesha A1 - Cullell, Natalia A1 - Dartigues, Jean-François A1 - Delavaran, Hossein A1 - Delgado, Pilar A1 - Dörr, Marcus A1 - Engström, Gunnar A1 - Ford, Ian A1 - Gurpreet, Wander S A1 - Hamsten, Anders A1 - Heitsch, Laura A1 - Hozawa, Atsushi A1 - Ibanez, Laura A1 - Ilinca, Andreea A1 - Ingelsson, Martin A1 - Iwasaki, Motoki A1 - Jackson, Rebecca D A1 - Jood, Katarina A1 - Jousilahti, Pekka A1 - Kaffashian, Sara A1 - Kalra, Lalit A1 - Kamouchi, Masahiro A1 - Kitazono, Takanari A1 - Kjartansson, Olafur A1 - Kloss, Manja A1 - Koudstaal, Peter J A1 - Krupinski, Jerzy A1 - Labovitz, Daniel L A1 - Laurie, Cathy C A1 - Levi, Christopher R A1 - Li, Linxin A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lioutas, Vasileios A1 - Liu, Yong Mei A1 - Lopez, Oscar L A1 - Makoto, Hirata A1 - Martinez-Majander, Nicolas A1 - Matsuda, Koichi A1 - Minegishi, Naoko A1 - Montaner, Joan A1 - Morris, Andrew P A1 - Muiño, Elena A1 - Müller-Nurasyid, Martina A1 - Norrving, Bo A1 - Ogishima, Soichi A1 - Parati, Eugenio A A1 - Peddareddygari, Leema Reddy A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Perola, Markus A1 - Pezzini, Alessandro A1 - Pileggi, Silvana A1 - Rabionet, Raquel A1 - Riba-Llena, Iolanda A1 - Ribasés, Marta A1 - Romero, Jose R A1 - Roquer, Jaume A1 - Rudd, Anthony G A1 - Sarin, Antti-Pekka A1 - Sarju, Ralhan A1 - Sarnowski, Chloe A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Satoh, Mamoru A1 - Sattar, Naveed A1 - Sawada, Norie A1 - Sibolt, Gerli A1 - Sigurdsson, Ásgeir A1 - Smith, Albert A1 - Sobue, Kenji A1 - Soriano-Tárraga, Carolina A1 - Stanne, Tara A1 - Stine, O Colin A1 - Stott, David J A1 - Strauch, Konstantin A1 - Takai, Takako A1 - Tanaka, Hideo A1 - Tanno, Kozo A1 - Teumer, Alexander A1 - Tomppo, Liisa A1 - Torres-Aguila, Nuria P A1 - Touze, Emmanuel A1 - Tsugane, Shoichiro A1 - Uitterlinden, André G A1 - Valdimarsson, Einar M A1 - van der Lee, Sven J A1 - Völzke, Henry A1 - Wakai, Kenji A1 - Weir, David A1 - Williams, Stephen R A1 - Wolfe, Charles D A A1 - Wong, Quenna A1 - Xu, Huichun A1 - Yamaji, Taiki A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin AB -

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

VL - 50 IS - 4 ER - TY - JOUR T1 - PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. JF - Nat Commun Y1 - 2018 A1 - van Setten, Jessica A1 - Brody, Jennifer A A1 - Jamshidi, Yalda A1 - Swenson, Brenton R A1 - Butler, Anne M A1 - Campbell, Harry A1 - Del Greco, Fabiola M A1 - Evans, Daniel S A1 - Gibson, Quince A1 - Gudbjartsson, Daniel F A1 - Kerr, Kathleen F A1 - Krijthe, Bouwe P A1 - Lyytikäinen, Leo-Pekka A1 - Müller, Christian A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Ritchie, Marylyn D A1 - Robino, Antonietta A1 - Smith, Albert V A1 - Steri, Maristella A1 - Tanaka, Toshiko A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Ulivi, Sheila A1 - Verweij, Niek A1 - Yin, Xiaoyan A1 - Arnar, David O A1 - Asselbergs, Folkert W A1 - Bader, Joel S A1 - Barnard, John A1 - Bis, Josh A1 - Blankenberg, Stefan A1 - Boerwinkle, Eric A1 - Bradford, Yuki A1 - Buckley, Brendan M A1 - Chung, Mina K A1 - Crawford, Dana A1 - den Hoed, Marcel A1 - Denny, Josh C A1 - Dominiczak, Anna F A1 - Ehret, Georg B A1 - Eijgelsheim, Mark A1 - Ellinor, Patrick T A1 - Felix, Stephan B A1 - Franco, Oscar H A1 - Franke, Lude A1 - Harris, Tamara B A1 - Holm, Hilma A1 - Ilaria, Gandin A1 - Iorio, Annamaria A1 - Kähönen, Mika A1 - Kolcic, Ivana A1 - Kors, Jan A A1 - Lakatta, Edward G A1 - Launer, Lenore J A1 - Lin, Honghuang A1 - Lin, Henry J A1 - Loos, Ruth J F A1 - Lubitz, Steven A A1 - Macfarlane, Peter W A1 - Magnani, Jared W A1 - Leach, Irene Mateo A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Münzel, Thomas A1 - Papanicolaou, George J A1 - Peters, Annette A1 - Pfeufer, Arne A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Schlessinger, David A1 - Silva Aldana, Claudia T A1 - Sinner, Moritz F A1 - Smith, Jonathan D A1 - Snieder, Harold A1 - Soliman, Elsayed Z A1 - Spector, Timothy D A1 - Stott, David J A1 - Strauch, Konstantin A1 - Tarasov, Kirill V A1 - Thorsteinsdottir, Unnur A1 - Uitterlinden, André G A1 - Van Wagoner, David R A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Jan Westra, Harm A1 - Wild, Philipp S A1 - Zeller, Tanja A1 - Alonso, Alvaro A1 - Avery, Christy L A1 - Bandinelli, Stefania A1 - Benjamin, Emelia J A1 - Cucca, Francesco A1 - Dörr, Marcus A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hicks, Andrew A A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Munroe, Patricia B A1 - Parsa, Afshin A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Roden, Dan M A1 - Schnabel, Renate B A1 - Sinagra, Gianfranco A1 - Stefansson, Kari A1 - Stricker, Bruno H A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Wilson, James F A1 - Gharib, Sina A A1 - de Bakker, Paul I W A1 - Isaacs, Aaron A1 - Arking, Dan E A1 - Sotoodehnia, Nona AB -

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

VL - 9 IS - 1 ER -