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1. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Ilaria, Gandin, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth JF, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thomas, Mitchell, Braxton D, Munzel, Thomas, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcus, and Ferrucci, Luigi

Subjects
Biological Sciences, Genetics, Human Genome, Heart Disease, Biotechnology, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Atrial Function, Atrioventricular Node, Electrocardiography, Electrophysiological Phenomena, Female, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Mutation, Missense, Risk Factors
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.

Published
2018

2. Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

Author

Nolte, Ilja, Munoz, M, Tragante, Vinicius, Amare, Azmeraw, Jansen, Rick, Vaez, Ahmad, von der Heyde, Benedikt, Avery, Christy, Bis, Joshua, Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie, Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen, Kluttig, Alexander, Krijthe, Bouwe, Kumar, Jitender, van der Laan, Sander, Lyytikäinen, Leo-Pekka, Maihofer, Adam, Minassian, Arpi, van der Most, Peter, Müller-Nurasyid, Martina, Nivard, Michel, Salvi, Erika, Stewart, James, Thayer, Julian, Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen, de Bakker, Paul, Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob, Boomsma, Dorret, Boucher, Gabrielle, Britton, Annie, Christophersen, Ingrid, Dietrich, Andrea, Ehret, George, Ellinor, Patrick, Eskola, Markku, Felix, Janine, Floras, John, Franco, Oscar, Friberg, Peter, Gademan, Maaike, Geyer, Mark, Giedraitis, Vilmantas, Hartman, Catharina, Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki, Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti, Kors, Jan, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy, Lefrandt, Joop, Li, Yong, Li, Yun, Liao, Duanping, Limacher, Marian, Lin, Henry, Lindgren, Cecilia, Lubitz, Steven, Mahajan, Anubha, McKnight, Barbara, Zu Schwabedissen, Henriette, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew, Nalls, Mike, Navis, Gerjan, Neijts, Melanie, Nikus, Kjell, North, Kari, OConnor, Daniel, Ormel, Johan, Perz, Siegfried, Peters, Annette, and Psaty, Bruce

Abstract

This corrects the article DOI: 10.1038/ncomms15805.

Published
2017

3. Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

Author

Nolte, Ilja M, Munoz, M Loretto, Tragante, Vinicius, Amare, Azmeraw T, Jansen, Rick, Vaez, Ahmad, von der Heyde, Benedikt, Avery, Christy L, Bis, Joshua C, Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M, Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P, Kumar, Jitender, van der Laan, Sander W, Lyytikäinen, Leo-Pekka, Maihofer, Adam X, Minassian, Arpi, van der Most, Peter J, Müller-Nurasyid, Martina, Nivard, Michel, Salvi, Erika, Stewart, James D, Thayer, Julian F, Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad H, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G, de Bakker, Paul IW, Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J, Boomsma, Dorret, Boucher, Gabrielle, Britton, Annie R, Christophersen, Ingrid, Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F, Floras, John S, Franco, Oscar H, Friberg, Peter, Gademan, Maaike GJ, Geyer, Mark A, Giedraitis, Vilmantas, Hartman, Catharina A, Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki, Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M, Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C, Lefrandt, Joop D, Li, Yong, Li, Yun, Liao, Duanping, Limacher, Marian C, Lin, Henry J, Lindgren, Cecilia M, Lubitz, Steven A, Mahajan, Anubha, McKnight, Barbara, Zu Schwabedissen, Henriette Meyer, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P, Nalls, Mike A, Navis, Gerjan, Neijts, Melanie, Nikus, Kjell, North, Kari E, O'Connor, Daniel T, Ormel, Johan, Perz, Siegfried, Peters, Annette, and Psaty, Bruce M

Subjects
Humans, Heart Diseases, Genetic Predisposition to Disease, RGS Proteins, Potassium Channels, Muscle Proteins, Risk Factors, Cohort Studies, Blood Pressure, Heart Rate, Polymorphism, Single Nucleotide, Quantitative Trait Loci, European Continental Ancestry Group, Genome-Wide Association Study, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Cardiovascular, Genetics, Heart Disease
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 (-0.74g

Published
2017

4. Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium

Author

Weng, Lu-Chen, Lunetta, Kathryn L, Müller-Nurasyid, Martina, Smith, Albert Vernon, Thériault, Sébastien, Weeke, Peter E, Barnard, John, Bis, Joshua C, Lyytikäinen, Leo-Pekka, Kleber, Marcus E, Martinsson, Andreas, Lin, Henry J, Rienstra, Michiel, Trompet, Stella, Krijthe, Bouwe P, Dörr, Marcus, Klarin, Derek, Chasman, Daniel I, Sinner, Moritz F, Waldenberger, Melanie, Launer, Lenore J, Harris, Tamara B, Soliman, Elsayed Z, Alonso, Alvaro, Paré, Guillaume, Teixeira, Pedro L, Denny, Joshua C, Shoemaker, M Benjamin, Van Wagoner, David R, Smith, Jonathan D, Psaty, Bruce M, Sotoodehnia, Nona, Taylor, Kent D, Kähönen, Mika, Nikus, Kjell, Delgado, Graciela E, Melander, Olle, Engström, Gunnar, Yao, Jie, Guo, Xiuqing, Christophersen, Ingrid E, Ellinor, Patrick T, Geelhoed, Bastiaan, Verweij, Niek, Macfarlane, Peter, Ford, Ian, Heeringa, Jan, Franco, Oscar H, Uitterlinden, André G, Völker, Uwe, Teumer, Alexander, Rose, Lynda M, Kääb, Stefan, Gudnason, Vilmundur, Arking, Dan E, Conen, David, Roden, Dan M, Chung, Mina K, Heckbert, Susan R, Benjamin, Emelia J, Lehtimäki, Terho, März, Winfried, Smith, J Gustav, Rotter, Jerome I, van der Harst, Pim, Jukema, J Wouter, Stricker, Bruno H, Felix, Stephan B, Albert, Christine M, and Lubitz, Steven A

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Heart Disease, Cardiovascular, Prevention, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Age Factors, Aged, Atrial Fibrillation, Body Mass Index, Chromosomes, Human, Pair 4, Epistasis, Genetic, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Reproducibility of Results, Risk Factors, Sex Characteristics
Abstract

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

Published
2017

5. Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.

Author

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

Subjects
Humans, Cardiovascular Diseases, Hypertension, Antihypertensive Agents, Treatment Outcome, Incidence, Polymorphism, Single Nucleotide, Aged, Middle Aged, African Americans, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

BackgroundHypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.MethodsUsing a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).ResultsAlthough drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

Published
2015

6. Novel Genetic Markers Associate With Atrial Fibrillation Risk in Europeans and Japanese

Author

Lubitz, Steven A, Lunetta, Kathryn L, Lin, Honghuang, Arking, Dan E, Trompet, Stella, Li, Guo, Krijthe, Bouwe P, Chasman, Daniel I, Barnard, John, Kleber, Marcus E, Dörr, Marcus, Ozaki, Kouichi, Smith, Albert V, Müller-Nurasyid, Martina, Walter, Stefan, Agarwal, Sunil K, Bis, Joshua C, Brody, Jennifer A, Chen, Lin Y, Everett, Brendan M, Ford, Ian, Franco, Oscar H, Harris, Tamara B, Hofman, Albert, Kääb, Stefan, Mahida, Saagar, Kathiresan, Sekar, Kubo, Michiaki, Launer, Lenore J, Macfarlane, Peter W, Magnani, Jared W, McKnight, Barbara, McManus, David D, Peters, Annette, Psaty, Bruce M, Rose, Lynda M, Rotter, Jerome I, Silbernagel, Guenther, Smith, Jonathan D, Sotoodehnia, Nona, Stott, David J, Taylor, Kent D, Tomaschitz, Andreas, Tsunoda, Tatsuhiko, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Murabito, Joanne M, Sinner, Moritz F, Gudnason, Vilmundur, Felix, Stephan B, März, Winfried, Chung, Mina, Albert, Christine M, Stricker, Bruno H, Tanaka, Toshihiro, Heckbert, Susan R, Jukema, J Wouter, Alonso, Alvaro, Benjamin, Emelia J, and Ellinor, Patrick T

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Heart Disease, Cardiovascular, Clinical Research, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Aged, 80 and over, Asian People, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, Europe, Female, Genetic Markers, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Polymorphism, Single Nucleotide, Transcription Factors, White People, atrial fibrillation, atrial flutter, genetic, prognosis, risk, Cardiorespiratory Medicine and Haematology, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

ObjectivesThis study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.BackgroundAF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.MethodsWe performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).ResultsWe observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.ConclusionsThe chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Published
2014

7. Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest

Author

Lemaitre, Rozenn N, Johnson, Catherine O, Hesselson, Stephanie, Sotoodhenia, Nona, McKnight, Barbara, Sitlani, Colleen M, Rea, Thomas D, King, Irena B, Kwok, Pui-Yan, Mak, Angel, Li, Guo, Brody, Jennifer, Larson, Eric, Mozaffarian, Dariush, Psaty, Bruce M, Huertas-Vazquez, Adriana, Tardif, Jean-Claude, Albert, Christine M, Lyytikäinen, Leo-Pekka, Arking, Dan E, Kääb, Stefan, Huikuri, Heikki V, Krijthe, Bouwe P, Eijgelsheim, Mark, Wang, Ying A, Reinier, Kyndaron, Lehtimäki, Terho, Pulit, Sara L, Brugada, Ramon, Müller-Nurasyid, Martina, Newton-Cheh, Chris H, Karhunen, Pekka J, Stricker, Bruno H, Goyette, Philippe, Rotter, Jerome I, Chugh, Sumeet S, Chakravarti, Aravinda, Jouven, Xavier, and Siscovick, David S

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Cardiovascular, Clinical Research, Prevention, Genetics, Aetiology, 2.1 Biological and endogenous factors, 1-Acylglycerophosphocholine O-Acyltransferase, Aged, Algorithms, Alleles, Case-Control Studies, Death, Sudden, Cardiac, Fatty Acids, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Risk Factors, Death, Sudden, Genetic epidemiology, Biomedical Engineering, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundThere is limited information on genetic factors associated with sudden cardiac arrest (SCA).ObjectiveTo assess the association of common variation in genes in fatty acid pathways with SCA risk.MethodsWe selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of

Published
2014

9. Is methotrexate safe for men with an immune-mediated inflammatory disease and an active desire to become a father? Results of a prospective cohort study (iFAME-MTX)

Author

Perez-Garcia, Luis Fernando, Röder, Esther, Krijthe, Bouwe P., Kranenburg-Van Koppen, Laura J.C., Van Adrichem, Roxanne, Zirkzee, Els, Griffioen, Pieter H., Peeters, Kris, Lin, Marry, Struys, Eduard A., Jansen, Gerrit, Van Doorn, Martijn B.A., De Jonge, Robert, Dohle, Gert R., Dolhain, Radboud J.E.M., Perez-Garcia, Luis Fernando, Röder, Esther, Krijthe, Bouwe P., Kranenburg-Van Koppen, Laura J.C., Van Adrichem, Roxanne, Zirkzee, Els, Griffioen, Pieter H., Peeters, Kris, Lin, Marry, Struys, Eduard A., Jansen, Gerrit, Van Doorn, Martijn B.A., De Jonge, Robert, Dohle, Gert R., and Dolhain, Radboud J.E.M.

Abstract

Introduction Current scientific evidence guiding the decision whether men with an active desire to become a father should be treated with methotrexate (MTX) remains controversial. We aimed to prospectively evaluate the testicular toxicity profile of MTX focusing on several markers of male fertility, including semen parameters and sperm DNA fragmentation index (sDFI). As a secondary outcome, we aimed to evaluate whether MTX-polyglutamates can be detected in spermatozoa and seminal plasma and to evaluate the enzymatic activity in spermatozoa of folylpolyglutamate synthetase (FPGS). Methods In a prospective cohort study, men ≥18 years who started therapy with MTX were invited to participate (MTX-starters). Participants were instructed to produce two semen samples (a pre-exposure and a post-exposure sample after 13 weeks). Healthy men ≥18 years were invited to participate as controls. Conventional semen analyses, male reproductive endocrine axis and sDFI were compared between groups. FPGS enzymatic activity and MTX-PG1-5 concentrations were determined by mass spectrometry analytical methods. Results In total, 20 MTX-starters and 25 controls were included. The pre-exposure and postexposure semen parameters of MTX-starters were not statistically significant different. Compared with healthy controls, the conventional semen parameters and the sDFI of MTX-starters were not statistically significant different. These data were corroborated by the marginal accumulation of MTX-PGs in spermatozoa, consistent with the very low FPGS enzymatic activity associated with the expression of an alternative FPGS splice-variant. Discussion Treatment with MTX is not associated with testicular toxicity, consistent with the very low concentration of intracellular MTX-PG. Therefore, therapy with MTX can be safely started or continued in men and with a wish to become a father.

Published
2023

10. Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

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

Published
2017
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11. Paternal inflammatory arthritis is associated with a higher risk of miscarriage:results of a large multicentre study (iFAME-Fertility)

Author

Perez-Garcia, Luis F, Röder, Esther, Smeele, Hieronymus T W, Goekoop, Robbert, Hazes, Johanna M W, Kok, Marc R, Tchetverikov, Ilja, van der Helm-van Mil, Annette, van der Kaap, Jos, Kok, Petra, Krijthe, Bouwe P, Dolhain, Radboud J E M, Perez-Garcia, Luis F, Röder, Esther, Smeele, Hieronymus T W, Goekoop, Robbert, Hazes, Johanna M W, Kok, Marc R, Tchetverikov, Ilja, van der Helm-van Mil, Annette, van der Kaap, Jos, Kok, Petra, Krijthe, Bouwe P, and Dolhain, Radboud J E M

Abstract

Objectives: Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have never been studied. Our objective was to describe the pregnancy outcomes of partners of men diagnosed with IA. Methods: We performed a multicentre cross-sectional retrospective study conducted in the Netherlands. Men with IA who were over 40 years old that reported at least one positive pregnancy test were included. To analyse the impact of IA on pregnancy outcomes, pregnancies were classified into two groups: pregnancies conceived after the diagnosis of IA and before the diagnosis of IA. Results: In total, 408 male participants diagnosed with IA reported 897 singleton pregnancies that resulted in 794 live births. Pregnancies conceived after the diagnosis of IA had higher rate of miscarriage (12.27 vs 7.53%, P = <0.05). This increased risk was still present after adjusting for confounders [OR 2.03 (95% CI 1.12, 3.69) P = 0.015]. Conclusions: This is the largest study to describe the pregnancy outcomes of partners of men diagnosed with IA and the first to demonstrate that paternal IA is associated with a higher risk of miscarriage. Notwithstanding, the overall rate of miscarriage reported in our study could be comparable to previously reported population estimates.

Published
2022

12. Paternal inflammatory arthritis is associated with a higher risk of miscarriage: results of a large multicentre study (iFAME-Fertility)

Author

Perez-Garcia, Luis F, primary, Röder, Esther, additional, Smeele, Hieronymus T W, additional, Goekoop, Robbert, additional, Hazes, Johanna M W, additional, Kok, Marc R, additional, Tchetverikov, Ilja, additional, van der Helm-van Mil, Annette, additional, van der Kaap, Jos, additional, Kok, Petra, additional, Krijthe, Bouwe P, additional, and Dolhain, Radboud J E M, additional

Published
2021
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13. Impaired fertility in men diagnosed with inflammatory arthritis:Results of a large multicentre study (iFAME-Fertility)

Author

Perez-Garcia, Luis Fernando, Röder, Esther, Goekoop, Robbert J., Hazes, Johanna M.W., Kok, Marc R., Smeele, Hieronymus T.W., Tchetverikov, Ilja, Van Der Helm-Van Mil, Annette H.M., Van Der Kaap, Jos H., Kok, Petra, Krijthe, Bouwe P., Dolhain, Radboud J.E.M., Perez-Garcia, Luis Fernando, Röder, Esther, Goekoop, Robbert J., Hazes, Johanna M.W., Kok, Marc R., Smeele, Hieronymus T.W., Tchetverikov, Ilja, Van Der Helm-Van Mil, Annette H.M., Van Der Kaap, Jos H., Kok, Petra, Krijthe, Bouwe P., and Dolhain, Radboud J.E.M.

Abstract

Objectives The impact of inflammatory arthritis (IA) on male fertility remains unexplored. Our objective was to evaluate the impact of IA on several male fertility outcomes; fertility rate (number of biological children per man), family planning, childlessness and fertility problems. Methods We performed a multicentre cross-sectional study (iFAME-Fertility). Men with IA 40 years or older who indicated that their family size was complete were invited to participate. Participants completed a questionnaire that included demographic, medical and fertility-related questions. To analyse the impact of IA on fertility rate, patients were divided into groups according to the age at the time of their diagnosis: ≤30 years (before the peak of reproductive age), between 31 and 40 years (during the peak) and ≥41 years (after the peak). Results In total 628 participants diagnosed with IA were included. Men diagnosed ≤30 years had a lower mean number of children (1.32 (SD 1.14)) than men diagnosed between 31 and 40 years (1.60 (SD 1.35)) and men diagnosed ≥41 years (1.88 (SD 1.14)).This was statistically significant (p=0.0004).The percentages of men diagnosed ≤30 and 31-40 years who were involuntary childless (12.03% vs 10.34% vs 3.98%, p=0.001) and who reported having received medical evaluations for fertility problems (20.61%, 20.69% and 11.36%, p=0.027) were statistically significant higher than men diagnosed ≥41 years. Conclusions This is the first study that shows that IA can impair male fertility. Men diagnosed with IA before and during the peak of reproductive age had a lower fertility rate, higher childlessness rate and more fertility problems. Increased awareness and more research into the causes behind this association are urgently needed.

Published
2021

14. B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies

Author

Sinner, Moritz F., Stepas, Katherine A., Moser, Carlee B., Krijthe, Bouwe P., Aspelund, Thor, Sotoodehnia, Nona, Fontes, João D., Janssens, A. Cecile J.W., Kronmal, Richard A., Magnani, Jared W., Witteman, Jacqueline C., Chamberlain, Alanna M., Lubitz, Steven A., Schnabel, Renate B., Vasan, Ramachandran S., Wang, Thomas J., Agarwal, Sunil K., McManus, David D., Franco, Oscar H., Yin, Xiaoyan, Larson, Martin G., Burke, Gregory L., Launer, Lenore J., Hofman, Albert, Levy, Daniel, Gottdiener, John S., Kääb, Stefan, Couper, David, Harris, Tamara B., Astor, Brad C., Ballantyne, Christie M., Hoogeveen, Ron C., Arai, Andrew E., Soliman, Elsayed Z., Ellinor, Patrick T., Stricker, Bruno H.C., Gudnason, Vilmundur, Heckbert, Susan R., Pencina, Michael J., Benjamin, Emelia J., and Alonso, Alvaro

Published
2014
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15. Paternal inflammatory arthritis is associated with a higher risk of miscarriage: results of a large multicentre study (iFAME-Fertility).

Author

Perez-Garcia, Luis F, Röder, Esther, Smeele, Hieronymus T W, Goekoop, Robbert, Hazes, Johanna M W, Kok, Marc R, Tchetverikov, Ilja, Mil, Annette van der Helm-van, van der Kaap, Jos, Kok, Petra, Krijthe, Bouwe P, and Dolhain, Radboud J E M

Subjects
RISK factors in miscarriages, RESEARCH, CONFIDENCE intervals, CROSS-sectional method, FATHERS, RETROSPECTIVE studies, PREGNANCY outcomes, RISK assessment, RHEUMATOID arthritis, ODDS ratio, DISEASE complications
Abstract

Objectives Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have never been studied. Our objective was to describe the pregnancy outcomes of partners of men diagnosed with IA. Methods We performed a multicentre cross-sectional retrospective study conducted in the Netherlands. Men with IA who were over 40 years old that reported at least one positive pregnancy test were included. To analyse the impact of IA on pregnancy outcomes, pregnancies were classified into two groups: pregnancies conceived after the diagnosis of IA and before the diagnosis of IA. Results In total, 408 male participants diagnosed with IA reported 897 singleton pregnancies that resulted in 794 live births. Pregnancies conceived after the diagnosis of IA had higher rate of miscarriage (12.27 vs 7.53%, P  = <0.05). This increased risk was still present after adjusting for confounders [OR 2.03 (95% CI 1.12, 3.69) P  = 0.015]. Conclusions This is the largest study to describe the pregnancy outcomes of partners of men diagnosed with IA and the first to demonstrate that paternal IA is associated with a higher risk of miscarriage. Notwithstanding, the overall rate of miscarriage reported in our study could be comparable to previously reported population estimates. [ABSTRACT FROM AUTHOR]

Published
2022
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18. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

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

Published
2018

19. Genetic loci associated with heart rate variability and their effects on cardiac disease risk (vol 8, pg 15805, 2017)

Author

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

Subjects
Netherlands Twin Register (NTR), Cardiovascular genetics Genome-wide association studies Risk factors
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

Published
2017
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20. Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

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

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 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

Published
2017
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21. Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

Circulatory Health, Onderzoek Precision medicine, Experimentele Afd. Cardiologie 1, CMM Groep Kaaij, Infection & Immunity, Aios en Stafsecr. Cardiologie, Team Medisch, Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, van der Laan, Sander W, Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., de Bakker, Paul I W, Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Zu Schwabedissen, Henriette Meyer, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W, Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, de Geus, Eco J. C., Circulatory Health, Onderzoek Precision medicine, Experimentele Afd. Cardiologie 1, CMM Groep Kaaij, Infection & Immunity, Aios en Stafsecr. Cardiologie, Team Medisch, Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, van der Laan, Sander W, Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., de Bakker, Paul I W, Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Zu Schwabedissen, Henriette Meyer, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W, Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, and de Geus, Eco J. C.

Published
2017

22. Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

Aios en Stafsecr. Cardiologie, Circulatory Health, Onderzoek Precision medicine, Experimentele Afd. Cardiologie 1, Genetica, Cardiovasculaire Epi Team 7a, CMM Groep Kaaij, Infection & Immunity, Team Medisch, Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, Van Der Laan, Sander W., Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., De Bakker, Paul I.W., Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Meyer Zu Schwabedissen, Henriette, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., Van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W., Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, de Geus, Eco J. C., Aios en Stafsecr. Cardiologie, Circulatory Health, Onderzoek Precision medicine, Experimentele Afd. Cardiologie 1, Genetica, Cardiovasculaire Epi Team 7a, CMM Groep Kaaij, Infection & Immunity, Team Medisch, Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, Van Der Laan, Sander W., Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., De Bakker, Paul I.W., Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Meyer Zu Schwabedissen, Henriette, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., Van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W., Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, and de Geus, Eco J. C.

Published
2017

23. Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease:A Pharmacogenomics Study from the CHARGE Consortium

Author

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

Abstract

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

Published
2015

24. Prevalence of Pulmonary Hypertension in the General Population: The Rotterdam Study

Author

Moreira, Eduardo M., primary, Gall, Henning, additional, Leening, Maarten J. G., additional, Lahousse, Lies, additional, Loth, Daan W., additional, Krijthe, Bouwe P., additional, Kiefte-de Jong, Jessica C., additional, Brusselle, Guy G., additional, Hofman, Albert, additional, Stricker, Bruno H., additional, Ghofrani, Hossein A., additional, Franco, Oscar H., additional, and Felix, Janine F., additional

Published
2015
Full Text
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25. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

Author

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

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.

Published
2014
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26. Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation

Author

Sinner, Moritz F, Tucker, Nathan R, Lunetta, Kathryn L, Ozaki, Kouichi, Smith, J Gustav, Trompet, Stella, Bis, Joshua C, Lin, Honghuang, Chung, Mina K, Nielsen, Jonas B, Lubitz, Steven A, Krijthe, Bouwe P, Magnani, Jared W, Ye, Jiangchuan, Gollob, Michael H, Tsunoda, Tatsuhiko, Müller-Nurasyid, Martina, Lichtner, Peter, Peters, Annette, Dolmatova, Elena, Kubo, Michiaki, Smith, Jonathan D, Psaty, Bruce M, Smith, Nicholas L, Jukema, J Wouter, Chasman, Daniel I, Albert, Christine M, Ebana, Yusuke, Furukawa, Tetsushi, Macfarlane, Peter W, Harris, Tamara B, Darbar, Dawood, Dörr, Marcus, Holst, Anders G, Svendsen, Jesper H, Hofman, Albert, Uitterlinden, Andre G, Gudnason, Vilmundur, Isobe, Mitsuaki, Malik, Rainer, Dichgans, Martin, Rosand, Jonathan, Van Wagoner, David R, Benjamin, Emelia J, Milan, David J, Melander, Olle, Heckbert, Susan R, Ford, Ian, Liu, Yongmei, Olesen, Morten S, Sinner, Moritz F, Tucker, Nathan R, Lunetta, Kathryn L, Ozaki, Kouichi, Smith, J Gustav, Trompet, Stella, Bis, Joshua C, Lin, Honghuang, Chung, Mina K, Nielsen, Jonas B, Lubitz, Steven A, Krijthe, Bouwe P, Magnani, Jared W, Ye, Jiangchuan, Gollob, Michael H, Tsunoda, Tatsuhiko, Müller-Nurasyid, Martina, Lichtner, Peter, Peters, Annette, Dolmatova, Elena, Kubo, Michiaki, Smith, Jonathan D, Psaty, Bruce M, Smith, Nicholas L, Jukema, J Wouter, Chasman, Daniel I, Albert, Christine M, Ebana, Yusuke, Furukawa, Tetsushi, Macfarlane, Peter W, Harris, Tamara B, Darbar, Dawood, Dörr, Marcus, Holst, Anders G, Svendsen, Jesper H, Hofman, Albert, Uitterlinden, Andre G, Gudnason, Vilmundur, Isobe, Mitsuaki, Malik, Rainer, Dichgans, Martin, Rosand, Jonathan, Van Wagoner, David R, Benjamin, Emelia J, Milan, David J, Melander, Olle, Heckbert, Susan R, Ford, Ian, Liu, Yongmei, and Olesen, Morten S

Abstract

BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively).CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

Published
2014

27. Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics

Author

Lundby, Alicia, Rossin, Elizabeth J, Steffensen, Annette B, Acha, Moshe Rav, Newton-Cheh, Christopher, Pfeufer, Arne, Lynch, Stacey N, Olesen, Søren-Peter, Brunak, Søren, Ellinor, Patrick T, Jukema, J Wouter, Trompet, Stella, Ford, Ian, Macfarlane, Peter W, Krijthe, Bouwe P, Hofman, Albert, Uitterlinden, André G, Stricker, Bruno H, Nathoe, Hendrik M, Spiering, Wilko, Daly, Mark J, Asselbergs, Folkert W, van der Harst, Pim, Milan, David J, de Bakker, Paul I W, Hansen, Kasper Lage, Olsen, Jesper V, Lundby, Alicia, Rossin, Elizabeth J, Steffensen, Annette B, Acha, Moshe Rav, Newton-Cheh, Christopher, Pfeufer, Arne, Lynch, Stacey N, Olesen, Søren-Peter, Brunak, Søren, Ellinor, Patrick T, Jukema, J Wouter, Trompet, Stella, Ford, Ian, Macfarlane, Peter W, Krijthe, Bouwe P, Hofman, Albert, Uitterlinden, André G, Stricker, Bruno H, Nathoe, Hendrik M, Spiering, Wilko, Daly, Mark J, Asselbergs, Folkert W, van der Harst, Pim, Milan, David J, de Bakker, Paul I W, Hansen, Kasper Lage, and Olsen, Jesper V

Abstract

Genome-wide association studies (GWAS) have identified thousands of loci associated with complex traits, but it is challenging to pinpoint causal genes in these loci and to exploit subtle association signals. We used tissue-specific quantitative interaction proteomics to map a network of five genes involved in the Mendelian disorder long QT syndrome (LQTS). We integrated the LQTS network with GWAS loci from the corresponding common complex trait, QT-interval variation, to identify candidate genes that were subsequently confirmed in Xenopus laevis oocytes and zebrafish. We used the LQTS protein network to filter weak GWAS signals by identifying single-nucleotide polymorphisms (SNPs) in proximity to genes in the network supported by strong proteomic evidence. Three SNPs passing this filter reached genome-wide significance after replication genotyping. Overall, we present a general strategy to propose candidates in GWAS loci for functional studies and to systematically filter subtle association signals using tissue-specific quantitative interaction proteomics.

Published
2014

28. Integrating Genetic, Transcriptional, and Functional Analyses to Identify 5 Novel Genes for Atrial Fibrillation

Author

Sinner, Moritz F., primary, Tucker, Nathan R., additional, Lunetta, Kathryn L., additional, Ozaki, Kouichi, additional, Smith, J. Gustav, additional, Trompet, Stella, additional, Bis, Joshua C., additional, Lin, Honghuang, additional, Chung, Mina K., additional, Nielsen, Jonas B., additional, Lubitz, Steven A., additional, Krijthe, Bouwe P., additional, Magnani, Jared W., additional, Ye, Jiangchuan, additional, Gollob, Michael H., additional, Tsunoda, Tatsuhiko, additional, Müller-Nurasyid, Martina, additional, Lichtner, Peter, additional, Peters, Annette, additional, Dolmatova, Elena, additional, Kubo, Michiaki, additional, Smith, Jonathan D., additional, Psaty, Bruce M., additional, Smith, Nicholas L., additional, Jukema, J. Wouter, additional, Chasman, Daniel I., additional, Albert, Christine M., additional, Ebana, Yusuke, additional, Furukawa, Tetsushi, additional, Macfarlane, Peter W., additional, Harris, Tamara B., additional, Darbar, Dawood, additional, Dörr, Marcus, additional, Holst, Anders G., additional, Svendsen, Jesper H., additional, Hofman, Albert, additional, Uitterlinden, Andre G., additional, Gudnason, Vilmundur, additional, Isobe, Mitsuaki, additional, Malik, Rainer, additional, Dichgans, Martin, additional, Rosand, Jonathan, additional, Van Wagoner, David R., additional, Benjamin, Emelia J., additional, Milan, David J., additional, Melander, Olle, additional, Heckbert, Susan R., additional, Ford, Ian, additional, Liu, Yongmei, additional, Barnard, John, additional, Olesen, Morten S., additional, Stricker, Bruno H.C., additional, Tanaka, Toshihiro, additional, Kääb, Stefan, additional, and Ellinor, Patrick T., additional

Published
2014
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30. Simple Risk Model Predicts Incidence of Atrial Fibrillation in a Racially and Geographically Diverse Population: the CHARGE‐AF Consortium

Author

Alonso, Alvaro, primary, Krijthe, Bouwe P., additional, Aspelund, Thor, additional, Stepas, Katherine A., additional, Pencina, Michael J., additional, Moser, Carlee B., additional, Sinner, Moritz F., additional, Sotoodehnia, Nona, additional, Fontes, João D., additional, Janssens, A. Cecile J. W., additional, Kronmal, Richard A., additional, Magnani, Jared W., additional, Witteman, Jacqueline C., additional, Chamberlain, Alanna M., additional, Lubitz, Steven A., additional, Schnabel, Renate B., additional, Agarwal, Sunil K., additional, McManus, David D., additional, Ellinor, Patrick T., additional, Larson, Martin G., additional, Burke, Gregory L., additional, Launer, Lenore J., additional, Hofman, Albert, additional, Levy, Daniel, additional, Gottdiener, John S., additional, Kääb, Stefan, additional, Couper, David, additional, Harris, Tamara B., additional, Soliman, Elsayed Z., additional, Stricker, Bruno H. C., additional, Gudnason, Vilmundur, additional, Heckbert, Susan R., additional, and Benjamin, Emelia J., additional

Published
2013
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31. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

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

Subjects
genome-wide association study, QT interval, Long QT Syndrome, sudden cardiac death, myocardial repolarization, arrhythmias
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 QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for 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 novel candidate genes for ventricular arrhythmias, LQTS,and SCD.

Published
2014
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32. Serum potassium levels and the risk of atrial fibrillation The Rotterdam Study

Author

Krijthe, Bouwe P., Heeringa, Jan, Kors, Jan A., Hofman, Albert, Franco, Oscar H., Witteman, Jacqueline C.M., and Stricker, Bruno H.

Subjects
Epidemiology, Serum potassium, cardiovascular system, macromolecular substances, cardiovascular diseases, Atrial fibrillation
Abstract

BackgroundAtrial fibrillation is the most common sustained arrhythmia in the elderly. Serum potassium is associated with ventricular arrhythmias and cardiac arrest. Little is known about the association of serum potassium with atrial fibrillation. The objective of this study was to investigate the association of serum potassium and the risk of atrial fibrillation in a population based setting.MethodsThe study was performed within the prospective population-based Rotterdam Study. The study population consisted of 4059 participants without atrial fibrillation at baseline for whom baseline levels of serum potassium were measured. Atrial fibrillation was ascertained from centre visit ECG assessments as well as medical records.ResultsDuring a mean follow up of 11.8years (SD=5.2yr), 474 participants developed atrial fibrillation. Participants with hypokalemia (

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33. Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval

Author

Avery, Christy L., Sitlani, Colleen M., Arking, Dan E., Arnett, Donna K., Bis, Joshua C., Boerwinkle, Eric, Buckley, Brendan M., Chen, Y.-D. Ida, de Craen, Anton JM, Eijgelsheim, Mark, Enquobahrie, Daniel, Evans, Daniel S., Ford, Ian, Garcia, Melissa E., Gudnason, Vilmundur, Harris, Tamara B., Heckbert, Susan R., Hochner, Hagit, Hofman, Albert, Hsueh, Wen-Chi, Isaacs, Aaron, Jukema, J. Wouter, Knekt, Paul, Kors, Jan A., Krijthe, Bouwe P., Kristiansson, Kati, Laaksonen, Maarit, Liu, Yongmei, Li, Xiaohui, MacFarlane, Peter W., Newton-Cheh, Christopher, Nieminen, Markku S., Oostra, Ben A., Peloso, Gina M., Porthan, Kimmo, Rice, Kenneth, Rivadeneira, Fernando F., Rotter, Jerome I., Salomaa, Veikko, Sattar, Naveed, Siscovick, David S., Slagboom, P. Eline, Smith, Albert V., Sotoodehnia, Nona, Stott, David J., Stricker, Bruno H., Stürmer, Til, Trompet, Stella, Uitterlinden, Andre G., van Duijn, Cornelia M., Westendorp, Rudi GJ, Witteman, Jacqueline C., Whitsel, Eric A., and Psaty, Bruce M.

Subjects
QT interval, pharmacogenomics, gene-environment interaction
Abstract

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the “missing heritability” of complex traits. Here, we describe four independent analyses in 33,781 participants of European ancestry from ten cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%), and QT prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-SNP interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0×10−8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Published
2013
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34. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

Bruno H. Stricker, Antonietta Robino, Gandin Ilaria, Marylyn D. Ritchie, Mark Eijgelsheim, Hilma Holm, Marcus Dörr, Philipp S. Wild, Jessica van Setten, Stephan B. Felix, Maristella Steri, Jared W. Magnani, Brendan M. Buckley, Peter P. Pramstaller, Claudia T. Silva Aldana, Niek Verweij, Tim D. Spector, Ruth J. F. Loos, Dan M. Roden, Martina Müller-Nurasyid, Mina K. Chung, Sandosh Padmanabhan, Stefania Bandinelli, Harm-Jan Westra, James F. Wilson, Honghuang Lin, Braxton D. Mitchell, Patrick T. Ellinor, Patricia B. Munroe, Harold Snieder, Thomas Münzel, Sheila Ulivi, Andrew A. Hicks, Nona Sotoodehnia, Daniel S. Evans, Annamaria Iorio, Peter W. Macfarlane, Vilmundur Gudnason, Christy L. Avery, Caroline Hayward, Cornelia M. van Duijn, John Barnard, Alvaro Alonso, Dana C. Crawford, Uwe Völker, David R. Van Wagoner, Tamara B. Harris, Harry Campbell, Ozren Polasek, Daniel F. Gudbjartsson, Ilja M. Nolte, Bouwe P. Krijthe, Eric Boerwinkle, Moritz F. Sinner, Elsayed Z. Soliman, Mika Kähönen, Christian Müller, Renate B. Schnabel, Unnur Thorsteinsdottir, Leo-Pekka Lyytikäinen, George J. Papanicolaou, Ivana Kolcic, Stella Trompet, Jerome I. Rotter, Dan E. Arking, Kirill V. Tarasov, Igor Rudan, Bruce M. Psaty, Gianfranco Sinagra, Alexander Teumer, Yalda Jamshidi, David O. Arnar, Toshiko Tanaka, Melanie Waldenberger, Henry J. Lin, Luigi Ferrucci, Susan R. Heckbert, Jan A. Kors, Irene Mateo Leach, Joel S. Bader, Konstantin Strauch, Albert V. Smith, Paul I.W. de Bakker, Stefan Blankenberg, J. C. Bis, Edward G. Lakatta, Lenore J. Launer, Thomas Meitinger, Anna F. Dominiczak, Marcel den Hoed, Steven A. Lubitz, Stefan Kääb, David J. Stott, Francesco Cucca, Olli T. Raitakari, Afshin Parsa, Nilesh J. Samani, Josh C. Denny, Lude Franke, Oscar H. Franco, Yongmei Liu, Folkert W. Asselbergs, Henry Völzke, Terho Lehtimäki, Arne Pfeufer, Annette Peters, David Schlessinger, Xiaoyan Yin, Jennifer A. Brody, J. Wouter Jukema, Paolo Gasparini, Tanja Zeller, Aaron Isaacs, Anne M. Butler, Sina A. Gharib, Kathleen F. Kerr, Jonathan D. Smith, Pim van der Harst, André G. Uitterlinden, Quince Gibson, Yuki Bradford, Brenton R. Swenson, Emelia J. Benjamin, Georg Ehret, Kari Stefansson, Fabiola M. Del Greco, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Gandin, Ilaria, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth J F, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thoma, Mitchell, Braxton D, Munzel, Thoma, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcu, Ferrucci, Luigi, Gasparini, Paolo, Gudnason, Vilmundur, Hayward, Caroline, Heckbert, Susan R, Hicks, Andrew A, Jukema, J Wouter, Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Munroe, Patricia B, Parsa, Afshin, Polasek, Ozren, Psaty, Bruce M, Roden, Dan M, Schnabel, Renate B, Sinagra, Gianfranco, Stefansson, Kari, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Wilson, James F, Gharib, Sina A, de Bakker, Paul I W, Isaacs, Aaron, Arking, Dan E, Sotoodehnia, Nona, Faculty of Medicine (UI), Læknadeild (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Epidemiology, Medical Informatics, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Male, QRS duration, Epidemiology, Genome-wide association study, Biochemistry, Linkage Disequilibrium, Electrocardiography, 0302 clinical medicine, Atrioventricular Conduction, lcsh:Science, COMMON VARIANTS, Heart Depolarization, Canal de iones, Cardiovascular system, Gene Locus, Blood, cardiovascular system, Qrs Interval, FIBRILLATION, Enfermedades cardiovasculares, Human, Missense Mutation, Heart block, Science, HEART-RATE, Single-nucleotide polymorphism, Missense/genetics, Physics and Astronomy(all), Factor de transcripción, European, General Biochemistry, Genetics and Molecular Biology, Article, PR interval genome, atrial electrical activity, atrioventricular electrical activity, 03 medical and health sciences, CARDIAC CONDUCTION, Cardiac conduction, Humans, Sistema cardiovascular, Common variants, Sangre, Cardiovascular genetics, medicine.disease, Heart-rate, Enfermedades, Electrophysiological Phenomena, 030104 developmental biology, Heart Block, Electric Activity, Mutation, lcsh:Q, Cell Junction, Cohorts, Meta-Analysis, 0301 basic medicine, Chemistry(all), Transcription Factor, General Physics and Astronomy, 030204 cardiovascular system & hematology, Fibrilación auricular, Electrophysiological Phenomena/genetics, RARE, Ion Channel, Heart Rate, Risk Factors, Atrial Fibrillation, EPIDEMIOLOGY, Bloqueo cardíaco, SNPS, Genetics, RISK, Multidisciplinary, Genome, Atrial fibrillation, Genetic Analysis, Atrioventricular Node/physiology, Atrial Function, Phenotype, Heart Disease, Rare, Atrioventricular Node, Female, medicine.symptom, QRS DURATION, Atrial Function/physiology, Medical Genetics, SNPs, Signal Transduction, Risk, Heart Diseases, Mutation, Missense, macromolecular substances, Biology, QRS complex, medicine, Disequilibrium, Linkage Disequilibrium/genetics, cardiovascular diseases, PR interval, Medicinsk genetik, Fibrillation, Biochemistry, Genetics and Molecular Biology(all), Risk Factor, African, General Chemistry, COHORTS, Pr Interval, Gene Linkage Disequilibrium, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., 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., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.

Published
2018

35. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

Yuki Bradford, Toshiko Tanaka, Jeffrey R. O'Connell, Florence Kyndt, Unnur Thorsteinsdottir, Ivana Kolcic, Xiaoyan Yin, Vincent Probst, Manolis Kellis, Christopher Newton-Cheh, Stefan Kääb, Argelia Medeiros-Domingo, Markus M. Nöthen, Paolo Gasparini, Jean-Jacques Schott, Ruth J. F. Loos, Thomas W. Mühleisen, Annukka Marjamaa, Morris Brown, Igor Rudan, Runjun D. Kumar, Peter J. Schwartz, Lars Lind, Martina Müller-Nurasyid, Xinchen Wang, Joshua C. Denny, Roberto Insolia, Soumya Raychaudhuri, Stephen W. Scherer, Bruno H. Stricker, Alexander Kluttig, Adamo Pio D'Adamo, Laurie A. Boyer, Moritz F. Sinner, Norbert Frey, Nour Eddine El Mokhtari, Thomas Meitinger, Jesper V. Olsen, Gerjan Navis, Steven R. Cummings, Richard W Morris, Nynke Hofman, Marcel den Hoed, Rudolf A. de Boer, Gonçalo R. Abecasis, Mark J. Daly, Dan M. Roden, Christian Gieger, Lyudmyla Kedenko, Marcus Dörr, Thomas P. Cappola, Afshin Parsa, Kari Stefansson, Markus Perola, Mark Eijgelsheim, Fredrik Nyberg, Robert M. Hamilton, Yalda Jamshidi, W. H. Linda Kao, Terho Lehtimäki, Annette Peters, David Schlessinger, Peter P. Pramstaller, James F. Wilson, Vilmundur Gudnason, Florian Kronenberg, Aroon D. Hingorani, Connie R. Bezzina, Abdennasser Bardai, Marylyn D. Ritchie, Andrew S. Plump, Johan Sundström, Daryl Waggott, Chrysoula Dalageorgou, Paul I.W. de Bakker, Uwe Völker, Aaron Isaacs, Oscar H. Franco, Yongmei Liu, Andrew N. Nicolaides, Lia Crotti, Cornelia M. van Duijn, Ben A. Oostra, Arne Pfeufer, Karl Werdan, Michael Morley, Jan A. Kors, Julien Barc, Lewin Eisele, Siegfried Perz, Stéphanie Chatel, Pieter A. van der Vleuten, Sara L. Pulit, Anna F. Dominiczak, Harry Campbell, Alice Ghidoni, Irene Mateo Leach, Nona Sotoodehnia, Nina Mononen, Henriette E. Meyer zu Schwabedissen, Alvaro Alonso, Fabiola Del Greco M, Dan E. Arking, Vera Adamkova, Mike A. Nalls, Valur Emilsson, Edward G. Lakatta, Kirill Tarasov, Alan F. Wright, Lenore J. Launer, Erik Ingelsson, Karin Halina Greiser, Ozren Polasek, Massimo Carella, Daniel F. Gudbjartsson, Bouwe P. Krijthe, Hanna Prucha, Per Hoffmann, Maura Griffin, Stefan Kiechl, Angel Carracedo, Ilja M. Nolte, Christine E. Moravec, Johann Willeit, Joshua C. Bis, Patricia B. Munroe, Marcello Ricardo Paulista Markus, Hailiang Huang, Mika Kähönen, Albert Hofman, Peter H. Whincup, Dirk J. van Veldhuisen, Michael Knoflach, Alicia Lundby, Serena Sanna, Hagen Kälsch, Bernhard Paulweber, Kamil Slowikowski, Luigi Ferrucci, Melanie Waldenberger, Marco Bobbo, Annukka M. Lahtinen, Ann-Christine Syvänen, J. Gustav Smith, Åsa Torinsson Naluai, Jaroslav A. Hubacek, Jeffrey Brandimarto, Wendy S. Post, Lude Franke, Mark J. Caulfield, Folkert W. Asselbergs, André G. Uitterlinden, Stefan Gustafsson, Pim van der Harst, David J. Tester, David S. Siscovick, David O. Arnar, Sarah H Wild, Elizabeth J. Rossin, Albert V. Smith, Bruce M. Psaty, Georg Ehret, Alan R. Shuldiner, Stephen Newhouse, Kimmo Kontula, Maria Brion, Andre Franke, Peter W. Macfarlane, Mika Kivimäki, Tamara B. Harris, Lasse Oikarinen, Tamara T. Koopmann, Kenneth B. Margulies, Aravinda Chakravarti, Gianfranco Sinagra, Maarten P. van den Berg, Veikko Salomaa, Karl-Heinz Jöckel, Daniel S. Evans, Caroline Hayward, Kimmo Porthan, Michael J. Ackerman, Jacqueline C.M. Witteman, Arthur A.M. Wilde, Martin G. Larson, Kasper Lage, Manuela Uda, Susan R. Heckbert, Joel S. Bader, Graham Watt, María Dolores Torres, Stephan B. Felix, Jerome I. Rotter, Pau Navarro, Meena Kumari, Johan Ärnlöv, Andrew D. Paterson, Antti Jula, Olli T. Raitakari, Raimund Erbel, Christopher J. O'Donnell, Britt M. Beckmann, Peter A. Noseworthy, Tim D. Spector, Wai K. Lee, Leopoldo Zelante, Nilesh J. Samani, John R. Giudicessi, Harold Snieder, Dag S. Thelle, David Ellinghaus, Eimo Martens, James B. Strait, Jorma S. A. Viikari, Andrew D. Johnson, Antonella Mulas, Hilma Holm, Johannes Haerting, Annamaria Iorio, Rebecca L. Zuvich, Sheila Ulivi, Andrew A. Hicks, Elijah R. Behr, Leo-Pekka Lyytikäinen, Bernhard Strohmer, Marco Orru, Claudia Lamina, Sandosh Padmanabhan, Christian Fuchsberger, Andrie G. Panayiotou, Ehret, Georg Benedikt, Internal Medicine, Public Health, Epidemiology, Rehabilitation Medicine, Medical Informatics, Clinical Genetics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Ethical, Legal, Social Issues in Genetics (ELSI), Stem Cell Aging Leukemia and Lymphoma (SALL), Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, Dan E., Pulit, Sara L., Crotti, Lia, Van Der Harst, Pim, Munroe, Patricia B., Koopmann, Tamara T., Sotoodehnia, Nona, Rossin, Elizabeth J., Morley, Michael, Wang, Xinchen, Johnson, Andrew D., Lundby, Alicia, Gudbjartsson, Daníel F., Noseworthy, Peter A., Eijgelsheim, Mark, Bradford, Yuki, Tarasov, Kirill V., Dörr, Marcu, Müller Nurasyid, Martina, Lahtinen, Annukka M., Nolte, Ilja M., Smith, Albert Vernon, Bis, Joshua C., Isaacs, Aaron, Newhouse, Stephen J., Evans, Daniel S., Post, Wendy S., Waggott, Daryl, Lyytikäinen, Leo Pekka, Hicks, Andrew A., Eisele, Lewin, Ellinghaus, David, Hayward, Caroline, Navarro, Pau, Ulivi, Sheila, Tanaka, Toshiko, Tester, David J., Chatel, Stéphanie, Gustafsson, Stefan, Kumari, Meena, Morris, Richard W., Naluai, Asa T., Padmanabhan, Sandosh, Kluttig, Alexander, Strohmer, Bernhard, Panayiotou, Andrie G., Torres, Maria, Knoflach, Michael, Hubacek, Jaroslav A., Slowikowski, Kamil, Raychaudhuri, Soumya, Kumar, Runjun D., Harris, Tamara B., Launer, Lenore J., Shuldiner, Alan R., Alonso, Alvaro, Bader, Joel S., Ehret, Georg, Huang, Hailiang, Kao, W. H. Linda, Strait, James B., Macfarlane, Peter W., Brown, Morri, Caulfield, Mark J., Samani, Nilesh J., Kronenberg, Florian, Willeit, Johann, Smith, J. Gustav, Greiser, Karin H., Zu Schwabedissen, Henriette Meyer, Werdan, Karl, Carella, Massimo, Zelante, Leopoldo, Heckbert, Susan R., Psaty, Bruce M., Rotter, Jerome I., Kolcic, Ivana, Polašek, Ozren, Wright, Alan F., Griffin, Maura, Daly, Mark J., Arnar, David O., Hólm, Hilma, Thorsteinsdottir, Unnur, Denny, Joshua C., Roden, Dan M., Zuvich, Rebecca L., Emilsson, Valur, Plump, Andrew S., Larson, Martin G., O'Donnell, Christopher J., Yin, Xiaoyan, Bobbo, Marco, D'Adamo, ADAMO PIO, Iorio, Annamaria, Sinagra, Gianfranco, Carracedo, Angel, Cummings, Steven R., Nalls, Michael A., Jula, Antti, Kontula, Kimmo K., Marjamaa, Annukka, Oikarinen, Lasse, Perola, Marku, Porthan, Kimmo, Erbel, Raimund, Hoffmann, Per, Jöckel, Karl Heinz, Kälsch, Hagen, Nöthen, Markus M., Den Hoed, Marcel, Loos, Ruth J. F., Thelle, Dag S., Gieger, Christian, Meitinger, Thoma, Perz, Siegfried, Peters, Annette, Prucha, Hanna, Sinner, Moritz F., Waldenberger, Melanie, De Boer, Rudolf A., Franke, Lude, Van Der Vleuten, Pieter A., Beckmann, Britt Maria, Martens, Eimo, Bardai, Abdennasser, Hofman, Nynke, Wilde, Arthur A. M., Behr, Elijah R., Dalageorgou, Chrysoula, Giudicessi, John R., Medeiros Domingo, Argelia, Barc, Julien, Kyndt, Florence, Probst, Vincent, Ghidoni, Alice, Insolia, Roberto, Hamilton, Robert M., Scherer, Stephen W., Brandimarto, Jeffrey, Margulies, Kenneth, Moravec, Christine E., Del Greco M, Fabiola, Fuchsberger, Christian, O'Connell, Jeffrey R., Lee, Wai K., Watt, Graham C. M., Campbell, Harry, Wild, Sarah H., El Mokhtari, Nour E., Frey, Norbert, Asselbergs, Folkert W., Leach, Irene Mateo, Navis, Gerjan, Van Den Berg, Maarten P., Van Veldhuisen, Dirk J., Kellis, Manoli, Krijthe, Bouwe P., Franco, Oscar H., Hofman, Albert, Kors, Jan A., Uitterlinden, André G., Witteman, Jacqueline C. M., Kedenko, Lyudmyla, Lamina, Claudia, Oostra, Ben A., Abecasis, Gonçalo R., Lakatta, Edward G., Mulas, Antonella, Orrú, Marco, Schlessinger, David, Uda, Manuela, Markus, Marcello R. P., Völker, Uwe, Snieder, Harold, Spector, Timothy D., Ärnlöv, Johan, Lind, Lar, Sundström, Johan, Syvänen, Ann Christine, Kivimaki, Mika, Kähönen, Mika, Mononen, Nina, Raitakari, Olli T., Viikari, Jorma S., Adamkova, Vera, Kiechl, Stefan, Brion, Maria, Nicolaides, Andrew N., Paulweber, Bernhard, Haerting, Johanne, Dominiczak, Anna F., Nyberg, Fredrik, Whincup, Peter H., Hingorani, Aroon D., Schott, Jean Jacque, Bezzina, Connie R., Ingelsson, Erik, Ferrucci, Luigi, Gasparini, Paolo, Wilson, James F., Rudan, Igor, Franke, Andre, Mühleisen, Thomas W., Pramstaller, Peter P., Lehtimäki, Terho J., Paterson, Andrew D., Parsa, Afshin, Liu, Yongmei, Van Duijn, Cornelia M., Siscovick, David S., Gudnason, Vilmundur, Jamshidi, Yalda, Salomaa, Veikko, Felix, Stephan B., Sanna, Serena, Ritchie, Marylyn D., Stricker, Bruno H., Stefansson, Kari, Boyer, Laurie A., Cappola, Thomas P., Olsen, Jesper V., Lage, Kasper, Schwartz, Peter J., Kääb, Stefan, Chakravarti, Aravinda, Ackerman, Michael J., Pfeufer, Arne, De Bakker, Paul I. W., Newton Cheh, Christopher, Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics

Subjects
Male, Candidate gene, Myocardium/metabolism, LOCI, Medizin, Heart electrophysiology, Genome-wide association study, Arrhythmias, Bioinformatics, Medical and Health Sciences, Heart Ventricle, Sudden cardiac death, Electrocardiography, PR INTERVAL, Arrhythmias, Cardiac/genetics, Death, Sudden, Cardiac/etiology, Genetics, ddc:616, Cardiac electrophysiology, Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Middle Aged, Myocardium, Polymorphism, Single Nucleotide, COMMON VARIANTS, Heart Ventricles/metabolism, Single Nucleotide, Long QT Syndrome/genetics, CHRONIC HEART-FAILURE, Death, Heart ventricle arrhythmia, genetic association study, gene, SNP, heart, Genome-Wide Association Study/methods, Long QT syndrome, QRS DURATION, Cardiac, Cardiac/etiology, Human, QT interval, congenital, hereditary, and neonatal diseases and abnormalities, Electrocardiography/methods, TRPM7, BIO/18 - GENETICA, Cardiac/genetics, Biology, Article, sudden cardiac death, QRS complex, CARDIAC REPOLARIZATION, medicine, Repolarization, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, MED/01 - STATISTICA MEDICA, calcium, ta1184, Calcium signaling, Calcium Signaling/genetics, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, ta3121, Cardiovascular risk, medicine.disease, SARCOPLASMIC-RETICULUM, Sudden, MODEL, Genetic association, myocardial repolarization, Genetic variability, Gene expression, Clinical Medicine, genetic, Controlled study
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 similar to 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.

Published
2014

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