@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 {1244, title = {Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Dec}, pages = {1068-76}, abstract = {

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 {\texttimes} 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.

}, keywords = {Animals, Animals, Newborn, Chromosomes, Human, Computational Biology, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Mice, Mice, Transgenic, Models, Animal, Myocytes, Cardiac, NAV1.8 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sodium Channels}, issn = {1546-1718}, doi = {10.1038/ng.716}, author = {Sotoodehnia, Nona and Isaacs, Aaron and de Bakker, Paul I W and D{\"o}rr, Marcus and Newton-Cheh, Christopher and Nolte, Ilja M and van der Harst, Pim and M{\"u}ller, Martina and Eijgelsheim, Mark and Alonso, Alvaro and Hicks, Andrew A and Padmanabhan, Sandosh and Hayward, Caroline and Smith, Albert Vernon and Polasek, Ozren and Giovannone, Steven and Fu, Jingyuan and Magnani, Jared W and Marciante, Kristin D and Pfeufer, Arne and Gharib, Sina A and Teumer, Alexander and Li, Man and Bis, Joshua C and Rivadeneira, Fernando and Aspelund, Thor and K{\"o}ttgen, Anna and Johnson, Toby and Rice, Kenneth and Sie, Mark P S and Wang, Ying A and Klopp, Norman and Fuchsberger, Christian and Wild, Sarah H and Mateo Leach, Irene and Estrada, Karol and V{\"o}lker, Uwe and Wright, Alan F and Asselbergs, Folkert W and Qu, Jiaxiang and Chakravarti, Aravinda and Sinner, Moritz F and Kors, Jan A and Petersmann, Astrid and Harris, Tamara B and Soliman, Elsayed Z and Munroe, Patricia B and Psaty, Bruce M and Oostra, Ben A and Cupples, L Adrienne and Perz, Siegfried and de Boer, Rudolf A and Uitterlinden, Andr{\'e} G and V{\"o}lzke, Henry and Spector, Timothy D and Liu, Fang-Yu and Boerwinkle, Eric and Dominiczak, Anna F and Rotter, Jerome I and van Herpen, G{\'e} and Levy, Daniel and Wichmann, H-Erich and van Gilst, Wiek H and Witteman, Jacqueline C M and Kroemer, Heyo K and Kao, W H Linda and Heckbert, Susan R and Meitinger, Thomas and Hofman, Albert and Campbell, Harry and Folsom, Aaron R and van Veldhuisen, Dirk J and Schwienbacher, Christine and O{\textquoteright}Donnell, Christopher J and Volpato, Claudia Beu and Caulfield, Mark J and Connell, John M and Launer, Lenore and Lu, Xiaowen and Franke, Lude and Fehrmann, Rudolf S N and te Meerman, Gerard and Groen, Harry J M and Weersma, Rinse K and van den Berg, Leonard H and Wijmenga, Cisca and Ophoff, Roel A and Navis, Gerjan and Rudan, Igor and Snieder, Harold and Wilson, James F and Pramstaller, Peter P and Siscovick, David S and Wang, Thomas J and Gudnason, Vilmundur and van Duijn, Cornelia M and Felix, Stephan B and Fishman, Glenn I and Jamshidi, Yalda and Stricker, Bruno H Ch and Samani, Nilesh J and K{\"a}{\"a}b, Stefan and Arking, Dan E} } @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 {5863, title = {Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.}, journal = {Lancet Neurol}, volume = {11}, year = {2012}, month = {2012 Nov}, pages = {951-62}, abstract = {

BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.

METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.

FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2{\textperiodcentered}8{\texttimes}10(-16)) and ZFHX3 (p=2{\textperiodcentered}28{\texttimes}10(-8)), and for large-vessel stroke at a 9p21 locus (p=3{\textperiodcentered}32{\texttimes}10(-5)) and HDAC9 (p=2{\textperiodcentered}03{\texttimes}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{\texttimes}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).

}, keywords = {Brain Ischemia, Databases, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Risk Factors, Stroke}, issn = {1474-4465}, doi = {10.1016/S1474-4422(12)70234-X}, author = {Traylor, Matthew and Farrall, Martin and Holliday, Elizabeth G and Sudlow, Cathie and Hopewell, Jemma C and Cheng, Yu-Ching and Fornage, Myriam and Ikram, M Arfan and Malik, Rainer and Bevan, Steve and Thorsteinsdottir, Unnur and Nalls, Mike A and Longstreth, Wt and Wiggins, Kerri L and Yadav, Sunaina and Parati, Eugenio A and DeStefano, Anita L and Worrall, Bradford B and Kittner, Steven J and Khan, Muhammad Saleem and Reiner, Alex P and Helgadottir, Anna and Achterberg, Sefanja and Fernandez-Cadenas, Israel and Abboud, Sherine and Schmidt, Reinhold and Walters, Matthew and Chen, Wei-Min and Ringelstein, E Bernd and O{\textquoteright}Donnell, Martin and Ho, Weang Kee and Pera, Joanna and Lemmens, Robin and Norrving, Bo and Higgins, Peter and Benn, Marianne and Sale, Michele and Kuhlenb{\"a}umer, Gregor and Doney, Alexander S F and Vicente, Astrid M and Delavaran, Hossein and Algra, Ale and Davies, Gail and Oliveira, Sofia A and Palmer, Colin N A and Deary, Ian and Schmidt, Helena and Pandolfo, Massimo and Montaner, Joan and Carty, Cara and de Bakker, Paul I W and Kostulas, Konstantinos and Ferro, Jose M and van Zuydam, Natalie R and Valdimarsson, Einar and Nordestgaard, B{\o}rge G and Lindgren, Arne and Thijs, Vincent and Slowik, Agnieszka and Saleheen, Danish and Par{\'e}, Guillaume and Berger, Klaus and Thorleifsson, Gudmar and Hofman, Albert and Mosley, Thomas H and Mitchell, Braxton D and Furie, Karen and Clarke, Robert and Levi, Christopher and Seshadri, Sudha and Gschwendtner, Andreas and Boncoraglio, Giorgio B and Sharma, Pankaj and Bis, Joshua C and Gretarsdottir, Solveig and Psaty, Bruce M and Rothwell, Peter M and Rosand, Jonathan and Meschia, James F and Stefansson, Kari and Dichgans, Martin and Markus, Hugh S} } @article {8015, title = {Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Jun}, pages = {621-31}, abstract = {

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.

}, keywords = {Animals, Arrhythmias, Cardiac, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Heart Rate, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1546-1718}, doi = {10.1038/ng.2610}, author = {den Hoed, Marcel and Eijgelsheim, Mark and Esko, T{\~o}nu and Brundel, Bianca J J M and Peal, David S and Evans, David M and Nolte, Ilja M and Segr{\`e}, Ayellet V and Holm, Hilma and Handsaker, Robert E and Westra, Harm-Jan and Johnson, Toby and Isaacs, Aaron and Yang, Jian and Lundby, Alicia and Zhao, Jing Hua and Kim, Young Jin and Go, Min Jin and Almgren, Peter and Bochud, Murielle and Boucher, Gabrielle and Cornelis, Marilyn C and Gudbjartsson, Daniel and Hadley, David and van der Harst, Pim and Hayward, Caroline and den Heijer, Martin and Igl, Wilmar and Jackson, Anne U and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Kemp, John P and Kristiansson, Kati and Ladenvall, Claes and Lorentzon, Mattias and Montasser, May E and Njajou, Omer T and O{\textquoteright}Reilly, Paul F and Padmanabhan, Sandosh and St Pourcain, Beate and Rankinen, Tuomo and Salo, Perttu and Tanaka, Toshiko and Timpson, Nicholas J and Vitart, Veronique and Waite, Lindsay and Wheeler, William and Zhang, Weihua and Draisma, Harmen H M and Feitosa, Mary F and Kerr, Kathleen F and Lind, Penelope A and Mihailov, Evelin and Onland-Moret, N Charlotte and Song, Ci and Weedon, Michael N and Xie, Weijia and Yengo, Loic and Absher, Devin and Albert, Christine M and Alonso, Alvaro and Arking, Dan E and de Bakker, Paul I W and Balkau, Beverley and Barlassina, Cristina and Benaglio, Paola and Bis, Joshua C and Bouatia-Naji, Nabila and Brage, S{\o}ren and Chanock, Stephen J and Chines, Peter S and Chung, Mina and Darbar, Dawood and Dina, Christian and D{\"o}rr, Marcus and Elliott, Paul and Felix, Stephan B and Fischer, Krista and Fuchsberger, Christian and de Geus, Eco J C and Goyette, Philippe and Gudnason, Vilmundur and Harris, Tamara B and Hartikainen, Anna-Liisa and Havulinna, Aki S and Heckbert, Susan R and Hicks, Andrew A and Hofman, Albert and Holewijn, Suzanne and Hoogstra-Berends, Femke and Hottenga, Jouke-Jan and Jensen, Majken K and Johansson, Asa and Junttila, Juhani and K{\"a}{\"a}b, Stefan and Kanon, Bart and Ketkar, Shamika and Khaw, Kay-Tee and Knowles, Joshua W and Kooner, Angrad S and Kors, Jan A and Kumari, Meena and Milani, Lili and Laiho, P{\"a}ivi and Lakatta, Edward G and Langenberg, Claudia and Leusink, Maarten and Liu, Yongmei and Luben, Robert N and Lunetta, Kathryn L and Lynch, Stacey N and Markus, Marcello R P and Marques-Vidal, Pedro and Mateo Leach, Irene and McArdle, Wendy L and McCarroll, Steven A and Medland, Sarah E and Miller, Kathryn A and Montgomery, Grant W and Morrison, Alanna C and M{\"u}ller-Nurasyid, Martina and Navarro, Pau and Nelis, Mari and O{\textquoteright}Connell, Jeffrey R and O{\textquoteright}Donnell, Christopher J and Ong, Ken K and Newman, Anne B and Peters, Annette and Polasek, Ozren and Pouta, Anneli and Pramstaller, Peter P and Psaty, Bruce M and Rao, Dabeeru C and Ring, Susan M and Rossin, Elizabeth J and Rudan, Diana and Sanna, Serena and Scott, Robert A and Sehmi, Jaban S and Sharp, Stephen and Shin, Jordan T and Singleton, Andrew B and Smith, Albert V and Soranzo, Nicole and Spector, Tim D and Stewart, Chip and Stringham, Heather M and Tarasov, Kirill V and Uitterlinden, Andr{\'e} G and Vandenput, Liesbeth and Hwang, Shih-Jen and Whitfield, John B and Wijmenga, Cisca and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Witteman, Jacqueline C M and Wong, Andrew and Wong, Quenna and Jamshidi, Yalda and Zitting, Paavo and Boer, Jolanda M A and Boomsma, Dorret I and Borecki, Ingrid B and van Duijn, Cornelia M and Ekelund, Ulf and Forouhi, Nita G and Froguel, Philippe and Hingorani, Aroon and Ingelsson, Erik and Kivimaki, Mika and Kronmal, Richard A and Kuh, Diana and Lind, Lars and Martin, Nicholas G and Oostra, Ben A and Pedersen, Nancy L and Quertermous, Thomas and Rotter, Jerome I and van der Schouw, Yvonne T and Verschuren, W M Monique and Walker, Mark and Albanes, Demetrius and Arnar, David O and Assimes, Themistocles L and Bandinelli, Stefania and Boehnke, Michael and de Boer, Rudolf A and Bouchard, Claude and Caulfield, W L Mark and Chambers, John C and Curhan, Gary and Cusi, Daniele and Eriksson, Johan and Ferrucci, Luigi and van Gilst, Wiek H and Glorioso, Nicola and de Graaf, Jacqueline and Groop, Leif and Gyllensten, Ulf and Hsueh, Wen-Chi and Hu, Frank B and Huikuri, Heikki V and Hunter, David J and Iribarren, Carlos and Isomaa, Bo and Jarvelin, Marjo-Riitta and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kiemeney, Lambertus A and van der Klauw, Melanie M and Kooner, Jaspal S and Kraft, Peter and Iacoviello, Licia and Lehtim{\"a}ki, Terho and Lokki, Marja-Liisa L and Mitchell, Braxton D and Navis, Gerjan and Nieminen, Markku S and Ohlsson, Claes and Poulter, Neil R and Qi, Lu and Raitakari, Olli T and Rimm, Eric B and Rioux, John D and Rizzi, Federica and Rudan, Igor and Salomaa, Veikko and Sever, Peter S and Shields, Denis C and Shuldiner, Alan R and Sinisalo, Juha and Stanton, Alice V and Stolk, Ronald P and Strachan, David P and Tardif, Jean-Claude and Thorsteinsdottir, Unnur and Tuomilehto, Jaako and van Veldhuisen, Dirk J and Virtamo, Jarmo and Viikari, Jorma and Vollenweider, Peter and Waeber, G{\'e}rard and Widen, Elisabeth and Cho, Yoon Shin and Olsen, Jesper V and Visscher, Peter M and Willer, Cristen and Franke, Lude and Erdmann, Jeanette and Thompson, John R and Pfeufer, Arne and Sotoodehnia, Nona and Newton-Cheh, Christopher and Ellinor, Patrick T and Stricker, Bruno H Ch and Metspalu, Andres and Perola, Markus and Beckmann, Jacques S and Smith, George Davey and Stefansson, Kari and Wareham, Nicholas J and Munroe, Patricia B and Sibon, Ody C M and Milan, David J and Snieder, Harold and Samani, Nilesh J and Loos, Ruth J F} } @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} } @article {6574, title = {Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12.}, journal = {Neurology}, volume = {83}, year = {2014}, month = {2014 Aug 19}, pages = {678-85}, abstract = {

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 {\texttimes} 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.

}, keywords = {Brain Ischemia, Cerebral Hemorrhage, Chromosomes, Human, Pair 12, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Risk, Stroke}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000000707}, author = {Kilarski, Laura L and Achterberg, Sefanja and Devan, William J and Traylor, Matthew and Malik, Rainer and Lindgren, Arne and Pare, Guillame and Sharma, Pankaj and Slowik, Agniesczka and Thijs, Vincent and Walters, Matthew and Worrall, Bradford B and Sale, Mich{\`e}le M and Algra, Ale and Kappelle, L Jaap and Wijmenga, Cisca and Norrving, Bo and Sandling, Johanna K and R{\"o}nnblom, Lars and Goris, An and Franke, Andre and Sudlow, Cathie and Rothwell, Peter M and Levi, Christopher and Holliday, Elizabeth G and Fornage, Myriam and Psaty, Bruce and Gretarsdottir, Solveig and Thorsteinsdottir, Unnar and Seshadri, Sudha and Mitchell, Braxton D and Kittner, Steven and Clarke, Robert and Hopewell, Jemma C and Bis, Joshua C and Boncoraglio, Giorgio B and Meschia, James and Ikram, M Arfan and Hansen, Bjorn M and Montaner, Joan and Thorleifsson, Gudmar and Stefanson, Kari and Rosand, Jonathan and de Bakker, Paul I W and Farrall, Martin and Dichgans, Martin and Markus, Hugh S and Bevan, Steve} } @article {6682, title = {Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.}, journal = {Nat Commun}, volume = {6}, year = {2015}, month = {2015}, pages = {6065}, abstract = {

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 {\texttimes} 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.

}, keywords = {ATP-Binding Cassette Transporters, Cholesterol, Gene Frequency, Genetic Association Studies, Humans, Mutation, Missense, Netherlands}, issn = {2041-1723}, doi = {10.1038/ncomms7065}, author = {van Leeuwen, Elisabeth M and Karssen, Lennart C and Deelen, Joris and Isaacs, Aaron and Medina-G{\'o}mez, Carolina and Mbarek, Hamdi and Kanterakis, Alexandros and Trompet, Stella and Postmus, Iris and Verweij, Niek and van Enckevort, David J and Huffman, Jennifer E and White, Charles C and Feitosa, Mary F and Bartz, Traci M and Manichaikul, Ani and Joshi, Peter K and Peloso, Gina M and Deelen, Patrick and van Dijk, Freerk and Willemsen, Gonneke and de Geus, Eco J and Milaneschi, Yuri and Penninx, Brenda W J H and Francioli, Laurent C and Menelaou, Androniki and Pulit, Sara L and Rivadeneira, Fernando and Hofman, Albert and Oostra, Ben A and Franco, Oscar H and Mateo Leach, Irene and Beekman, Marian and de Craen, Anton J M and Uh, Hae-Won and Trochet, Holly and Hocking, Lynne J and Porteous, David J and Sattar, Naveed and Packard, Chris J and Buckley, Brendan M and Brody, Jennifer A and Bis, Joshua C and Rotter, Jerome I and Mychaleckyj, Josyf C and Campbell, Harry and Duan, Qing and Lange, Leslie A and Wilson, James F and Hayward, Caroline and Polasek, Ozren and Vitart, Veronique and Rudan, Igor and Wright, Alan F and Rich, Stephen S and Psaty, Bruce M and Borecki, Ingrid B and Kearney, Patricia M and Stott, David J and Adrienne Cupples, L and Jukema, J Wouter and van der Harst, Pim and Sijbrands, Eric J and Hottenga, Jouke-Jan and Uitterlinden, Andr{\'e} G and Swertz, Morris A and van Ommen, Gert-Jan B and de Bakker, Paul I W and Eline Slagboom, P and Boomsma, Dorret I and Wijmenga, Cisca and van Duijn, Cornelia M} } @article {6568, title = {Mendelian randomization of blood lipids for coronary heart disease.}, journal = {Eur Heart J}, volume = {36}, year = {2015}, month = {2015 Mar 01}, pages = {539-50}, abstract = {

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 {\texttimes} 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.

}, keywords = {Case-Control Studies, Cholesterol, HDL, Coronary Artery Disease, Female, Gene Frequency, Genotype, Genotyping Techniques, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Triglycerides}, issn = {1522-9645}, doi = {10.1093/eurheartj/eht571}, author = {Holmes, Michael V and Asselbergs, Folkert W and Palmer, Tom M and Drenos, Fotios and Lanktree, Matthew B and Nelson, Christopher P and Dale, Caroline E and Padmanabhan, Sandosh and Finan, Chris and Swerdlow, Daniel I and Tragante, Vinicius and van Iperen, Erik P A and Sivapalaratnam, Suthesh and Shah, Sonia and Elbers, Clara C and Shah, Tina and Engmann, Jorgen and Giambartolomei, Claudia and White, Jon and Zabaneh, Delilah and Sofat, Reecha and McLachlan, Stela and Doevendans, Pieter A and Balmforth, Anthony J and Hall, Alistair S and North, Kari E and Almoguera, Berta and Hoogeveen, Ron C and Cushman, Mary and Fornage, Myriam and Patel, Sanjay R and Redline, Susan and Siscovick, David S and Tsai, Michael Y and Karczewski, Konrad J and Hofker, Marten H and Verschuren, W Monique and Bots, Michiel L and van der Schouw, Yvonne T and Melander, Olle and Dominiczak, Anna F and Morris, Richard and Ben-Shlomo, Yoav and Price, Jackie and Kumari, Meena and Baumert, Jens and Peters, Annette and Thorand, Barbara and Koenig, Wolfgang and Gaunt, Tom R and Humphries, Steve E and Clarke, Robert and Watkins, Hugh and Farrall, Martin and Wilson, James G and Rich, Stephen S and de Bakker, Paul I W and Lange, Leslie A and Davey Smith, George and Reiner, Alex P and Talmud, Philippa J and Kivimaki, Mika and Lawlor, Debbie A and Dudbridge, Frank and Samani, Nilesh J and Keating, Brendan J and Hingorani, Aroon D and Casas, Juan P} } @article {7262, title = {52 Genetic Loci Influencing Myocardial~Mass.}, journal = {J Am Coll Cardiol}, volume = {68}, year = {2016}, month = {2016 Sep 27}, pages = {1435-48}, abstract = {

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~{\texttimes} 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.

}, issn = {1558-3597}, doi = {10.1016/j.jacc.2016.07.729}, author = {van der Harst, Pim and van Setten, Jessica and Verweij, Niek and Vogler, Georg and Franke, Lude and Maurano, Matthew T and Wang, Xinchen and Mateo Leach, Irene and Eijgelsheim, Mark and Sotoodehnia, Nona and Hayward, Caroline and Sorice, Rossella and Meirelles, Osorio and Lyytik{\"a}inen, Leo-Pekka and Polasek, Ozren and Tanaka, Toshiko and Arking, Dan E and Ulivi, Sheila and Trompet, Stella and M{\"u}ller-Nurasyid, Martina and Smith, Albert V and D{\"o}rr, Marcus and Kerr, Kathleen F and Magnani, Jared W and del Greco M, Fabiola and Zhang, Weihua and Nolte, Ilja M and Silva, Claudia T and Padmanabhan, Sandosh and Tragante, Vinicius and Esko, T{\~o}nu and Abecasis, Goncalo R and Adriaens, Michiel E and Andersen, Karl and Barnett, Phil and Bis, Joshua C and Bodmer, Rolf and Buckley, Brendan M and Campbell, Harry and Cannon, Megan V and Chakravarti, Aravinda and Chen, Lin Y and Delitala, Alessandro and Devereux, Richard B and Doevendans, Pieter A and Dominiczak, Anna F and Ferrucci, Luigi and Ford, Ian and Gieger, Christian and Harris, Tamara B and Haugen, Eric and Heinig, Matthias and Hernandez, Dena G and Hillege, Hans L and Hirschhorn, Joel N and Hofman, Albert and Hubner, Norbert and Hwang, Shih-Jen and Iorio, Annamaria and K{\"a}h{\"o}nen, Mika and Kellis, Manolis and Kolcic, Ivana and Kooner, Ishminder K and Kooner, Jaspal S and Kors, Jan A and Lakatta, Edward G and Lage, Kasper and Launer, Lenore J and Levy, Daniel and Lundby, Alicia and Macfarlane, Peter W and May, Dalit and Meitinger, Thomas and Metspalu, Andres and Nappo, Stefania and Naitza, Silvia and Neph, Shane and Nord, Alex S and Nutile, Teresa and Okin, Peter M and Olsen, Jesper V and Oostra, Ben A and Penninger, Josef M and Pennacchio, Len A and Pers, Tune H and Perz, Siegfried and Peters, Annette and Pinto, Yigal M and Pfeufer, Arne and Pilia, Maria Grazia and Pramstaller, Peter P and Prins, Bram P and Raitakari, Olli T and Raychaudhuri, Soumya and Rice, Ken M and Rossin, Elizabeth J and Rotter, Jerome I and Schafer, Sebastian and Schlessinger, David and Schmidt, Carsten O and Sehmi, Jobanpreet and Sillj{\'e}, Herman H W and Sinagra, Gianfranco and Sinner, Moritz F and Slowikowski, Kamil and Soliman, Elsayed Z and Spector, Timothy D and Spiering, Wilko and Stamatoyannopoulos, John A and Stolk, Ronald P and Strauch, Konstantin and Tan, Sian-Tsung and Tarasov, Kirill V and Trinh, Bosco and Uitterlinden, Andr{\'e} G and van den Boogaard, Malou and van Duijn, Cornelia M and van Gilst, Wiek H and Viikari, Jorma S and Visscher, Peter M and Vitart, Veronique and V{\"o}lker, Uwe and Waldenberger, Melanie and Weichenberger, Christian X and Westra, Harm-Jan and Wijmenga, Cisca and Wolffenbuttel, Bruce H and Yang, Jian and Bezzina, Connie R and Munroe, Patricia B and Snieder, Harold and Wright, Alan F and Rudan, Igor and Boyer, Laurie A and Asselbergs, Folkert W and van Veldhuisen, Dirk J and Stricker, Bruno H and Psaty, Bruce M and Ciullo, Marina and Sanna, Serena and Lehtim{\"a}ki, Terho and Wilson, James F and Bandinelli, Stefania and Alonso, Alvaro and Gasparini, Paolo and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and Gudnason, Vilmundur and Felix, Stephan B and Heckbert, Susan R and de Boer, Rudolf A and Newton-Cheh, Christopher and Hicks, Andrew A and Chambers, John C and Jamshidi, Yalda and Visel, Axel and Christoffels, Vincent M and Isaacs, Aaron and Samani, Nilesh J and de Bakker, Paul I W} } @article {7604, title = {Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 05 15}, pages = {2093-2103}, abstract = {

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.

}, keywords = {Adaptor Proteins, Signal Transducing, Arrhythmias, Cardiac, Basic Helix-Loop-Helix Transcription Factors, Brugada Syndrome, Cardiac Conduction System Disease, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Conduction System, Humans, Male, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Repressor Proteins, Shab Potassium Channels, Shal Potassium Channels}, issn = {1460-2083}, doi = {10.1093/hmg/ddw058}, author = {Verweij, Niek and Mateo Leach, Irene and Isaacs, Aaron and Arking, Dan E and Bis, Joshua C and Pers, Tune H and van den Berg, Marten E and Lyytik{\"a}inen, Leo-Pekka and Barnett, Phil and Wang, Xinchen and Soliman, Elsayed Z and van Duijn, Cornelia M and K{\"a}h{\"o}nen, Mika and van Veldhuisen, Dirk J and Kors, Jan A and Raitakari, Olli T and Silva, Claudia T and Lehtim{\"a}ki, Terho and Hillege, Hans L and Hirschhorn, Joel N and Boyer, Laurie A and van Gilst, Wiek H and Alonso, Alvaro and Sotoodehnia, Nona and Eijgelsheim, Mark and de Boer, Rudolf A and de Bakker, Paul I W and Franke, Lude and van der Harst, Pim} } @article {7579, title = {Genetic loci associated with heart rate variability and their effects on cardiac disease risk.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 Jun 14}, pages = {15805}, abstract = {

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}, issn = {2041-1723}, doi = {10.1038/ncomms15805}, author = {Nolte, Ilja M and Munoz, M Loretto and Tragante, Vinicius and Amare, Azmeraw T and Jansen, Rick and Vaez, Ahmad and von der Heyde, Benedikt and Avery, Christy L and Bis, Joshua C and Dierckx, Bram and van Dongen, Jenny and Gogarten, Stephanie M and Goyette, Philippe and Hernesniemi, Jussi and Huikari, Ville and Hwang, Shih-Jen and Jaju, Deepali and Kerr, Kathleen F and Kluttig, Alexander and Krijthe, Bouwe P and Kumar, Jitender and van der Laan, Sander W and Lyytik{\"a}inen, Leo-Pekka and Maihofer, Adam X and Minassian, Arpi and van der Most, Peter J and M{\"u}ller-Nurasyid, Martina and Nivard, Michel and Salvi, Erika and Stewart, James D and Thayer, Julian F and Verweij, Niek and Wong, Andrew and Zabaneh, Delilah and Zafarmand, Mohammad H and Abdellaoui, Abdel and Albarwani, Sulayma and Albert, Christine and Alonso, Alvaro and Ashar, Foram and Auvinen, Juha and Axelsson, Tomas and Baker, Dewleen G and de Bakker, Paul I W and Barcella, Matteo and Bayoumi, Riad and Bieringa, Rob J and Boomsma, Dorret and Boucher, Gabrielle and Britton, Annie R and Christophersen, Ingrid and Dietrich, Andrea and Ehret, George B and Ellinor, Patrick T and Eskola, Markku and Felix, Janine F and Floras, John S and Franco, Oscar H and Friberg, Peter and Gademan, Maaike G J and Geyer, Mark A and Giedraitis, Vilmantas and Hartman, Catharina A and Hemerich, Daiane and Hofman, Albert and Hottenga, Jouke-Jan and Huikuri, Heikki and Hutri-K{\"a}h{\"o}nen, Nina and Jouven, Xavier and Junttila, Juhani and Juonala, Markus and Kiviniemi, Antti M and Kors, Jan A and Kumari, Meena and Kuznetsova, Tatiana and Laurie, Cathy C and Lefrandt, Joop D and Li, Yong and Li, Yun and Liao, Duanping and Limacher, Marian C and Lin, Henry J and Lindgren, Cecilia M and Lubitz, Steven A and Mahajan, Anubha and McKnight, Barbara and Zu Schwabedissen, Henriette Meyer and Milaneschi, Yuri and Mononen, Nina and Morris, Andrew P and Nalls, Mike A and Navis, Gerjan and Neijts, Melanie and Nikus, Kjell and North, Kari E and O{\textquoteright}Connor, Daniel T and Ormel, Johan and Perz, Siegfried and Peters, Annette and Psaty, Bruce M and Raitakari, Olli T and Risbrough, Victoria B and Sinner, Moritz F and Siscovick, David and Smit, Johannes H and Smith, Nicholas L and Soliman, Elsayed Z and Sotoodehnia, Nona and Staessen, Jan A and Stein, Phyllis K and Stilp, Adrienne M and Stolarz-Skrzypek, Katarzyna and Strauch, Konstantin and Sundstr{\"o}m, Johan and Swenne, Cees A and Syv{\"a}nen, Ann-Christine and Tardif, Jean-Claude and Taylor, Kent D and Teumer, Alexander and Thornton, Timothy A and Tinker, Lesley E and Uitterlinden, Andr{\'e} G and van Setten, Jessica and Voss, Andreas and Waldenberger, Melanie and Wilhelmsen, Kirk C and Willemsen, Gonneke and Wong, Quenna and Zhang, Zhu-Ming and Zonderman, Alan B and Cusi, Daniele and Evans, Michele K and Greiser, Halina K and van der Harst, Pim and Hassan, Mohammad and Ingelsson, Erik and Jarvelin, Marjo-Riitta and K{\"a}{\"a}b, Stefan and K{\"a}h{\"o}nen, Mika and Kivimaki, Mika and Kooperberg, Charles and Kuh, Diana and Lehtim{\"a}ki, Terho and Lind, Lars and Nievergelt, Caroline M and O{\textquoteright}Donnell, Chris J and Oldehinkel, Albertine J and Penninx, Brenda and Reiner, Alexander P and Riese, Harri{\"e}tte and van Roon, Arie M and Rioux, John D and Rotter, Jerome I and Sofer, Tamar and Stricker, Bruno H and Tiemeier, Henning and Vrijkotte, Tanja G M and Asselbergs, Folkert W and Brundel, Bianca J J M and Heckbert, Susan R and Whitsel, Eric A and den Hoed, Marcel and Snieder, Harold and de Geus, Eco J C} } @article {7778, title = {A comprehensive evaluation of the genetic architecture of sudden cardiac arrest.}, journal = {Eur Heart J}, year = {2018}, month = {2018 Aug 28}, abstract = {

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.

}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehy474}, author = {Ashar, Foram N and Mitchell, Rebecca N and Albert, Christine M and Newton-Cheh, Christopher and Brody, Jennifer A and M{\"u}ller-Nurasyid, Martina and Moes, Anna and Meitinger, Thomas and Mak, Angel and Huikuri, Heikki and Junttila, M Juhani and Goyette, Philippe and Pulit, Sara L and Pazoki, Raha and Tanck, Michael W and Blom, Marieke T and Zhao, XiaoQing and Havulinna, Aki S and Jabbari, Reza and Glinge, Charlotte and Tragante, Vinicius and Escher, Stefan A and Chakravarti, Aravinda and Ehret, Georg and Coresh, Josef and Li, Man and Prineas, Ronald J and Franco, Oscar H and Kwok, Pui-Yan and Lumley, Thomas and Dumas, Florence and McKnight, Barbara and Rotter, Jerome I and Lemaitre, Rozenn N and Heckbert, Susan R and O{\textquoteright}Donnell, Christopher J and Hwang, Shih-Jen and Tardif, Jean-Claude and VanDenburgh, Martin and Uitterlinden, Andr{\'e} G and Hofman, Albert and Stricker, Bruno H C and de Bakker, Paul I W and Franks, Paul W and Jansson, Jan-H{\r a}kan and Asselbergs, Folkert W and Halushka, Marc K and Maleszewski, Joseph J and Tfelt-Hansen, Jacob and Engstr{\o}m, Thomas and Salomaa, Veikko and Virmani, Renu and Kolodgie, Frank and Wilde, Arthur A M and Tan, Hanno L and Bezzina, Connie R and Eijgelsheim, Mark and Rioux, John D and Jouven, Xavier and K{\"a}{\"a}b, Stefan and Psaty, Bruce M and Siscovick, David S and Arking, Dan E and Sotoodehnia, Nona} } @article {7683, title = {Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Apr}, pages = {524-537}, abstract = {

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.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0058-3}, author = {Malik, Rainer and Chauhan, Ganesh and Traylor, Matthew and Sargurupremraj, Muralidharan and Okada, Yukinori and Mishra, Aniket and Rutten-Jacobs, Loes and Giese, Anne-Katrin and van der Laan, Sander W and Gretarsdottir, Solveig and Anderson, Christopher D and Chong, Michael and Adams, Hieab H H and Ago, Tetsuro and Almgren, Peter and Amouyel, Philippe and Ay, Hakan and Bartz, Traci M and Benavente, Oscar R and Bevan, Steve and Boncoraglio, Giorgio B and Brown, Robert D and Butterworth, Adam S and Carrera, Caty and Carty, Cara L and Chasman, Daniel I and Chen, Wei-Min and Cole, John W and Correa, Adolfo and Cotlarciuc, Ioana and Cruchaga, Carlos and Danesh, John and de Bakker, Paul I W and DeStefano, Anita L and den Hoed, Marcel and Duan, Qing and Engelter, Stefan T and Falcone, Guido J and Gottesman, Rebecca F and Grewal, Raji P and Gudnason, Vilmundur and Gustafsson, Stefan and Haessler, Jeffrey and Harris, Tamara B and Hassan, Ahamad and Havulinna, Aki S and Heckbert, Susan R and Holliday, Elizabeth G and Howard, George and Hsu, Fang-Chi and Hyacinth, Hyacinth I and Ikram, M Arfan and Ingelsson, Erik and Irvin, Marguerite R and Jian, Xueqiu and Jimenez-Conde, Jordi and Johnson, Julie A and Jukema, J Wouter and Kanai, Masahiro and Keene, Keith L and Kissela, Brett M and Kleindorfer, Dawn O and Kooperberg, Charles and Kubo, Michiaki and Lange, Leslie A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lee, Jin-Moo and Lemmens, Robin and Leys, Didier and Lewis, Cathryn M and Lin, Wei-Yu and Lindgren, Arne G and Lorentzen, Erik and Magnusson, Patrik K and Maguire, Jane and Manichaikul, Ani and McArdle, Patrick F and Meschia, James F and Mitchell, Braxton D and Mosley, Thomas H and Nalls, Michael A and Ninomiya, Toshiharu and O{\textquoteright}Donnell, Martin J and Psaty, Bruce M and Pulit, Sara L and Rannikmae, Kristiina and Reiner, Alexander P and Rexrode, Kathryn M and Rice, Kenneth and Rich, Stephen S and Ridker, Paul M and Rost, Natalia S and Rothwell, Peter M and Rotter, Jerome I and Rundek, Tatjana and Sacco, Ralph L and Sakaue, Saori and Sale, Mich{\`e}le M and Salomaa, Veikko and Sapkota, Bishwa R and Schmidt, Reinhold and Schmidt, Carsten O and Schminke, Ulf and Sharma, Pankaj and Slowik, Agnieszka and Sudlow, Cathie L M and Tanislav, Christian and Tatlisumak, Turgut and Taylor, Kent D and Thijs, Vincent N S and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiedt, Steffen and Trompet, Stella and Tzourio, Christophe and van Duijn, Cornelia M and Walters, Matthew and Wareham, Nicholas J and Wassertheil-Smoller, Sylvia and Wilson, James G and Wiggins, Kerri L and Yang, Qiong and Yusuf, Salim and Bis, Joshua C and Pastinen, Tomi and Ruusalepp, Arno and Schadt, Eric E and Koplev, Simon and Bj{\"o}rkegren, Johan L M and Codoni, Veronica and Civelek, Mete and Smith, Nicholas L and Tr{\'e}gou{\"e}t, David A and Christophersen, Ingrid E and Roselli, Carolina and Lubitz, Steven A and Ellinor, Patrick T and Tai, E Shyong and Kooner, Jaspal S and Kato, Norihiro and He, Jiang and van der Harst, Pim and Elliott, Paul and Chambers, John C and Takeuchi, Fumihiko and Johnson, Andrew D and Sanghera, Dharambir K and Melander, Olle and Jern, Christina and Strbian, Daniel and Fernandez-Cadenas, Israel and Longstreth, W T and Rolfs, Arndt and Hata, Jun and Woo, Daniel and Rosand, Jonathan and Par{\'e}, Guillaume and Hopewell, Jemma C and Saleheen, Danish and Stefansson, Kari and Worrall, Bradford B and Kittner, Steven J and Seshadri, Sudha and Fornage, Myriam and Markus, Hugh S and Howson, Joanna M M and Kamatani, Yoichiro and Debette, Stephanie and Dichgans, Martin and Malik, Rainer and Chauhan, Ganesh and Traylor, Matthew and Sargurupremraj, Muralidharan and Okada, Yukinori and Mishra, Aniket and Rutten-Jacobs, Loes and Giese, Anne-Katrin and van der Laan, Sander W and Gretarsdottir, Solveig and Anderson, Christopher D and Chong, Michael and Adams, Hieab H H and Ago, Tetsuro and Almgren, Peter and Amouyel, Philippe and Ay, Hakan and Bartz, Traci M and Benavente, Oscar R and Bevan, Steve and Boncoraglio, Giorgio B and Brown, Robert D and Butterworth, Adam S and Carrera, Caty and Carty, Cara L and Chasman, Daniel I and Chen, Wei-Min and Cole, John W and Correa, Adolfo and Cotlarciuc, Ioana and Cruchaga, Carlos and Danesh, John and de Bakker, Paul I W and DeStefano, Anita L and Hoed, Marcel den and Duan, Qing and Engelter, Stefan T and Falcone, Guido J and Gottesman, Rebecca F and Grewal, Raji P and Gudnason, Vilmundur and Gustafsson, Stefan and Haessler, Jeffrey and Harris, Tamara B and Hassan, Ahamad and Havulinna, Aki S and Heckbert, Susan R and Holliday, Elizabeth G and Howard, George and Hsu, Fang-Chi and Hyacinth, Hyacinth I and Ikram, M Arfan and Ingelsson, Erik and Irvin, Marguerite R and Jian, Xueqiu and Jimenez-Conde, Jordi and Johnson, Julie A and Jukema, J Wouter and Kanai, Masahiro and Keene, Keith L and Kissela, Brett M and Kleindorfer, Dawn O and Kooperberg, Charles and Kubo, Michiaki and Lange, Leslie A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lee, Jin-Moo and Lemmens, Robin and Leys, Didier and Lewis, Cathryn M and Lin, Wei-Yu and Lindgren, Arne G and Lorentzen, Erik and Magnusson, Patrik K and Maguire, Jane and Manichaikul, Ani and McArdle, Patrick F and Meschia, James F and Mitchell, Braxton D and Mosley, Thomas H and Nalls, Michael A and Ninomiya, Toshiharu and O{\textquoteright}Donnell, Martin J and Psaty, Bruce M and Pulit, Sara L and Rannikmae, Kristiina and Reiner, Alexander P and Rexrode, Kathryn M and Rice, Kenneth and Rich, Stephen S and Ridker, Paul M and Rost, Natalia S and Rothwell, Peter M and Rotter, Jerome I and Rundek, Tatjana and Sacco, Ralph L and Sakaue, Saori and Sale, Mich{\`e}le M and Salomaa, Veikko and Sapkota, Bishwa R and Schmidt, Reinhold and Schmidt, Carsten O and Schminke, Ulf and Sharma, Pankaj and Slowik, Agnieszka and Sudlow, Cathie L M and Tanislav, Christian and Tatlisumak, Turgut and Taylor, Kent D and Thijs, Vincent N S and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiedt, Steffen and Trompet, Stella and Tzourio, Christophe and van Duijn, Cornelia M and Walters, Matthew and Wareham, Nicholas J and Wassertheil-Smoller, Sylvia and Wilson, James G and Wiggins, Kerri L and Yang, Qiong and Yusuf, Salim and Amin, Najaf and Aparicio, Hugo S and Arnett, Donna K and Attia, John and Beiser, Alexa S and Berr, Claudine and Buring, Julie E and Bustamante, Mariana and Caso, Valeria and Cheng, Yu-Ching and Choi, Seung Hoan and Chowhan, Ayesha and Cullell, Natalia and Dartigues, Jean-Fran{\c c}ois and Delavaran, Hossein and Delgado, Pilar and D{\"o}rr, Marcus and Engstr{\"o}m, Gunnar and Ford, Ian and Gurpreet, Wander S and Hamsten, Anders and Heitsch, Laura and Hozawa, Atsushi and Ibanez, Laura and Ilinca, Andreea and Ingelsson, Martin and Iwasaki, Motoki and Jackson, Rebecca D and Jood, Katarina and Jousilahti, Pekka and Kaffashian, Sara and Kalra, Lalit and Kamouchi, Masahiro and Kitazono, Takanari and Kjartansson, Olafur and Kloss, Manja and Koudstaal, Peter J and Krupinski, Jerzy and Labovitz, Daniel L and Laurie, Cathy C and Levi, Christopher R and Li, Linxin and Lind, Lars and Lindgren, Cecilia M and Lioutas, Vasileios and Liu, Yong Mei and Lopez, Oscar L and Makoto, Hirata and Martinez-Majander, Nicolas and Matsuda, Koichi and Minegishi, Naoko and Montaner, Joan and Morris, Andrew P and Mui{\~n}o, Elena and M{\"u}ller-Nurasyid, Martina and Norrving, Bo and Ogishima, Soichi and Parati, Eugenio A and Peddareddygari, Leema Reddy and Pedersen, Nancy L and Pera, Joanna and Perola, Markus and Pezzini, Alessandro and Pileggi, Silvana and Rabionet, Raquel and Riba-Llena, Iolanda and Ribas{\'e}s, Marta and Romero, Jose R and Roquer, Jaume and Rudd, Anthony G and Sarin, Antti-Pekka and Sarju, Ralhan and Sarnowski, Chloe and Sasaki, Makoto and Satizabal, Claudia L and Satoh, Mamoru and Sattar, Naveed and Sawada, Norie and Sibolt, Gerli and Sigurdsson, {\'A}sgeir and Smith, Albert and Sobue, Kenji and Soriano-T{\'a}rraga, Carolina and Stanne, Tara and Stine, O Colin and Stott, David J and Strauch, Konstantin and Takai, Takako and Tanaka, Hideo and Tanno, Kozo and Teumer, Alexander and Tomppo, Liisa and Torres-Aguila, Nuria P and Touze, Emmanuel and Tsugane, Shoichiro and Uitterlinden, Andr{\'e} G and Valdimarsson, Einar M and van der Lee, Sven J and V{\"o}lzke, Henry and Wakai, Kenji and Weir, David and Williams, Stephen R and Wolfe, Charles D A and Wong, Quenna and Xu, Huichun and Yamaji, Taiki and Sanghera, Dharambir K and Melander, Olle and Jern, Christina and Strbian, Daniel and Fernandez-Cadenas, Israel and Longstreth, W T and Rolfs, Arndt and Hata, Jun and Woo, Daniel and Rosand, Jonathan and Par{\'e}, Guillaume and Hopewell, Jemma C and Saleheen, Danish and Stefansson, Kari and Worrall, Bradford B and Kittner, Steven J and Seshadri, Sudha and Fornage, Myriam and Markus, Hugh S and Howson, Joanna M M and Kamatani, Yoichiro and Debette, Stephanie and Dichgans, Martin} } @article {7815, title = {PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Jul 25}, pages = {2904}, abstract = {

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.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-04766-9}, author = {van Setten, Jessica and Brody, Jennifer A and Jamshidi, Yalda and Swenson, Brenton R and Butler, Anne M and Campbell, Harry and Del Greco, Fabiola M and Evans, Daniel S and Gibson, Quince and Gudbjartsson, Daniel F and Kerr, Kathleen F and Krijthe, Bouwe P and Lyytik{\"a}inen, Leo-Pekka and M{\"u}ller, Christian and M{\"u}ller-Nurasyid, Martina and Nolte, Ilja M and Padmanabhan, Sandosh and Ritchie, Marylyn D and Robino, Antonietta and Smith, Albert V and Steri, Maristella and Tanaka, Toshiko and Teumer, Alexander and Trompet, Stella and Ulivi, Sheila and Verweij, Niek and Yin, Xiaoyan and Arnar, David O and Asselbergs, Folkert W and Bader, Joel S and Barnard, John and Bis, Josh and Blankenberg, Stefan and Boerwinkle, Eric and Bradford, Yuki and Buckley, Brendan M and Chung, Mina K and Crawford, Dana and den Hoed, Marcel and Denny, Josh C and Dominiczak, Anna F and Ehret, Georg B and Eijgelsheim, Mark and Ellinor, Patrick T and Felix, Stephan B and Franco, Oscar H and Franke, Lude and Harris, Tamara B and Holm, Hilma and Ilaria, Gandin and Iorio, Annamaria and K{\"a}h{\"o}nen, Mika and Kolcic, Ivana and Kors, Jan A and Lakatta, Edward G and Launer, Lenore J and Lin, Honghuang and Lin, Henry J and Loos, Ruth J F and Lubitz, Steven A and Macfarlane, Peter W and Magnani, Jared W and Leach, Irene Mateo and Meitinger, Thomas and Mitchell, Braxton D and M{\"u}nzel, Thomas and Papanicolaou, George J and Peters, Annette and Pfeufer, Arne and Pramstaller, Peter P and Raitakari, Olli T and Rotter, Jerome I and Rudan, Igor and Samani, Nilesh J and Schlessinger, David and Silva Aldana, Claudia T and Sinner, Moritz F and Smith, Jonathan D and Snieder, Harold and Soliman, Elsayed Z and Spector, Timothy D and Stott, David J and Strauch, Konstantin and Tarasov, Kirill V and Thorsteinsdottir, Unnur and Uitterlinden, Andr{\'e} G and Van Wagoner, David R and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Jan Westra, Harm and Wild, Philipp S and Zeller, Tanja and Alonso, Alvaro and Avery, Christy L and Bandinelli, Stefania and Benjamin, Emelia J and Cucca, Francesco and D{\"o}rr, Marcus and Ferrucci, Luigi and Gasparini, Paolo and Gudnason, Vilmundur and Hayward, Caroline and Heckbert, Susan R and Hicks, Andrew A and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and Lehtim{\"a}ki, Terho and Liu, Yongmei and Munroe, Patricia B and Parsa, Afshin and Polasek, Ozren and Psaty, Bruce M and Roden, Dan M and Schnabel, Renate B and Sinagra, Gianfranco and Stefansson, Kari and Stricker, Bruno H and van der Harst, Pim and van Duijn, Cornelia M and Wilson, James F and Gharib, Sina A and de Bakker, Paul I W and Isaacs, Aaron and Arking, Dan E and Sotoodehnia, Nona} }