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1. Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase

Author

Danny V. Jeyaraju, Maryam Alapa, Ann Polonskaia, Alberto Risueño, Prakash Subramanyam, Amit Anand, Kaushik Ghosh, Charalampos Kyriakopoulos, Daiane Hemerich, Rose Hurren, Xiaoming Wang, Marcela Gronda, Aarif Ahsan, Hsiling Chiu, Geethu Thomas, Evan F. Lind, Daniel L Menezes, Aaron D. Schimmer, Patrick R. Hagner, Anita Gandhi, and Anjan G. Thakurta

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Oral azacitidine (oral-Aza) treatment results in longer median overall survival (OS) (24.7 vs. 14.8 months in placebo) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy. The dosing schedule of oral-Aza (14 days/28-day cycle) allows for low exposure of Aza for an extended duration thereby facilitating a sustained therapeutic effect. However, the underlying mechanisms supporting the clinical impact of oral-Aza in maintenance therapy remain to be fully understood. In this preclinical work, we explore the mechanistic basis of oral-Aza/extended exposure to Aza through in vitro and in vivo modeling. In cell lines, extended exposure to Aza results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to Aza, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of Aza induces differentiation and depletes CD34+CD38- LSC. Mechanistically, LSC differentiation is driven in part by increased myeloperoxidase (MPO) expression. Inhibition of MPO activity either by using an MPO-specific inhibitor or blocking oxidative stress, a known mechanism of MPO, partly reverses the differentiation of LSC. Overall, our preclinical work reveals novel mechanistic insights into oral-Aza and its ability to target LSC.

Published
2023
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2. Effect of tissue-grouped regulatory variants associated to type 2 diabetes in related secondary outcomes

Author

Daiane Hemerich, Roelof A. J. Smit, Michael Preuss, Lauren Stalbow, Sander W. van der Laan, Folkert W. Asselbergs, Jessica van Setten, and Vinicius Tragante

Subjects
Medicine, Science
Abstract

Abstract Genome-wide association studies have identified over five hundred loci that contribute to variation in type 2 diabetes (T2D), an established risk factor for many diseases. However, the mechanisms and extent through which these loci contribute to subsequent outcomes remain elusive. We hypothesized that combinations of T2D-associated variants acting on tissue-specific regulatory elements might account for greater risk for tissue-specific outcomes, leading to diversity in T2D disease progression. We searched for T2D-associated variants acting on regulatory elements and expression quantitative trait loci (eQTLs) in nine tissues. We used T2D tissue-grouped variant sets as genetic instruments to conduct 2-Sample Mendelian Randomization (MR) in ten related outcomes whose risk is increased by T2D using the FinnGen cohort. We performed PheWAS analysis to investigate whether the T2D tissue-grouped variant sets had specific predicted disease signatures. We identified an average of 176 variants acting in nine tissues implicated in T2D, and an average of 30 variants acting on regulatory elements that are unique to the nine tissues of interest. In 2-Sample MR analyses, all subsets of regulatory variants acting in different tissues were associated with increased risk of the ten secondary outcomes studied on similar levels. No tissue-grouped variant set was associated with an outcome significantly more than other tissue-grouped variant sets. We did not identify different disease progression profiles based on tissue-specific regulatory and transcriptome information. Bigger sample sizes and other layers of regulatory information in critical tissues may help identify subsets of T2D variants that are implicated in certain secondary outcomes, uncovering system-specific disease progression.

Published
2023
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3. An oviduct-on-a-chip provides an enhanced in vitro environment for zygote genome reprogramming

Author

Marcia A. M. M. Ferraz, Hoon Suk Rho, Daiane Hemerich, Heiko H. W. Henning, Helena T. A. van Tol, Michael Hölker, Urban Besenfelder, Michal Mokry, Peter L. A. M. Vos, Tom A. E. Stout, Séverine Le Gac, and Bart M. Gadella

Subjects
Science
Abstract

In vitro culture has detrimental effects on transcriptomes and epigenetic programming of zygotes. Here the authors use microfluidic technology to co-culture bovine oviduct epithelial cells with zygotes and show that the transcriptomes and global methylation patterns of these zygotes are more similar to in vivo zygotes than to conventionally cultured zygotes.

Published
2018
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4. Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

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

Subjects
Science
Abstract

Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.

Published
2017
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5. Integrative Bioinformatics Approaches for Identification of Drug Targets in Hypertension

Author

Daiane Hemerich, Jessica van Setten, Vinicius Tragante, and Folkert W. Asselbergs

Subjects
hypertension, blood pressure, epigenetic regulation, GWAS, data integration, functional annotation, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

High blood pressure or hypertension is an established risk factor for a myriad of cardiovascular diseases. Genome-wide association studies have successfully found over nine hundred loci that contribute to blood pressure. However, the mechanisms through which these loci contribute to disease are still relatively undetermined as less than 10% of hypertension-associated variants are located in coding regions. Phenotypic cell-type specificity analyses and expression quantitative trait loci show predominant vascular and cardiac tissue involvement for blood pressure-associated variants. Maps of chromosomal conformation and expression quantitative trait loci (eQTL) in critical tissues identified 2,424 genes interacting with blood pressure-associated loci, of which 517 are druggable. Integrating genome, regulome and transcriptome information in relevant cell-types could help to functionally annotate blood pressure associated loci and identify drug targets.

Published
2018
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6. Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

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

Subjects
Science
Abstract

Nature Communications 8: Article number: 15805 (2017); Published: 14 June 2017; Updated: 2 August 2017 In Supplementary Fig. 10 of this Article, images for panels a and b were inadvertently omitted. The correct version of Supplementary Fig. 10 is provided as Supplementary Information associated withthis Erratum.

Published
2017
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8. Physical activity and sedentary behavior; mechanistic insights and role in disease prevention

Author

Marcel den Hoed, Zhe Wang, Andrew Emmerich, Nicolas Pillon, Timothy Moore, Daiane Hemerich, Marilyn Cornelis, Eugenia Mazzaferro, Siacia Broos, Adam Ameur, Stefania Bandinelli, Joshua Bis, Michael Boehnke, Claude Bouchard, Daniel Chasman, Eco de Geus, Louise Deldicque, Marcus Dörr, Michele Evans, Luigi Ferrucci, Myriam Fornage, Caroline Fox, Theodore Garland, Ulf Gyllensten, Torben Hansen, Caroline Hayward, Bernardo Horta, Elina Hypponen, W. Craig Johnson, Sharon Kardia, Lambertus Kiemeney, Markku Laakso, Claudia Langenberg, Terho Lehtimäki, Loic Le Marchand, Patrik Magnusson, Nicholas Martin, Mads Melbye, Andres Metspalu, David Meyre, Kari North, Claes Ohlsson, Albertine Oldehinkel, Marju Orho-Melander, Guillaume Pare, Taesung Park, Oluf Pedersen, Brenda Penninx, Tune Pers, Ozren Polasek, Inga Prokopenko, Charles Rotimi, Nilesh Samani, Xueling Sim, George Davey Smith, Harold Snieder, Thorkild Sorensen, Tim Spector, Nicholas Timpson, Rob van Dam, Nathalie van der Velde, Peter Vollenweider, Henry Völzke, Trudy Voortman, Gerard Waeber, Nick Wareham, David Weir, Erich Wichmann, James Wilson, Andrea Hevener, Anna Krook, Juleen Zierath, Martine Thomis, and Ruth Loos

Abstract

Even though physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Here, we combine data for up to 674,980 individuals from 51 studies in a trans-ancestry meta-analysis of genome-wide association studies for self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA); leisure screen time (LST); sedentary commuting; and sedentary behavior at work. We identify 99 loci that associate with at least one trait. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. Molecular dynamics simulations suggest that the Glu to Ala substitution encoded by rs2229456 (ACTN3) – associated with more MVPA – disrupts salt bridge interactions and makes the alpha actinin 3 filaments more flexible. In isolated type IIA muscle fibers, the Ala-encoding allele is associated with lower maximal force and power during an isometric contraction, suggesting protection from exercise-induced muscle damage. Finally, Mendelian Randomization analyses show that the causal effect of LST on BMI is 2-3 times larger than the effect of body mass index (BMI) on LST, and that beneficial effects of LST and MVPA on several risk factors and diseases are mediated or confounded by BMI. Taken together, our results provide mechanistic insights into the regulation of MVPA and into the role of LST and MVPA in disease prevention. These insights may facilitate the development of tailored physical activity interventions.

Published
2021
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9. Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Author

Magdalena Harakalova, Benjamin Meder, Philippe Charron, Manuel Gómez-Bueno, Jorg J. A. Calis, François Cambien, David-Alexandre Trégouët, Maurizia Grasso, Steven McGinn, Uwe Völker, Thomas Meitinger, Stefan Weiss, L. Duboscq-Bidot, Richard Dorent, Vera Regitz-Zagrosek, Folkert W. Asselbergs, Hélène Blanché, Olivier Dubourg, Patrick Lacolley, Pierre Boutouyrie, Delphine Bacq-Daian, Vincent Fontaine, Volker Ruppert, Marine Germain, K Lehnert, Jean-Noël Trochu, Stuart A. Cook, Angélique Curjol, Brendan J. Keating, Ibticem Raji, Anne Boland, J. Erdmann, Michael Morley, Jean-François Aupetit, Paloma Remior, Luigi Tavazzi, Gérard Roizès, Michal Mokry, Konstantin Strauch, Richard Isnard, Jean-Philippe Empana, Robert Olaso, Kenneth B. Marguiles, Zofia T. Bilińska, Stephan B. Felix, Marcus Dörr, Thomas P. Cappola, Stefan Blankenberg, Jan Haas, Céline Besse, Jean-François Deleuze, Christine E. Seidman, Christian Hengstenberg, Jessica van Setten, Hakon Hakonarson, Sanjay K Prasad, Daiane Hemerich, Pascal de Groote, Thomas Wichter, Alain van Mil, Michel Komajda, Renee Maas, Carole Proust, Declan P. O'Regan, Xavier Jouven, Ganapathi Varma Saripella, Georgios Kararigas, Eloisa Arbustini, Jin Li, Klaus Stark, Laurent Fauchier, Flavie Ader, Melanie Waldenberger, Martina Müller-Nurasyid, Eric Villard, Sophie Garnier, Cardiology, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique-Hôpitaux de Paris, Fondation Leducq, Société Française de Cardiologie, Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München, Université de Bordeaux, Medical Research Council, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University Medical Center [Utrecht], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Pennsylvania, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), National Heart Centre Singapore (NHCS), Children’s Hospital of Philadelphia (CHOP ), University of Regensburg, Royal Brompton Hospital, Imperial College London, Istituti Clinici Scientifici Maugeri [Pavia] (IRCCS Pavia - ICS Maugeri), Helmholtz Zentrum München = German Research Center for Environmental Health, Ludwig-Maximilians-Universität München (LMU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), University Medical Center of the Johannes Gutenberg-University Mainz, Perelman School of Medicine, Harvard Medical School [Boston] (HMS), University of Iceland [Reykjavik], Heidelberg University, Stanford University Medical School, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universität zu Lübeck = University of Lübeck [Lübeck], Universitätklinikum Gießen und Marburg GmbH, Maria Cecilia Hospital [Cotignola], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital cardiologique, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier Saint Joseph - Saint Luc [Lyon], National Institute of Cardiology [Varsovie, Pologne], University of Medicine Greifswald, Centre de Référence Maladies Cardiaques Héréditaires, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Swedish University of Agricultural Sciences (SLU), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Groupe Hospitalier Paris Saint Joseph, Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), and University College of London [London] (UCL)

Subjects
Cardiac & Cardiovascular Systems, Cardiomyopathy, Dilated/genetics, [SDV]Life Sciences [q-bio], Signal Transducing/genetics, Dilated cardiomyopathy, Genome-wide association study, Adaptor Proteins, Signal Transducing/genetics, 030204 cardiovascular system & hematology, TAURINE, 0302 clinical medicine, GWAS, Medicine, POSITION STATEMENT, 1102 Cardiorespiratory Medicine and Haematology, Genetics, 0303 health sciences, education.field_of_study, Genetic Predisposition to Disease/genetics, Adaptor Proteins, 4C-sequencing, Polymorphism, Single Nucleotide/genetics, Genetic risk score, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, Single Nucleotide/genetics, Cardiomyopathy, Dilated, Cardiomyopathy, Population, Locus (genetics), Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Chromosomes, 03 medical and health sciences, Systolic/genetics, Heart Failure, Systolic/genetics, SNP, Animals, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, education, Imputation, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Heart Failure, Science & Technology, business.industry, WORKING GROUP, 1103 Clinical Sciences, medicine.disease, Genetic architecture, Cardiovascular System & Hematology, Dilated/genetics, Cardiovascular System & Cardiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Apoptosis Regulatory Proteins, Heart Failure, Systolic, Genome-Wide Association Study
Abstract

Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.

Published
2021
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10. Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits

Author

Yalda Jamshidi, Paul I.W. de Bakker, J. Wouter Jukema, Ilaria Gandin, Monika Stoll, Christopher P. Nelson, Moritz F. Sinner, Eco J. C. de Geus, André G. Uitterlinden, Jan A. Kors, Vilmundur Gudnason, Sheila Ulivi, Jouke-Jan Hottenga, Terho Lehtimäki, Antonietta Robino, Mark Eijgelsheim, Annamaria Iorio, Niek Verweij, Martina Müller-Nurasyid, Ian Ford, Hao Mei, James G. Wilson, Albert V. Smith, Thomas Meitinger, Gianfranco Sinagra, Claudia T. Silva Aldana, Maartje N. Niemeijer, Torben Hansen, Allan Linneberg, Jennifer A. Brody, Pim van der Harst, Stella Trompet, Paolo Gasparini, Bram P. Prins, Stefan Kääb, Hamdi Mbarek, Alvaro Alonso, Leanne M. Hall, Helen R. Warren, Dan E. Arking, Peter W. Macfarlane, Annette Peters, Olli T. Raitakari, Daiane Hemerich, Mark J. Caulfield, Folkert W. Asselbergs, Dorret I. Boomsma, Aaron Isaacs, Bruno H. Stricker, Tamara B. Harris, Susan R. Heckbert, Jessica van Setten, Niels Grarup, Patricia B. Munroe, Leo-Pekka Lyytikäinen, Nilesh J. Samani, Cornelia M. van Duijn, Elsayed Z. Soliman, Nona Sotoodehnia, Jørgen K. Kanters, Melanie Waldenberger, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, Erasmus MC other, Epidemiology, Medical Informatics, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, van Setten, Jessica, Verweij, Niek, Mbarek, Hamdi, Niemeijer, Maartje N., Trompet, Stella, Arking, Dan E., Brody, Jennifer A., Gandin, Ilaria, Grarup, Niel, Hall, Leanne M., Hemerich, Daiane, Lyytikäinen, Leo-Pekka, Mei, Hao, Müller-Nurasyid, Martina, Prins, Bram P., Robino, Antonietta, Smith, Albert V., Warren, Helen R., Asselbergs, Folkert W., Boomsma, Dorret I., Caulfield, Mark J., Eijgelsheim, Mark, Ford, Ian, Hansen, Torben, Harris, Tamara B., Heckbert, Susan R., Hottenga, Jouke-Jan, Iorio, Anita, Kors, Jan A., Linneberg, Allan, Macfarlane, Peter W., Meitinger, Thoma, Nelson, Christopher P., Raitakari, Olli T., Silva Aldana, Claudia T., Sinagra, Gianfranco, Sinner, Moritz, Soliman, Elsayed Z., Stoll, Monika, Uitterlinden, Andre, van Duijn, Cornelia M., Waldenberger, Melanie, Alonso, Alvaro, Gasparini, Paolo, Gudnason, Vilmundur, Jamshidi, Yalda, Kääb, Stefan, Kanters, Jørgen K., Lehtimäki, Terho, Munroe, Patricia B., Peters, Annette, Samani, Nilesh J., Sotoodehnia, Nona, Ulivi, Sheila, Wilson, James G., de Geus, Eco J. C., Jukema, J. Wouter, Stricker, Bruno, van der Harst, Pim, de Bakker, Paul I. W., Isaacs, Aaron, Cardiovascular Centre (CVC), Biochemie, RS: FHML MaCSBio, RS: CARIM - R1 - Thrombosis and haemostasis, and RS: Carim - B01 Blood proteins & engineering

Subjects
Male, Netherlands Twin Register (NTR), Genetics, Genetics (clinical), PROTEIN, Genome-wide association study, Quantitative trait, Genome-wide association studies, ANNOTATION, Gene locus, Electrocardiography, Computer model, Netherlands, Priority journal, Allele, 0303 health sciences, Genome, Rr interval, 030305 genetics & heredity, COMMON VARIANTS, ddc, GLUCOCORTICOID-RECEPTOR, Qrs interval, Female, Cohort analysis, Erfðarannsóknir, PHOSPHOLAMBAN, Human, QT INTERVAL DURATION, Genotype, Heart rate, HEART-RATE, Exon, Single-nucleotide polymorphism, Major clinical study, Biology, Quantitative trait locus, Dutchman, Polymorphism, Single Nucleotide, QT interval, Article, Sample, 03 medical and health sciences, QRS complex, Genetic, SDG 3 - Good Health and Well-being, Humans, PR interval, Gene mapping, Genetic association, MUTATIONS, Follow up, CONTRACTILITY, DNA-rannsóknir, R1, Gene frequency, POLYMORPHISM, Electrocardiogram, Single nucleotide polymorphism, Minor allele frequency, Genetic Loci, Meta analysis, Qt interval, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes., Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre.

Published
2019
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11. A comparison of two workflows for regulome and transcriptome-based prioritization of genetic variants associated with myocardial mass

Author

Jessica van Setten, Vinicius Tragante, Folkert W. Asselbergs, Magdalena Harakalova, Daiane Hemerich, Pim van der Harst, Jason H. Moore, Scott M. Williams, Elisabetta Manduchi, Jiayi Pei, and Cardiovascular Centre (CVC)

Subjects
Linkage disequilibrium, Epidemiology, Genome-wide association study, Single-nucleotide polymorphism, Regulome, Computational biology, Disease, Biology, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Workflow, 03 medical and health sciences, Humans, Promoter Regions, Genetic, Genetics (clinical), 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, Phenotype, Gene Expression Regulation, Multiple comparisons problem, Trait, Cardiomyopathies, Transcriptome, Functional genomics, Genome-Wide Association Study
Abstract

A typical task arising from main effect analyses in a Genome Wide Association Study (GWAS) is to identify single nucleotide polymorphisms (SNPs), in linkage disequilibrium with the observed signals, that are likely causal variants and the affected genes. The affected genes may not be those closest to associating SNPs. Functional genomics data from relevant tissues are believed to be helpful in selecting likely causal SNPs and interpreting implicated biological mechanisms, ultimately facilitating prevention and treatment in the case of a disease trait. These data are typically used post GWAS analyses to fine-map the statistically significant signals identified agnostically by testing all SNPs and applying a multiple testing correction. The number of tested SNPs is typically in the millions, so the multiple testing burden is high. Motivated by this, in this study we investigated an alternative workflow, which consists in utilizing the available functional genomics data as a first step to reduce the number of SNPs tested for association. We analyzed GWAS on electrocardiographic QRS duration using these two workflows. The alternative workflow identified more SNPs, including some residing in loci not discovered with the typical workflow. Moreover, the latter are corroborated by other reports on QRS duration. This indicates the potential value of incorporating functional genomics information at the onset in GWAS analyses.

Published
2019

12. Integrative Functional Annotation of 52 Genetic Loci Influencing Myocardial Mass Identifies Candidate Regulatory Variants and Target Genes

Author

Vinicius Tragante, Caroline Cheng, Michelle Michels, Michal Mokry, Folkert W. Asselbergs, Igor R. Efimov, Jolanda van der Velden, Daiane Hemerich, Sander Boymans, Bas J. Boukens, Jiayi Pei, Aryan Vink, Jason H. Moore, Jessica van Setten, Magdalena Harakalova, Pim van der Harst, Medical Biology, Amsterdam Cardiovascular Sciences, ACS - Heart failure & arrhythmias, Physiology, Cardiovascular Centre (CVC), and Cardiology

Subjects
Male, heart failure, Disease, DETERMINANTS, Regulatory Sequences, Nucleic Acid, ELECTROCARDIOGRAM, 0302 clinical medicine, Transcription (biology), genetics, TRANSCRIPTION, Promoter Regions, Genetic, Genetics, RISK, 0303 health sciences, ARCHITECTURE, Hypertrophic cardiomyopathy, General Medicine, ASSOCIATION, Middle Aged, CONFORMATION, heart failure genetics, Functional annotation, cardiovascular system, Female, CENP-A, Adult, cardiomyopathies, Adolescent, electrocardiography, ORGANIZATION, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, Journal Article, medicine, Humans, cardiovascular diseases, Enhancer, Gene, Myocardial mass, COMMON, 030304 developmental biology, acetylation, Myocardium, Promoter, Cardiomyopathy, Hypertrophic, medicine.disease, Genetic Loci, Case-Control Studies, Carrier Proteins, 030217 neurology & neurosurgery
Abstract

Background: Regulatory elements may be involved in the mechanisms by which 52 loci influence myocardial mass, reflected by abnormal amplitude and duration of the QRS complex on the ECG. Functional annotation thus far did not take into account how these elements are affected in disease context. Methods: We generated maps of regulatory elements on hypertrophic cardiomyopathy patients (ChIP-seq N=14 and RNA-seq N=11) and nondiseased hearts (ChIP-seq N=4 and RNA-seq N=11). We tested enrichment of QRS-associated loci on elements differentially acetylated and directly regulating differentially expressed genes between hypertrophic cardiomyopathy patients and controls. We further performed functional annotation on QRS-associated loci using these maps of differentially active regulatory elements. Results: Regions differentially affected in disease showed a stronger enrichment ( P =8.6×10 −5 ) for QRS-associated variants than those not showing differential activity ( P =0.01). Promoters of genes differentially regulated between hypertrophic cardiomyopathy patients and controls showed more enrichment ( P =0.001) than differentially acetylated enhancers ( P =0.8) and super-enhancers ( P =0.025). We also identified 74 potential causal variants overlapping these differential regulatory elements. Eighteen of the genes mapped confirmed previous findings, now also pinpointing the potentially affected regulatory elements and candidate causal variants. Fourteen new genes were also mapped. Conclusions: Our results suggest differentially active regulatory elements between hypertrophic cardiomyopathy patients and controls can offer more insights into the mechanisms of QRS-associated loci than elements not affected by disease.

Published
2019
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13. Basic Research

Author

Magdalena Harakalova, Daiane Hemerich, Folkert W. Asselbergs, Tragante, H Kerstens, Michal Mokry, and Patricia B. Munroe

Subjects
Genetics, Blood pressure, Clinical Biochemistry, General Medicine, Epigenetics, Computational biology, Biology, Biochemistry
Published
2016
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14. Druggability of Coronary Artery Disease Risk Loci

Author

Hester M. den Ruijter, Riyaz S. Patel, Vinicius Tragante, Daiane Hemerich, Jeanette Erdmann, Jason H. Moore, Folkert W. Asselbergs, Ingrid Braenne, Heribert Schunkert, Michael R. Barnes, Harri Lempiäinen, Mohammad A Alshabeeb, Surgery, CCA - Cancer Treatment and Quality of Life, and Cardiology

Subjects
0301 basic medicine, Drug-Related Side Effects and Adverse Reactions, Druggability, Drug Evaluation, Preclinical, Genome-wide association study, 030204 cardiovascular system & hematology, Bioinformatics, Polymorphism, Single Nucleotide, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Drug Discovery, medicine, Journal Article, Animals, Humans, Genetic Predisposition to Disease, Myocardial infarction, Molecular Targeted Therapy, Repurposing, myocardialinfarction, pharmacogenetics, genome-wideassociation study, business.industry, Drug Repositioning, Cardiovascular Agents, General Medicine, drug interactions, medicine.disease, Pharmacogenomic Testing, Molecular Docking Simulation, Drug repositioning, 030104 developmental biology, Drug development, Genetic Loci, Gene-Environment Interaction, business, Pharmacogenetics, Algorithms, coronary artery disease, Genome-Wide Association Study
Abstract

BACKGROUND: Genome-wide association studies have identified multiple loci associated with coronary artery disease and myocardial infarction, but only a few of these loci are current targets for on-market medications. To identify drugs suitable for repurposing and their targets, we created 2 unique pipelines integrating public data on 49 coronary artery disease/myocardial infarction-genome-wide association studies loci, drug-gene interactions, side effects, and chemical interactions. METHODS: We first used publicly available genome-wide association studies results on all phenotypes to predict relevant side effects, identified drug-gene interactions, and prioritized candidates for repurposing among existing drugs. Second, we prioritized gene product targets by calculating a druggability score to estimate how accessible pockets of coronary artery disease/myocardial infarction-associated gene products are, then used again the genome-wide association studies results to predict side effects, excluded loci with widespread cross-tissue expression to avoid housekeeping and genes involved in vital processes and accordingly ranked the remaining gene products. RESULTS: These pipelines ultimately led to 3 suggestions for drug repurposing: pentolinium, adenosine triphosphate, and riociguat (to target CHRNB4, ACSS2, and GUCY1A3, respectively); and 3 proteins for drug development: LMOD1 (leiomodin 1), HIP1 (huntingtin-interacting protein 1), and PPP2R3A (protein phosphatase 2, regulatory subunit b-double prime, α). Most current therapies for coronary artery disease/myocardial infarction treatment were also rediscovered. CONCLUSIONS: Integration of genomic and pharmacological data may prove beneficial for drug repurposing and development, as evidence from our pipelines suggests.

Published
2018

15. From lipid locus to drug target through human genomics

Author

Folkert W. Asselbergs, David Stacey, Daiane Hemerich, Angela M. Wood, Sander W. van der Laan, Eric L. Harshfield, Harshfield, Eric [0000-0001-8767-0928], Wood, Angela [0000-0002-7937-304X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Genetic Markers, Physiology, Druggability, Genomics, Locus (genetics), Genome-wide association study, Computational biology, Biology, 03 medical and health sciences, Delta-5 Fatty Acid Desaturase, Physiology (medical), Drug Discovery, Humans, Metabolomics, Genetic Predisposition to Disease, Molecular Targeted Therapy, Genetic association, Dyslipidemias, Hypolipidemic Agents, Drug discovery, PCSK9, Genetic Variation, Lipid metabolism, Cardiovascular disease, Lipid Metabolism, Lipids, 3. Good health, Causality, 030104 developmental biology, Phenotype, Cardiovascular Diseases, Lipidomics, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

In the last decade, over 175 genetic loci have robustly been associated to levels of major circulating blood lipids. Most loci are specific to one or two lipids, whereas some (SUGP1, ZPR1, TRIB1, HERPUD1, and FADS1) are associated to all. While exposing the polygenic architecture of circulating lipids and the underpinnings of dyslipidaemia, these genome-wide association studies (GWAS) have provided further evidence of the critical role that lipids play in coronary heart disease (CHD) risk, as indicated by the 2.7-fold enrichment for macrophage gene expression in atherosclerotic plaques and the association of 25 loci (such as PCSK9, APOB, ABCG5-G8, KCNK5, LPL, HMGCR, NPC1L1, CETP, TRIB1, ABO, PMAIP1-MC4R, and LDLR) with CHD. These GWAS also confirmed known and commonly used therapeutic targets, including HMGCR (statins), PCSK9 (antibodies), and NPC1L1 (ezetimibe). As we head into the post-GWAS era, we offer suggestions for how to move forward beyond genetic risk loci, towards refining the biology behind the associations and identifying causal genes and therapeutic targets. Deep phenotyping through lipidomics and metabolomics will refine and increase the resolution to find causal and druggable targets, and studies aimed at demonstrating gene transcriptional and regulatory effects of lipid associated loci will further aid in identifying these targets. Thus, we argue the need for deeply phenotyped, large genetic association studies to reduce costs and failures and increase the efficiency of the drug discovery pipeline. We conjecture that in the next decade a paradigm shift will tip the balance towards a data-driven approach to therapeutic target development and the application of precision medicine where human genomics takes centre stage.

Published
2018

16. Erratum

Author

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

Subjects
0301 basic medicine, Genetics, Multidisciplinary, Science, General Physics and Astronomy, General Chemistry, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Disease risk, Heart rate variability, 030217 neurology & neurosurgery
Abstract

Nature Communications 8: Article number: 15805 (2017); Published: 14 June 2017; Updated: 2 August 2017 In Supplementary Fig. 10 of this Article, images for panels a and b were inadvertently omitted. The correct version of Supplementary Fig. 10 is provided as Supplementary Information associated withthis Erratum.

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

Author

Gerjan Navis, Moritz F. Sinner, Kathleen F. Kerr, Heikki V. Huikuri, Daniele Cusi, Oscar H. Franco, Marian C. Limacher, Charles Kooperberg, Gabrielle Boucher, Riad Bayoumi, Juhani Junttila, Ann-Christine Syvänen, Andrew P. Morris, Anubha Mahajan, Andreas Voss, Paul I.W. de Bakker, Patrick T. Ellinor, Phyllis K. Stein, Janine F. Felix, Mark A. Geyer, Mike A. Nalls, Erik Ingelsson, Vinicius Tragante, Joshua C. Bis, Kari E. North, Jean-Claude Tardif, Harold Snieder, Azmeraw T. Amare, Katarzyna Stolarz-Skrzypek, Markku Eskola, Ilja M. Nolte, Tanja G. M. Vrijkotte, Elsayed Z. Soliman, Deepali Jaju, Melanie Neijts, Adrienne M. Stilp, Mika Kähönen, Henry J. Lin, Jessica van Setten, Meena Kumari, Halina Greiser, John S. Floras, Henriette E. Meyer zu Schwabedissen, Mohammad Hadi Zafarmand, Dewleen G. Baker, Rick Jansen, Cathy C. Laurie, Matteo Barcella, Christy L. Avery, Stefan Kääb, Michel G. Nivard, Jitender Kumar, Lars Lind, Alexander Teumer, Johan Sundström, Kirk C. Wilhelmsen, Barbara McKnight, Vilmantas Giedraitis, Johannes H. Smit, Gonneke Willemsen, Nona Sotoodehnia, Michele K. Evans, Christine M. Albert, Kent D. Taylor, Marcel den Hoed, James D. Stewart, Peter Friberg, Alvaro Alonso, Susan R. Heckbert, Kjell Nikus, Siegfried Perz, André G. Uitterlinden, Bruce M. Psaty, Antti M. Kiviniemi, G. Ehret, Jouke-Jan Hottenga, Sulayma Albarwani, Bouwe P. Krijthe, Timothy A. Thornton, Caroline M. Nievergelt, Delilah Zabaneh, Zhu Ming Zhang, Annie Britton, Ingrid E. Christophersen, Adam X. Maihofer, Juha Auvinen, David S. Siscovick, Arie M. van Roon, Xavier Jouven, Stephanie M. Gogarten, M. Loretto Munoz, Erika Salvi, Folkert W. Asselbergs, Bram Dierckx, Marjo-Riitta Järvelin, Cecilia M. Lindgren, Yun Li, Quenna Wong, Alan B. Zonderman, Yuri Milaneschi, John D. Rioux, Brenda W.J.H. Penninx, Philippe Goyette, Niek Verweij, Harriëtte Riese, Bruno H. Stricker, Markus Juonala, Rob J. Bieringa, Arpi Minassian, Jenny van Dongen, Abdel Abdellaoui, Foram N. Ashar, Jan A. Kors, Albertine J. Oldehinkel, Jussi Hernesniemi, Sander W. van der Laan, Ahmad Vaez, Nina Hutri-Kähönen, Annette Peters, Lesley E. Tinker, Albert Hofman, Dorret I. Boomsma, Victoria B. Risbrough, Tamar Sofer, Pim van der Harst, Konstantin Strauch, Steven A. Lubitz, Catharina A. Hartman, Jerome I. Rotter, Shih-Jen Hwang, Duanping Liao, Mika Kivimäki, Mohammad L. Hassan, Andrew Wong, Peter J. van der Most, Alexander Kluttig, Nina Mononen, Eco J. C. de Geus, Henning Tiemeier, Benedikt von der Heyde, Martina Müller-Nurasyid, Joop D. Lefrandt, Andrea Dietrich, Nicholas L. Smith, Terho Lehtimäki, Bianca J. J. M. Brundel, Jan A. Staessen, Cees A. Swenne, Julian F. Thayer, Daniel T. O'Connor, Christopher J. O'Donnell, Eric A. Whitsel, Tatiana Kuznetsova, Alexander P. Reiner, Johan Ormel, Ville Huikari, Yong Li, Tomas Axelsson, Olli T. Raitakari, Daiane Hemerich, Leo-Pekka Lyytikäinen, Maaike G. J. Gademan, Melanie Waldenberger, Diana Kuh, Ehret, Georg Benedikt, APH - Personalized Medicine, APH - Global Health, Other Research, ACS - Amsterdam Cardiovascular Sciences, Public and occupational health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, ARD - Amsterdam Reproduction and Development, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Physiology, ACS - Heart failure & arrhythmias, APH - Digital Health, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Vascular Ageing Programme (VAP), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Value, Affordability and Sustainability (VALUE), Biological Psychology, Praxis, Environmental Geography (former), Child and Adolescent Psychiatry / Psychology, Rheumatology, Epidemiology, Medical Informatics, and Internal Medicine

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Medicin och hälsovetenskap, Potassium Channels, Chemistry(all), Muscle Proteins, General Physics and Astronomy, Genome-wide association study, Blood Pressure, PEDIGREES, Bioinformatics, Biochemistry, Genome-wide association studies, Medical and Health Sciences, Cohort Studies, Heart Rate, Risk Factors, RGS Proteins/genetics, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, RECORDINGS, Heart rate variability, Vagal tone, European Continental Ancestry Group/genetics, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics, ddc:616, Muscle Proteins/genetics, Multidisciplinary, digestive, oral, and skin physiology, Single Nucleotide, Multidisciplinary Sciences, Science & Technology - Other Topics, Heart Diseases/genetics/physiopathology, Erratum, circulatory and respiratory physiology, Heart Diseases, Science, Quantitative Trait Loci, RESPIRATORY SINUS ARRHYTHMIA, Quantitative trait locus, Biology, Physics and Astronomy(all), Polymorphism, Single Nucleotide, White People, General Biochemistry, Genetics and Molecular Biology, Article, PARASYMPATHETIC REGULATION, 03 medical and health sciences, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Heart rate, Journal Article, Humans, Genetic Predisposition to Disease, COHORT, Polymorphism, GENOME-WIDE ASSOCIATION, METAANALYSIS, Genetic association, MODULATOR, Science & Technology, Biochemistry, Genetics and Molecular Biology(all), MORTALITY, Cardiovascular genetics, General Chemistry, Membrane hyperpolarization, ta3121, 030104 developmental biology, Expression quantitative trait loci, ATRIAL-FIBRILLATION, Potassium Channels/genetics, RGS Proteins, Genetics and Molecular Biology(all), Genome-Wide Association Study
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, Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.

Published
2017
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19. Impact of carotid atherosclerosis loci on cardiovascular events

Author

Gert J. de Borst, Hester M. den Ruijter, Paul I.W. de Bakker, Vinicius Tragante, Folkert W. Asselbergs, Gerard Pasterkamp, Sander W. van der Laan, and Daiane Hemerich

Subjects
Carotid Artery Diseases, Male, Genome-wide association study, Coronary Artery Disease, Single-nucleotide polymorphisms, Brain Ischemia, Coronary artery disease, Risk Factors, Odds Ratio, Carotid intima-media thickness, Stroke, Subclinical infection, Plaque, Aged, 80 and over, Middle Aged, Plaque, Atherosclerotic, 3. Good health, Carotid Arteries, Phenotype, Cardiology, cardiovascular system, Female, Cardiology and Cardiovascular Medicine, Adult, Genetic Markers, medicine.medical_specialty, Adolescent, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Risk Assessment, Peripheral Arterial Disease, Young Adult, Predictive Value of Tests, Internal medicine, medicine, Humans, Ankle Brachial Index, Genetic Predisposition to Disease, cardiovascular diseases, Genetic Association Studies, Aged, Proportional Hazards Models, business.industry, Case-control study, Odds ratio, medicine.disease, Atherosclerosis, Intima-media thickness, Genetic Loci, Case-Control Studies, business, Aortic Aneurysm, Abdominal
Abstract

Background: Genome-wide association studies (GWAS) have identified six single-nucleotide polymorphisms (SNPs) related to carotid intima media thickness (cIMT) or plaque. However, whether these loci relate to other vascular diseases and subsequent vascular events is unclear. Methods and results: We tested six SNPs (rs4888378, rs11781551, rs445925, rs6601530, rs17398575 and rs1878406) for association with subclinical atherosclerotic measures (cIMT, plaque presence and ankle-brachial index), as well as ischemic stroke, abdominal aortic aneurysm, peripheral or coronary artery disease (CAD) in the Second Manifestations of ARTerial disease (SMART) cohort. Four SNPs were associated with cIMT and two with plaque (p < 0.05). One SNP was also significantly associated to CAD (rs1878406, OR = 1.24, 95% CI = 1.08-1.42, p = 2 × 10-3). A genetic risk score (GRS) based on the cIMT-related SNPs was associated to increased risk of cIMT itself (p = 1 × 10-3), but not to other secondary outcomes or vascular events during follow-up (p = 0.86). Conclusions: In addition to replicating previously published associations for cIMT, we confirmed a nominally significant effect between the GRS and cIMT.

Published
2015
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