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1. Associations of very low Lipoprotein(a) levels with risks of new-onset diabetes and non-alcoholic liver disease

Author: Ming Wai Yeung, M. Abdullah Said, Yordi J. van de Vegte, Niek Verweij, Robin P.F. Dullaart, and Pim van der Harst
Subjects: Cardiovascular risk factor, Lipoprotein(a), Type 2 diabetes, NAFLD, Mendelian randomization, Prospective study, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background and aims: We aimed to study the association of very low serum Lipoprotein(a) [Lp(a)] concentrations with new-onset type 2 diabetes (T2D) and non-alcoholic liver disease (NAFLD) in the context of statin usage in the UK Biobank, a large prospective population cohort. Methods: Using an extended biomarker dataset, we identified 47,362 participants with very low Lp(a) concentrations (
Published: 2024
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2. Fetuin-A and its genetic association with cardiometabolic disease

Author: Lawien Al Ali, Yordi J. van de Vegte, M. Abdullah Said, Hilde E. Groot, Tom Hendriks, Ming Wai Yeung, Erik Lipsic, and Pim van der Harst
Subjects: Medicine, Science
Abstract: Abstract Fetuin-A acts as both an inhibitor of calcification and insulin signaling. Previous studies reported conflicting results on the association between fetuin-A and cardiometabolic diseases. We aim to provide further insights into the association between genetically predicted levels of fetuin-A and cardiometabolic diseases using a Mendelian randomization strategy. Genetic variants associated with fetuin-A and their effect sizes were obtained from previous genetic studies. A series of two-sample Mendelian randomization analyses in 412,444 unrelated individuals from the UK Biobank did not show evidence for an association of genetically predicted fetuin-A with any stroke, ischemic stroke, or myocardial infarction. We do find that increased levels of genetically predicted fetuin-A are associated with increased risk of type 2 diabetes (OR = 1.21, 95%CI 1.13–1.30, P =
Published: 2023
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3. Phenotypic but not genetically predicted heart rate variability associated with all-cause mortality

Author: Balewgizie S. Tegegne, M. Abdullah Said, Alireza Ani, Arie M. van Roon, Sonia Shah, Eco J. C. de Geus, Pim van der Harst, Harriëtte Riese, Ilja M. Nolte, and Harold Snieder
Subjects: Biology (General), QH301-705.5
Abstract: Abstract Low heart rate variability (HRV) has been widely reported as a predictor for increased mortality. However, the molecular mechanisms are poorly understood. Therefore, this study aimed to identify novel genetic loci associated with HRV and assess the association of phenotypic HRV and genetically predicted HRV with mortality. In a GWAS of 46,075 European ancestry individuals from UK biobank, we identified 17 independent genome-wide significant genetic variants in 16 loci associated with HRV traits. Notably, eight of these loci (RNF220, GNB4, LINCR-002, KLHL3/HNRNPA0, CHRM2, KCNJ5, MED13L, and C160rf72) have not been reported previously. In a prospective phenotypic relationship between HRV and mortality during a median follow-up of seven years, individuals with lower HRV had higher risk of dying from any cause. Genetically predicted HRV, as determined by the genetic risk scores, was not associated with mortality. To the best of our knowledge, the findings provide novel biological insights into the mechanisms underlying HRV. These results also underline the role of the cardiac autonomic nervous system, as indexed by HRV, in predicting mortality.
Published: 2023
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4. Genetic insights into resting heart rate and its role in cardiovascular disease

Author: Yordi J. van de Vegte, Ruben N. Eppinga, M. Yldau van der Ende, Yanick P. Hagemeijer, Yuvaraj Mahendran, Elias Salfati, Albert V. Smith, Vanessa Y. Tan, Dan E. Arking, Ioanna Ntalla, Emil V. Appel, Claudia Schurmann, Jennifer A. Brody, Rico Rueedi, Ozren Polasek, Gardar Sveinbjornsson, Cecile Lecoeur, Claes Ladenvall, Jing Hua Zhao, Aaron Isaacs, Lihua Wang, Jian’an Luan, Shih-Jen Hwang, Nina Mononen, Kirsi Auro, Anne U. Jackson, Lawrence F. Bielak, Linyao Zeng, Nabi Shah, Maria Nethander, Archie Campbell, Tuomo Rankinen, Sonali Pechlivanis, Lu Qi, Wei Zhao, Federica Rizzi, Toshiko Tanaka, Antonietta Robino, Massimiliano Cocca, Leslie Lange, Martina Müller-Nurasyid, Carolina Roselli, Weihua Zhang, Marcus E. Kleber, Xiuqing Guo, Henry J. Lin, Francesca Pavani, Tessel E. Galesloot, Raymond Noordam, Yuri Milaneschi, Katharina E. Schraut, Marcel den Hoed, Frauke Degenhardt, Stella Trompet, Marten E. van den Berg, Giorgio Pistis, Yih-Chung Tham, Stefan Weiss, Xueling S. Sim, Hengtong L. Li, Peter J. van der Most, Ilja M. Nolte, Leo-Pekka Lyytikäinen, M. Abdullah Said, Daniel R. Witte, Carlos Iribarren, Lenore Launer, Susan M. Ring, Paul S. de Vries, Peter Sever, Allan Linneberg, Erwin P. Bottinger, Sandosh Padmanabhan, Bruce M. Psaty, Nona Sotoodehnia, Ivana Kolcic, The DCCT/EDIC Research Group, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Beverley Balkau, Claudia T. Silva, Christopher H. Newton-Cheh, Kjell Nikus, Perttu Salo, Karen L. Mohlke, Patricia A. Peyser, Heribert Schunkert, Mattias Lorentzon, Jari Lahti, Dabeeru C. Rao, Marilyn C. Cornelis, Jessica D. Faul, Jennifer A. Smith, Katarzyna Stolarz-Skrzypek, Stefania Bandinelli, Maria Pina Concas, Gianfranco Sinagra, Thomas Meitinger, Melanie Waldenberger, Moritz F. Sinner, Konstantin Strauch, Graciela E. Delgado, Kent D. Taylor, Jie Yao, Luisa Foco, Olle Melander, Jacqueline de Graaf, Renée de Mutsert, Eco J. C. de Geus, Åsa Johansson, Peter K. Joshi, Lars Lind, Andre Franke, Peter W. Macfarlane, Kirill V. Tarasov, Nicholas Tan, Stephan B. Felix, E-Shyong Tai, Debra Q. Quek, Harold Snieder, Johan Ormel, Martin Ingelsson, Cecilia Lindgren, Andrew P. Morris, Olli T. Raitakari, Torben Hansen, Themistocles Assimes, Vilmundur Gudnason, Nicholas J. Timpson, Alanna C. Morrison, Patricia B. Munroe, David P. Strachan, Niels Grarup, Ruth J. F. Loos, Susan R. Heckbert, Peter Vollenweider, Caroline Hayward, Kari Stefansson, Philippe Froguel, Leif Groop, Nicholas J. Wareham, Cornelia M. van Duijn, Mary F. Feitosa, Christopher J. O’Donnell, Mika Kähönen, Markus Perola, Michael Boehnke, Sharon L. R. Kardia, Jeanette Erdmann, Colin N. A. Palmer, Claes Ohlsson, David J. Porteous, Johan G. Eriksson, Claude Bouchard, Susanne Moebus, Peter Kraft, David R. Weir, Daniele Cusi, Luigi Ferrucci, Sheila Ulivi, Giorgia Girotto, Adolfo Correa, Stefan Kääb, Annette Peters, John C. Chambers, Jaspal S. Kooner, Winfried März, Jerome I. Rotter, Andrew A. Hicks, J. Gustav Smith, Lambertus A. L. M. Kiemeney, Dennis O. Mook-Kanamori, Brenda W. J. H. Penninx, Ulf Gyllensten, James F. Wilson, Stephen Burgess, Johan Sundström, Wolfgang Lieb, J. Wouter Jukema, Mark Eijgelsheim, Edward L. M. Lakatta, Ching-Yu Cheng, Marcus Dörr, Tien-Yin Wong, Charumathi Sabanayagam, Albertine J. Oldehinkel, Harriette Riese, Terho Lehtimäki, Niek Verweij, and Pim van der Harst
Subjects: Science
Abstract: Abstract Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Published: 2023
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5. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author: Ioanna Ntalla, Lu-Chen Weng, James H. Cartwright, Amelia Weber Hall, Gardar Sveinbjornsson, Nathan R. Tucker, Seung Hoan Choi, Mark D. Chaffin, Carolina Roselli, Michael R. Barnes, Borbala Mifsud, Helen R. Warren, Caroline Hayward, Jonathan Marten, James J. Cranley, Maria Pina Concas, Paolo Gasparini, Thibaud Boutin, Ivana Kolcic, Ozren Polasek, Igor Rudan, Nathalia M. Araujo, Maria Fernanda Lima-Costa, Antonio Luiz P. Ribeiro, Renan P. Souza, Eduardo Tarazona-Santos, Vilmantas Giedraitis, Erik Ingelsson, Anubha Mahajan, Andrew P. Morris, Fabiola Del Greco M, Luisa Foco, Martin Gögele, Andrew A. Hicks, James P. Cook, Lars Lind, Cecilia M. Lindgren, Johan Sundström, Christopher P. Nelson, Muhammad B. Riaz, Nilesh J. Samani, Gianfranco Sinagra, Sheila Ulivi, Mika Kähönen, Pashupati P. Mishra, Nina Mononen, Kjell Nikus, Mark J. Caulfield, Anna Dominiczak, Sandosh Padmanabhan, May E. Montasser, Jeff R. O’Connell, Kathleen Ryan, Alan R. Shuldiner, Stefanie Aeschbacher, David Conen, Lorenz Risch, Sébastien Thériault, Nina Hutri-Kähönen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Olli T. Raitakari, Catriona L. K. Barnes, Harry Campbell, Peter K. Joshi, James F. Wilson, Aaron Isaacs, Jan A. Kors, Cornelia M. van Duijn, Paul L. Huang, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Erwin P. Bottinger, Ruth J. F. Loos, Girish N. Nadkarni, Michael H. Preuss, Adolfo Correa, Hao Mei, James Wilson, Thomas Meitinger, Martina Müller-Nurasyid, Annette Peters, Melanie Waldenberger, Massimo Mangino, Timothy D. Spector, Michiel Rienstra, Yordi J. van de Vegte, Pim van der Harst, Niek Verweij, Stefan Kääb, Katharina Schramm, Moritz F. Sinner, Konstantin Strauch, Michael J. Cutler, Diane Fatkin, Barry London, Morten Olesen, Dan M. Roden, M. Benjamin Shoemaker, J. Gustav Smith, Mary L. Biggs, Joshua C. Bis, Jennifer A. Brody, Bruce M. Psaty, Kenneth Rice, Nona Sotoodehnia, Alessandro De Grandi, Christian Fuchsberger, Cristian Pattaro, Peter P. Pramstaller, Ian Ford, J. Wouter Jukema, Peter W. Macfarlane, Stella Trompet, Marcus Dörr, Stephan B. Felix, Uwe Völker, Stefan Weiss, Aki S. Havulinna, Antti Jula, Katri Sääksjärvi, Veikko Salomaa, Xiuqing Guo, Susan R. Heckbert, Henry J. Lin, Jerome I. Rotter, Kent D. Taylor, Jie Yao, Renée de Mutsert, Arie C. Maan, Dennis O. Mook-Kanamori, Raymond Noordam, Francesco Cucca, Jun Ding, Edward G. Lakatta, Yong Qian, Kirill V. Tarasov, Daniel Levy, Honghuang Lin, Christopher H. Newton-Cheh, Kathryn L. Lunetta, Alison D. Murray, David J. Porteous, Blair H. Smith, Bruno H. Stricker, André Uitterlinden, Marten E. van den Berg, Jeffrey Haessler, Rebecca D. Jackson, Charles Kooperberg, Ulrike Peters, Alexander P. Reiner, Eric A. Whitsel, Alvaro Alonso, Dan E. Arking, Eric Boerwinkle, Georg B. Ehret, Elsayed Z. Soliman, Christy L. Avery, Stephanie M. Gogarten, Kathleen F. Kerr, Cathy C. Laurie, Amanda A. Seyerle, Adrienne Stilp, Solmaz Assa, M. Abdullah Said, M. Yldau van der Ende, Pier D. Lambiase, Michele Orini, Julia Ramirez, Stefan Van Duijvenboden, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Patrick Sulem, Gudmar Thorleifsson, Rosa B. Thorolfsdottir, Unnur Thorsteinsdottir, Emelia J. Benjamin, Andrew Tinker, Kari Stefansson, Patrick T. Ellinor, Yalda Jamshidi, Steven A. Lubitz, and Patricia B. Munroe
Subjects: Science
Abstract: On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
Published: 2020
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6. Genome-wide association studies and Mendelian randomization analyses for leisure sedentary behaviours

Author: Yordi J. van de Vegte, M. Abdullah Said, Michiel Rienstra, Pim van der Harst, and Niek Verweij
Subjects: Science
Abstract: Epidemiological studies have shown an association between sedentary behaviours and cardiovascular disease risk. Here, van de Vegte et al. perform GWAS for self-reported sedentary behaviours (TV watching, computer use, driving) and Mendelian randomization analyses to explore potential causal relationships with coronary artery disease.
Published: 2020
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7. An Erythropoietin-Independent Mechanism of Erythrocytic Precursor Proliferation Underlies Hypoxia Tolerance in Sea Nomads

Author: Melissa Ilardo, Maria C. Ferreira dos Santos, Niels Grote Beverborg, Malini Rajan, M. Abdullah Said, Niek Verweij, Pim Van Der Harst, Peter Van Der Meer, and Elizabeth A. Leibold
Subjects: hypoxia, red blood cell production, adaptation, evolution, spleen, Physiology, QP1-981
Abstract: The Bajau Sea Nomads were recently demonstrated to have evolved larger spleens as an adaptation to millennia of a marine foraging lifestyle. The large-spleen phenotype appears to derive from increases in thyroid hormone (TH) production as a result of reduced expression of phosphodiesterase 10A (PDE10A), though the exact mechanism remains unknown. Through pharmacological inhibition of PDE10A using the selective inhibitor MP-10 in mice, we were able to mimic the Bajau adaptation and show that treated mice had significantly larger spleens than control animals. This difference appears connected to an excess of early stage erythrocytes and an apparent increase in red blood cell (RBC) precursor proliferation in response to increased TH. However, we determined that the stimulation of RBC production in the mouse model via TH is Erythropoietin (EPO)-independent, unlike in the altitude (chronic hypoxemia) response. We confirmed this using human GWAS data; although the Bajau PDE10A variants are significantly associated with increased TH levels and RBC count, they are not associated with EPO levels, nor are other strongly thyroid-associated SNPs. We therefore suggest that an EPO-independent mechanism of stimulating RBC precursor proliferation via TH upregulation underlies the increase in spleen size observed in Sea Nomad populations.
Published: 2022
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8. Genomic insights in ascending aortic size and distensibility

Author: Jan Walter Benjamins, Ming Wai Yeung, Yordi J. van de Vegte, M. Abdullah Said, Thijs van der Linden, Daan Ties, Luis E. Juarez-Orozco, Niek Verweij, and Pim van der Harst
Subjects: Ascending aorta size, Ascending aorta distensibility, Artificial intelligence, Cardiovascular disease, Genome-wide association study, Mendelian randomization study, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Alterations in the anatomic and biomechanical properties of the ascending aorta (AAo) can give rise to various vascular pathologies. The aim of the current study is to gain additional insights in the biology of the AAo size and function. Methods: We developed an AI based analysis pipeline for the segmentation of the AAo, and the extraction of AAO parameters. We then performed genome-wide association studies of AAo maximum area, AAo minimum area and AAo distensibility in up to 37,910 individuals from the UK Biobank. Variants that were significantly associated with AAo phenotypes were used as instrumental variables in Mendelian randomization analyses to investigate potential causal relationships with coronary artery disease, myocardial infarction, stroke and aneurysms. Findings: Genome-wide association studies revealed a total of 107 SNPs in 78 loci. We annotated 101 candidate genes involved in various biological processes, including connective tissue development (THSD4 and COL6A3). Mendelian randomization analyses showed a causal association with aneurysm development, but not with other vascular diseases. Interpretation: We identified 78 loci that provide insights into mechanisms underlying AAo size and function in the general population and provide genetic evidence for their role in aortic aneurysm development.
Published: 2022
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9. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author: Amand F. Schmidt, Michael V. Holmes, David Preiss, Daniel I. Swerdlow, Spiros Denaxas, Ghazaleh Fatemifar, Rupert Faraway, Chris Finan, Dennis Valentine, Zammy Fairhurst-Hunter, Fernando Pires Hartwig, Bernardo Lessa Horta, Elina Hypponen, Christine Power, Max Moldovan, Erik van Iperen, Kees Hovingh, Ilja Demuth, Kristina Norman, Elisabeth Steinhagen-Thiessen, Juri Demuth, Lars Bertram, Christina M. Lill, Stefan Coassin, Johann Willeit, Stefan Kiechl, Karin Willeit, Dan Mason, John Wright, Richard Morris, Goya Wanamethee, Peter Whincup, Yoav Ben-Shlomo, Stela McLachlan, Jackie F. Price, Mika Kivimaki, Catherine Welch, Adelaida Sanchez-Galvez, Pedro Marques-Vidal, Andrew Nicolaides, Andrie G. Panayiotou, N. Charlotte Onland-Moret, Yvonne T. van der Schouw, Giuseppe Matullo, Giovanni Fiorito, Simonetta Guarrera, Carlotta Sacerdote, Nicholas J. Wareham, Claudia Langenberg, Robert A. Scott, Jian’an Luan, Martin Bobak, Sofia Malyutina, Andrzej Pająk, Ruzena Kubinova, Abdonas Tamosiunas, Hynek Pikhart, Niels Grarup, Oluf Pedersen, Torben Hansen, Allan Linneberg, Tine Jess, Jackie Cooper, Steve E. Humphries, Murray Brilliant, Terrie Kitchner, Hakon Hakonarson, David S. Carrell, Catherine A. McCarty, Kirchner H. Lester, Eric B. Larson, David R. Crosslin, Mariza de Andrade, Dan M. Roden, Joshua C. Denny, Cara Carty, Stephen Hancock, John Attia, Elizabeth Holliday, Rodney Scott, Peter Schofield, Martin O’Donnell, Salim Yusuf, Michael Chong, Guillaume Pare, Pim van der Harst, M. Abdullah Said, Ruben N. Eppinga, Niek Verweij, Harold Snieder, Lifelines Cohort authors, Tim Christen, D. O. Mook-Kanamori, the ICBP Consortium, Stefan Gustafsson, Lars Lind, Erik Ingelsson, Raha Pazoki, Oscar Franco, Albert Hofman, Andre Uitterlinden, Abbas Dehghan, Alexander Teumer, Sebastian Baumeister, Marcus Dörr, Markus M. Lerch, Uwe Völker, Henry Völzke, Joey Ward, Jill P. Pell, Tom Meade, Ingrid E. Christophersen, Anke H. Maitland-van der Zee, Ekaterina V. Baranova, Robin Young, Ian Ford, Archie Campbell, Sandosh Padmanabhan, Michiel L. Bots, Diederick E. Grobbee, Philippe Froguel, Dorothée Thuillier, Ronan Roussel, Amélie Bonnefond, Bertrand Cariou, Melissa Smart, Yanchun Bao, Meena Kumari, Anubha Mahajan, Jemma C. Hopewell, Sudha Seshadri, the METASTROKE Consortium of the ISGC, Caroline Dale, Rui Providencia E. Costa, Paul M. Ridker, Daniel I. Chasman, Alex P. Reiner, Marylyn D. Ritchie, Leslie A. Lange, Alex J. Cornish, Sara E. Dobbins, Kari Hemminki, Ben Kinnersley, Marc Sanson, Karim Labreche, Matthias Simon, Melissa Bondy, Philip Law, Helen Speedy, James Allan, Ni Li, Molly Went, Niels Weinhold, Gareth Morgan, Pieter Sonneveld, Björn Nilsson, Hartmut Goldschmidt, Amit Sud, Andreas Engert, Markus Hansson, Harry Hemingway, Folkert W. Asselbergs, Riyaz S. Patel, Brendan J. Keating, Naveed Sattar, Richard Houlston, Juan P. Casas, and Aroon D. Hingorani
Subjects: Genetic association studies, Mendelian randomisation, LDL-cholesterol, Phenome-wide association scan, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Abstract Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
Published: 2019
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10. Anti-Müllerian Hormone and Cardiometabolic Disease in Women: A Two-Sample Mendelian Randomization Study

Author: Renée M.G. Verdiesen, Joanna von Berg, M. Abdullah Said, Pim van der Harst, Anubha Mahajan, Carla H. van Gils, Yvonne T. van der Schouw, and N. Charlotte Onland-Moret
Subjects: anti-müllerian hormone, amh, coronary artery disease, stroke, type 2 diabetes, mendelian randomization, women, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background: Higher age-specific circulating anti-Müllerian hormone (AMH) levels have been linked to a lower risk of cardiometabolic outcomes. However, whether AMH has a casual role in the etiology of these diseases is unknown. The objective of this study was therefore to explore if circulating AMH levels have a causal effect on risk of coronary artery disease (CAD), ischemic stroke and type 2 diabetes (T2D) in women, using a two-sample Mendelian randomization (MR) approach. Methods: We used four single nucleotide polymorphisms (SNPs) from the most recent AMH GWAS meta-analysis as instrumental variables. Summary-level data for CAD (n = 149,752; 11,802 cases), ischemic stroke (n = 17,541; 4678 cases) and T2D (n = 464,389; 30,052 cases) were extracted from the UK Biobank, the Stroke Genetics Network, and DIAMANTE consortia, respectively. To assess the presence of potential pleiotropy we tested the association of the four AMH SNPs, both individually and combined in a weighted genetic risk score, with a range of cardiovascular risk factors and intermediate traits using UK Biobank data. Results: MR estimates, i.e., inverse variance-weighted odds ratios (ORIVW), did not support a causal effect of circulating AMH levels on CAD (ORIVW = 1.13, 95% CI: 0.95–1.35), ischemic stroke (ORIVW = 1.11, 95% CI: 0.83–1.49), and T2D (ORIVW = 0.98, 95% CI: 0.87–1.10). After adjustment for multiple testing, we observed associations between genetically predicted AMH and age at menopause, and age at menarche, but not with intermediate traits on the causal pathway between AMH and cardiometabolic health, such as atherosclerosis or glucose levels. Conclusions: This study does not provide evidence for a causal effect of circulating AMH levels on CAD, ischemic stroke and T2D in women, although weak instrument bias cannot be excluded.
Published: 2022
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11. Associations of Observational and Genetically Determined Caffeine Intake With Coronary Artery Disease and Diabetes Mellitus

Author: M. Abdullah Said, Yordi J. van de Vegte, Niek Verweij, and Pim van der Harst
Subjects: caffeine intake, coronary artery disease, genetics, Mendelian randomization, type 2 diabetes mellitus, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Caffeine is the most widely consumed psychostimulant and is associated with lower risk of coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). However, whether these associations are causal remains unknown. This study aimed to identify genetic variants associated with caffeine intake, and to investigate evidence for causal links with CAD or T2DM. In addition, we aimed to replicate previous observational findings. Methods and Results Observational associations were tested within UK Biobank using Cox regression analyses. Moderate observational caffeine intakes from coffee or tea were associated with lower risks of CAD or T2DM, with the lowest risks at intakes of 121 to 180 mg/day from coffee for CAD (hazard ratio [HR], 0.77 [95% CI, 0.73–0.82; P
Published: 2020
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12. Smoking does not accelerate leucocyte telomere attrition: a meta-analysis of 18 longitudinal cohorts

Author: Melissa Bateson, Abraham Aviv, Laila Bendix, Athanase Benetos, Yoav Ben-Shlomo, Stig E. Bojesen, Cyrus Cooper, Rachel Cooper, Ian J. Deary, Sara Hägg, Sarah E. Harris, Jeremy D. Kark, Florian Kronenberg, Diana Kuh, Carlos Labat, Carmen M. Martin-Ruiz, Craig Meyer, Børge G. Nordestgaard, Brenda W. J. H. Penninx, Gillian V. Pepper, Dóra Révész, M. Abdullah Said, John M. Starr, Holly Syddall, William Murray Thomson, Pim van der Harst, Mary Whooley, Thomas von Zglinicki, Peter Willeit, Yiqiang Zhan, and Daniel Nettle
Subjects: biological age, telomere length, telomere attrition, smoking, longitudinal, Science
Abstract: Smoking is associated with shorter leucocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking causes accelerated LTL attrition in adulthood, but the evidence for this is inconsistent. We analysed the association between smoking and LTL dynamics in 18 longitudinal cohorts. The dataset included data from 12 579 adults (4678 current smokers and 7901 non-smokers) over a mean follow-up interval of 8.6 years. Meta-analysis confirmed a cross-sectional difference in LTL between smokers and non-smokers, with mean LTL 84.61 bp shorter in smokers (95% CI: 22.62 to 146.61). However, LTL attrition was only 0.51 bp yr−1 faster in smokers than in non-smokers (95% CI: −2.09 to 1.08), a difference that equates to only 1.32% of the estimated age-related loss of 38.33 bp yr−1. Assuming a linear effect of smoking, 167 years of smoking would be required to generate the observed cross-sectional difference in LTL. Therefore, the difference in LTL between smokers and non-smokers is extremely unlikely to be explained by a linear, causal effect of smoking. Selective adoption, whereby individuals with short telomeres are more likely to start smoking, needs to be considered as a more plausible explanation for the observed pattern of telomere dynamics.
Published: 2019
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13. Relationship of Arterial Stiffness Index and Pulse Pressure With Cardiovascular Disease and Mortality

Author: M. Abdullah Said, Ruben N. Eppinga, Erik Lipsic, Niek Verweij, and Pim van der Harst
Subjects: arterial stiffness, cardiovascular disease, cardiovascular outcomes, mortality, pulse pressure, UK Biobank, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: BackgroundVascular aging results in stiffer arteries and may have a role in the development of cardiovascular disease (CVD). Arterial stiffness index (ASI), measured by finger photoplethysmography, and pulse pressure (PP) are 2 independent vascular aging indices. We investigated whether ASI or PP predict new‐onset CVD and mortality in a large community‐based population. Methods and ResultsWe studied 169 613 UK Biobank participants (mean age 56.8 years; 45.8% males) who underwent ASI measurement and blood pressure measurement for PP calculation. Mean±SD ASI was 9.30±3.1 m/s and mean±SD PP was 50.98±13.2 mm Hg. During a median disease follow‐up of 2.8 years (interquartile range 1.4–4.0), 18 190 participants developed CVD, of which 1587 myocardial infarction (MI), 4326 coronary heart disease, 1192 heart failure, and 1319 stroke. During a median mortality follow‐up of 6.1 years (interquartile range 5.8–6.3), 3678 participants died, of which 1180 of CVD. Higher ASI was associated with increased risk of overall CVD (unadjusted hazard ratio 1.27; 95% confidence interval [CI], 1.25–1.28), myocardial infarction (1.38; 95% CI, 1.32–1.44), coronary heart disease (1.31; 95% CI, 1.27–1.34), and heart failure (1.31; 95% CI 1.24–1.37). ASI also predicted mortality (all‐cause, CVD, other). Higher PP was associated with overall CVD (1.57; 95% CI, 1.55–1.59), myocardial infarction (1.48; 95% CI, 1.42–1.54), coronary heart disease (1.47; 95% CI, 1.43–1.50), heart failure (1.47; 95% CI, 1.40–1.55), and CVD mortality (1.47; 95% CI, 1.40–1.55). PP improved risk reclassification of CVD in a non–laboratory‐based Framingham Risk Score by 5.4%, ASI by 2.3%. ConclusionsASI and PP are independent predictors of CVD and mortality outcomes. Although both improved risk prediction for new‐onset disease, PP appears to have a larger clinical value than ASI.
Published: 2018
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14. Twenty-Five Novel Loci for Carotid Intima-Media Thickness: A Genome-Wide Association Study in >45 000 Individuals and Meta-Analysis of >100 000 Individuals

Author: Niek Verweij, Jessica van Setten, Ming Wai Yeung, Yordi J. van de Vegte, Siqi Wang, M Abdullah Said, Pim van der Harst, Oleg V. Borisov, Harold Snieder, Life Course Epidemiology (LCE), and Cardiovascular Centre (CVC)
Subjects: Male, Genetics, education.field_of_study, business.industry, Population, Genome-wide association study, Carotid Intima-Media Thickness, Polymorphism, Single Nucleotide, Biobank, Genetic architecture, Protein-Lysine 6-Oxidase, Intima-media thickness, Risk Factors, Subclinical atherosclerosis, Meta-analysis, Humans, Medicine, Female, Genetic Predisposition to Disease, Cardiology and Cardiovascular Medicine, business, education, Genome-Wide Association Study, Transcription Factors, Genetic association
Abstract: Objective: Carotid artery intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. Twenty susceptibility loci for cIMT were previously identified and the identification of additional susceptibility loci furthers our knowledge on the genetic architecture underlying atherosclerosis. Approach and Results: We performed 3 genome-wide association studies in 45 185 participants from the UK Biobank study who underwent cIMT measurements and had data on minimum, mean, and maximum thickness. We replicated 15 known loci and identified 20 novel loci associated with cIMT at P −8 . Seven novel loci ( ZNF385D , AD AMTS9 , EDNRA , HAND2 , MYOCD , ITCH/EDEM2/MMP24 , and MRTFA ) were identified in all 3 phenotypes. An additional new locus ( LOXL1 ) was identified in the meta-analysis of the 3 phenotypes. Sex interaction analysis revealed sex differences in 7 loci including a novel locus ( SYNE3 ) in males. Meta-analysis of UK Biobank data with a previous meta-analysis led to identification of three novel loci ( APOB, FIP1L1, and LOXL4 ). Transcriptome-wide association analyses implicated additional genes ARHGAP42 , NDRG4 , and KANK2 . Gene set analysis showed an enrichment in extracellular organization and the PDGF (platelet-derived growth factor) signaling pathway. We found positive genetic correlations of cIMT with coronary artery disease r g =0.21 ( P =1.4×10 -7 ), peripheral artery disease r g =0.45 ( P =5.3×10 -5 ), and systolic blood pressure r g =0.30 ( P =4.0×10 -18 ). A negative genetic correlation between average of maximum cIMT and high-density lipoprotein was found r g =−0.12 ( P =7.0×10 -4 ). Conclusions: Genome-wide association meta-analyses in >100 000 individuals identified 25 novel loci associated with cIMT providing insights into genes and tissue-specific regulatory mechanisms of proatherosclerotic processes. We found evidence for shared biological mechanisms with cardiovascular diseases.
Published: 2022
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15. Polygenic risk score and coronary artery disease: A meta-analysis of 979,286 participant data

Author: Jean Jacques Noubiap, Gemma A. Figtree, M. Abdullah Said, Edith Pascale Mofo Mato, Pim van der Harst, Derek P. Chew, and T. Agbaedeng
Subjects: Multifactorial Inheritance, medicine.medical_specialty, business.industry, Hazard ratio, Genome-wide association study, Coronary Artery Disease, Odds ratio, medicine.disease, Polymorphism, Single Nucleotide, Confidence interval, Coronary artery disease, Risk Factors, Meta-analysis, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Myocardial infarction, Cardiology and Cardiovascular Medicine, business, Prospective cohort study
Abstract: BACKGROUND AND AIMS: Coronary artery disease (CAD) is a complex disease with a strong genetic basis. While previous studies have combined common single-nucleotide polymorphisms (SNPs) into a polygenic risk score (PRS) to predict CAD risk, this association is poorly characterised. We performed a meta-analysis to estimate the effect of PRS on the risk of CAD.METHODS: Online databases were searched for studies reporting PRS and CAD. PRS computation was based on log-odds (PRSLN), pruning or clumping and thresholding (PRSP/C + T), Lassosum regression (PRSLassosum), LDpred (PRSLDpred), or metaGRS (PRSmetaGRS). The reported odds ratio (OR), hazard ratio (HR), C-indexes and their corresponding 95% confidence interval (95% CI) were pooled in a random-effects meta-analysis.RESULTS: Forty-nine studies were included (979,286 individuals). There was a significant association between 1-standard deviation [SD] increment in PRS and adjusted risks of both incident and prevalent CAD (OR [95% CI]: 1.67 [1.57-1.77] for PRSmetaGRS, 1.46 [1.26-1.68] for PRSLDpred). The risk of incident CAD was highest for PRSP/C + T (HR [95% CI]: 1.49 [1.26-1.78]), PRSmetaGRS (1.37 [1.27-1.47]), and PRSLDpred (1.36 [1.31-1.42]). Analysis of model performance demonstrated that PRS predicted incident CAD with C-index of up to 0.71. Importantly, addition of PRS to clinical risk scores resulted in modest but statistically significant improvements in CAD risk prediction, with 1.5% observed for PRSP/C + T (p < 0.001) and 1.6% for PRSLDpred (p < 0.001).CONCLUSIONS: Polygenic risk score is strongly associated with increased risks of CAD. Future prospective studies should explore the usefulness of polygenic risk scores for identifying individuals at a high risk of developing CAD.
Published: 2021
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16. Variants in the

Author: Antoine, Rimbert, Ming W, Yeung, Nawar, Dalila, Chris H L, Thio, Haojie, Yu, Natalia, Loaiza, Federico, Oldoni, Adriaan, van der Graaf, Siqi, Wang, M Abdullah, Said, Lisanne L, Blauw, Aurore, Girardeau, Lise, Bray, Amandine, Caillaud, Vincent W, Bloks, Marie, Marrec, Philippe, Moulin, Patrick C N, Rensen, Bart, van de Sluis, Harold, Snieder, Mathilde, Di Filippo, Pim, van der Harst, Anne, Tybjaerg-Hansen, Philip, Zimmerman, Bertrand, Cariou, and Jan Albert, Kuivenhoven
Subjects: Hypobetalipoproteinemias, Mice, C-Reactive Protein, Pharmaceutical Preparations, Cholesterol, HDL, Animals, Humans, Cholesterol, LDL, Atherosclerosis, Apolipoproteins B, Receptors, G-Protein-Coupled
Abstract: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown.Common and rare genetic variants in theIn the UK Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (This study shows that carriers of new genetic
Published: 2022

17. Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

Author: Antoine Rimbert, Ming W. Yeung, Nawar Dalila, Chris H.L. Thio, Haojie Yu, Natalia Loaiza, Federico Oldoni, Adriaan van der Graaf, Siqi Wang, M. Abdullah Said, Lisanne L. Blauw, Aurore Girardeau, Lise Bray, Amandine Caillaud, Vincent W. Bloks, Marie Marrec, Philippe Moulin, Patrick C.N. Rensen, Bart van de Sluis, Harold Snieder, Mathilde Di Filippo, Pim van der Harst, Anne Tybjaerg-Hansen, Philip Zimmerman, Bertrand Cariou, Jan Albert Kuivenhoven, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), University of Groningen [Groningen], Utrecht University [Utrecht], University of Copenhagen = Københavns Universitet (UCPH), National University of Singapore (NUS), University of Texas Southwestern Medical Center [Dallas], Leiden University Medical Center (LUMC), University Medical Center Groningen [Groningen] (UMCG), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Rigshospitalet [Copenhagen], Copenhagen University Hospital, NEBION AG [Zurich, Switzerland], CarMeN, laboratoire, Center for Liver, Digestive and Metabolic Diseases (CLDM), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
Subjects: mice, G-protein-coupled receptor, phenotype, [SDV]Life Sciences [q-bio], CHOLESTEROL, dyslipidemia, allele, LOCI, human genetics, PROTEIN, liver, metabolic diseases, cardiovascular diseases, [SDV] Life Sciences [q-bio], GENOME, DEFICIENCY, atherosclerosis, Cardiology and Cardiovascular Medicine
Abstract: Background:In mice, GPR146 (G-protein–coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown.Methods:Common and rare genetic variants in theGPR146gene locus were used as research instruments in the UK Biobank. The Lifelines, The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rareGPR146variants.Results:In the UK Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (P=0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship betweenGPR146gene expression and plasma lipid and liver enzyme levels.Conclusions:This study shows that carriers of new geneticGPR146variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans.
Published: 2022
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18. Effect of Systolic Blood Pressure on Left Ventricular Structure and Function

Author: M. Abdullah Said, M. Yldau van der Ende, Niek Verweij, Lara M.A. Janssen, Dirk J. van Veldhuisen, Tom Hendriks, Pim van der Harst, and Cardiovascular Centre (CVC)
Subjects: Male, 0301 basic medicine, Left ventricular structure, medicine.medical_specialty, GENETIC PREDISPOSITION, VARIANTS, MASS, 030204 cardiovascular system & hematology, Ventricular Function, Left, Body Mass Index, EJECTION FRACTION, Muscle hypertrophy, 03 medical and health sciences, 0302 clinical medicine, cardiovascular disease, RISK-FACTOR, Internal medicine, Mendelian randomization, Internal Medicine, medicine, Humans, GENOME-WIDE ASSOCIATION, METAANALYSIS, Aged, Body surface area, Ejection fraction, GEOMETRY, business.industry, body surface area, blood pressure, Heart, Mendelian Randomization Analysis, Middle Aged, Magnetic Resonance Imaging, REFERENCE VALUES, Structure and function, HYPERTROPHY, 030104 developmental biology, High systolic blood pressure, Blood pressure, Hypertension, Cardiology, biomarker, Female, Hypertrophy, Left Ventricular, business
Abstract: We aimed to estimate the effects of a lifelong exposure to high systolic blood pressure (SBP) on left ventricular (LV) structure and function using Mendelian randomization. A total of 5596 participants of the UK Biobank were included for whom cardiovascular magnetic resonance imaging and genetic data were available. Major exclusion criteria included nonwhite ethnicity, major cardiovascular disease, and body mass index >30 or 2 . A genetic risk score to estimate genetically predicted SBP (gSBP) was constructed based on 107 previously established genetic variants. Manual cardiovascular magnetic resonance imaging postprocessing analyses were performed in 300 individuals at the extremes of gSBP (150 highest and lowest). Multivariable linear regression analyses of imaging biomarkers were performed using gSBP as continuous independent variable. All analyses except myocardial strain were validated using previously derived imaging parameters in 2530 subjects. The mean (SD) age of the study population was 62 (7) years, and 52% of subjects were female. Corrected for age, sex, and body surface area, each 10 mm Hg increase in gSBP was significantly ( P P =0.002) increase in LV mass and with 2.80% (SE, 0.97; P =0.004) increase in LV global radial strain. In the validation cohort, after correction for age, sex, and body surface area, each 10 mm Hg increase in gSBP was associated with 5.27 g (SE, 1.50; P
Published: 2019
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19. Genome-Wide Association Study and Identification of a Protective Missense Variant on Lipoprotein(a) Concentration : Protective Missense Variant on Lipoprotein(a) Concentration-Brief Report

Author: M. Abdullah Said, Jan Walter Benjamins, P. van der Harst, Sanni Ruotsalainen, Robin P. F. Dullaart, Yordi J. van de Vegte, Ming Wai Yeung, Luis Eduardo Juarez-Orozco, Samuli Ripatti, Pradeep Natarajan, Niek Verweij, Institute for Molecular Medicine Finland, Complex Disease Genetics, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Biostatistics Helsinki, and Helsinki Institute of Life Science HiLIFE
Subjects: Male, single nucleotide, Genome-wide association study, 030204 cardiovascular system & hematology, polymorphism, chemistry.chemical_compound, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, GENETIC-VARIANTS, Medicine, Missense mutation, genetics, Prospective Studies, Genetics, RISK, 0303 health sciences, biology, 1184 Genetics, developmental biology, physiology, Lipoprotein(a), Middle Aged, 3. Good health, Up-Regulation, Female, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, coronary artery disease, Adult, causality, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, Mendelian randomization, Humans, METAANALYSIS, 030304 developmental biology, Aged, business.industry, Cholesterol, Mendelian Randomization Analysis, Protective Factors, Genetic architecture, lipoproteins, chemistry, biology.protein, business, Biomarkers, Lipoprotein, Genome-Wide Association Study
Abstract: Objective: Lipoprotein(a) (Lp[a]) is associated with coronary artery disease (CAD) but also to LDL (low-density lipoprotein) cholesterol. The genetic architecture of Lp(a) remains incompletely understood, as well as its independence of LDL cholesterol in its association to CAD. We investigated the genetic determinants of Lp(a) concentrations in a large prospective multiethnic cohort. We tested the association for potential causality between genetically determined higher Lp(a) concentrations and CAD using a multivariable Mendelian randomization strategy. Approach and Results: We studied 371 212 participants of the UK Biobank with available Lp(a) and genome-wide genetic data. Genome-wide association analyses confirmed 2 known and identified 37 novel loci ( P −8 ) associated with Lp(a). Testing these loci as instrumental variables in an independent cohort with 60 801 cases and 123 504 controls, each SD genetically elevated Lp(a) conferred a 1.30 ([95% CI, 1.20–1.41] P =5.53×10 − 11 ) higher odds of CAD. Importantly, this association was independent of LDL cholesterol. Genetic fine-mapping in the LPA gene region identified 15 potential causal variants. This included a rare missense variant (rs41267813[A]) associated with lower Lp(a) concentration. We observed a strong interaction between rs41267813 and rs10455872 on Lp(a) concentrations, indicating a protective effect of rs41267813(A). Conclusions: This study supports an LDL cholesterol–independent causal link between Lp(a) and CAD. A rare missense variant in the LPA gene locus appears to be protective in people with the Lp(a) increasing variant of rs10455872. In the search for therapeutic targets of Lp(a), future work should focus on understanding the functional consequences of this missense variant.
Published: 2021

20. Genetic and lifestyle risks of cardiovascular disease

Author: M. Abdullah Said, van der Harst, Pim, and Verweij, Niek
Subjects: medicine.medical_specialty, business.industry, medicine, Disease, Intensive care medicine, business
Abstract: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Over the past 5 decades, the identification and modification of cardiovascular risk factors, as well as the development of pharmaceutical and interventional therapies, have resulted in declining CVD mortality rates. To develop better and innovative preventive strategies, a better understanding of the pathophysiological mechanisms underlying CVD is necessary. Studying the genetic factors underlying CVD and their risk factors may aid us in this undertaking.Genome-wide association studies have identified thousands of associations between genetic variants with risk factors and diseases, thereby increasing our understanding of the biology underlying these traits. The evidence for a causal relationship between a risk factor and a disease can then be investigated using these genetic variants.This thesis presents evidence for causal relationships between risk factors such as telomere length and iron parameters, with CVD. We uncovered novel genetic variants associated with lipoprotein(a), but also with lifestyle factors such as caffeine intake and sedentary behaviors. We subsequently provide evidence for their causal relations with coronary artery disease. Additionally, we found genetic and lifestyle factors had additive effects on the risk of developing CVD. A healthy lifestyle was associated with lower risks compared to an unhealthy lifestyle, regardless of the genetic risk, and a high genetic risk with an unhealthy lifestyle both increased the risk of developing CVD. The findings described in this thesis help us better understand the pathophysiological mechanisms underlying CVD and may aid in improving risk stratifications.
Published: 2021
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21. Associations of Observational and Genetically Determined Caffeine Intake With Coronary Artery Disease and Diabetes Mellitus

Author: Niek Verweij, Pim van der Harst, M. Abdullah Said, Yordi J. van de Vegte, and Cardiovascular Centre (CVC)
Subjects: Male, type 2 diabetes mellitus, Physiology, Genome-wide association study, VARIANTS, Coffee, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Medicine, genetics, 030212 general & internal medicine, Original Research, RISK, 0303 health sciences, Hazard ratio, Middle Aged, caffeine intake, Causality, CARDIOVASCULAR-DISEASE, OBESITY, COFFEE CONSUMPTION, Female, Cardiology and Cardiovascular Medicine, Caffeine, coronary artery disease, POWER, HEART-DISEASE, Lower risk, 03 medical and health sciences, Mendelian randomization, Humans, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Aged, Proportional Hazards Models, Tea, Proportional hazards model, business.industry, Type 2 Diabetes Mellitus, Genetic Variation, Mendelian Randomization Analysis, chemistry, Diabetes Mellitus, Type 2, PLEIOTROPY, Observational study, business, Risk Reduction Behavior, Basic Science Research, Genome-Wide Association Study
Abstract: Background Caffeine is the most widely consumed psychostimulant and is associated with lower risk of coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). However, whether these associations are causal remains unknown. This study aimed to identify genetic variants associated with caffeine intake, and to investigate evidence for causal links with CAD or T2DM. In addition, we aimed to replicate previous observational findings. Methods and Results Observational associations were tested within UK Biobank using Cox regression analyses. Moderate observational caffeine intakes from coffee or tea were associated with lower risks of CAD or T2DM, with the lowest risks at intakes of 121 to 180 mg/day from coffee for CAD (hazard ratio [HR], 0.77 [95% CI, 0.73–0.82; P −16 ]), and 301 to 360 mg/day for T2DM (HR, 0.76 [95% CI, 0.67–0.86]; P =1.57×10 −5 ). Next, genome‐wide association studies were performed on self‐reported caffeine intake from coffee, tea, or both in 407 072 UK Biobank participants. These analyses identified 51 novel genetic variants associated with caffeine intake at P −8 . These loci were enriched for central nervous system genes. However, in contrast to the observational analyses, 2‐sample Mendelian randomization analyses using the identified loci in independent disease‐specific cohorts yielded no evidence for causal links between genetically determined caffeine intake and the development of CAD or T2DM. Conclusions Mendelian randomization analyses indicate genetically determined higher caffeine intake might not protect against CAD or T2DM, despite protective associations in observational analyses.
Published: 2020
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22. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author: Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center
Subjects: Male, Epidemiology, Genome-wide association study, Cardiovascular, MESH: Genotype, Substance Misuse, Alcohol Use and Health, 0302 clinical medicine, Aetiology, triglycerides, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Life Style, genome wide, gene-alcohol interaction, lipid levels, Lipid Measurement, Lifelines Cohort, DENSITY-LIPOPROTEIN CHOLESTEROL, MESH: Young Adult, 030220 oncology & carcinogenesis, Kexin, LOW-FREQUENCY, MESH: Cholesterol, HDL, MESH: Cholesterol, LDL, MESH: Triglycerides, HDL, Alcohol Drinking, Genotype, alcohol consumption, MESH: Phenotype, LDL, lipids, 03 medical and health sciences, Genetics, Humans, Life Style, METAANALYSIS, 01 Mathematical Sciences, Aged, MESH: Adolescent, HDL CHOLESTEROL, MESH: Humans, Science & Technology, Cholesterol, APOBEC1, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), MESH: Vascular Endothelial Growth Factor B, Racial Groups, cholesterol, The Netherlands, MESH: Adult, CONSUMPTION, chemistry, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Lipid profile, MESH: Female, MESH: Alcohol Drinking, MESH: Continental Population Groups, Vascular Endothelial Growth Factor B, Original Contributions, Blood lipids, VEGF-B, Medical and Health Sciences, Mathematical Sciences, BLOOD-LIPIDS, chemistry.chemical_compound, 2.1 Biological and endogenous factors, 030212 general & internal medicine, MESH: Aged, medicine.diagnostic_test, PLASMA, gene-environment interactions, Middle Aged, 3142 Public health care science, environmental and occupational health, Alcoholism, Phenotype, Female, gene-lifestyle interactions, genome-wide association studies, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, Groningen, Adult, Adolescent, Biology, Young Adult, medicine, CORONARY-HEART-DISEASE, Human Genome, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, InterAct Consortium, MESH: Lipids, MESH: Male, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract: © The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant
Published: 2019
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23. Genome-wide association studies and Mendelian randomization analyses for leisure sedentary behaviours

Author: Michiel Rienstra, Yordi J. van de Vegte, M. Abdullah Said, Pim van der Harst, Niek Verweij, and Cardiovascular Centre (CVC)
Subjects: 0301 basic medicine, Male, Epidemiology, LD SCORE REGRESSION, General Physics and Astronomy, Genome-wide association study, Disease, Coronary Artery Disease, Genome-wide association studies, Body Mass Index, 0302 clinical medicine, Risk Factors, 030212 general & internal medicine, lcsh:Science, RISK, Multidisciplinary, Mental Disorders, Mendelian Randomization Analysis, Middle Aged, TIME, RECEPTOR GENE, DISEASES, Behavioural genetics, Female, Adult, medicine.medical_specialty, Science, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Mendelian randomization, medicine, Humans, Coronary artery disease and stable angina, Risk factor, Aged, business.industry, MORTALITY, General Chemistry, ADULTS, United Kingdom, 030104 developmental biology, PHYSICAL-ACTIVITY, Observational study, lcsh:Q, Sedentary Behavior, business, Body mass index, Demography, Genome-Wide Association Study
Abstract: Leisure sedentary behaviours are associated with increased risk of cardiovascular disease, but whether this relationship is causal is unknown. The aim of this study is to identify genetic determinants associated with leisure sedentary behaviours and to estimate the potential causal effect on coronary artery disease (CAD). Genome wide association analyses of leisure television watching, leisure computer use and driving behaviour in the UK Biobank identify 145, 36 and 4 genetic loci (P, Epidemiological studies have shown an association between sedentary behaviours and cardiovascular disease risk. Here, van de Vegte et al. perform GWAS for self-reported sedentary behaviours (TV watching, computer use, driving) and Mendelian randomization analyses to explore potential causal relationships with coronary artery disease.
Published: 2020

24. Genetically Determined ABO Blood Group and its Associations With Health and Disease

Author: M. Abdullah Said, Hilde E. Groot, Jacco C. Karper, Laura E. Villegas Sierra, Erik Lipsic, Pim van der Harst, and Cardiovascular Centre (CVC)
Subjects: Adult, Male, 0301 basic medicine, Health Status, Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Risk Assessment, ABO Blood-Group System, Healthy Aging, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Risk Factors, ABO blood group system, Prevalence, Humans, Medicine, Genetic Predisposition to Disease, Aged, business.industry, Incidence, Age Factors, Middle Aged, Phenotype, United Kingdom, 030104 developmental biology, Cardiovascular Diseases, Immunology, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Objective: To determine the spectrum of phenotypes linked to the ABO blood group system, using genetic determinants of the ABO blood group system. Approach and Results: We assessed the risk of 41 health and disease outcomes, and 36 linear traits associated with the ABO blood group system in the UK Biobank cohort. A total of 406 755 unrelated individuals were included in this study. Blood groups A, B, and O were determined based on allele combinations of previously established single-nucleotide polymorphisms rs8176746, rs8176719 in the ABO gene. Group AB was excluded because of its relative small sample size. Overall, 187 387 (46%) were male with a mean (SD) age of 57±8.1 years and a median total exposure of 64 person-years (interquartile range, 57–70). Of 406 755 individuals, 182 621 (44.9%) participants had blood group O, 182 786 (44.9%) had blood group A, and 41 348 (10.2%) had blood group B. ABO blood groups were associated with 11 health and disease outcomes ( P −4 ). ABO blood groups were primarily associated with cardiovascular outcomes. Compared with individuals with blood group O, blood groups A and B were associated with increased odds of up to 1.56 (95% CI, 1.43–1.69) for thromboembolic events and decreased odds for hypertension (0.94 [95% CI, 0.92–0.97]). Conclusions: The ABO blood group system is associated with several parameters of healthy aging and disease development. Knowledge of ABO blood groups might be of interest for more personalized approaches towards health maintenance and the prevention of diseases.
Published: 2020

25. Genetically Determined High Levels of Iron Parameters Are Protective for Coronary Artery Disease

Author: Niek Verweij, Niels Grote Beverborg, Haye H. van der Wal, Peter van der Meer, M. Abdullah Said, Pim van der Harst, Cardiovascular Centre (CVC), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
Subjects: Male, ferritins, medicine.medical_specialty, Heart disease, Single-nucleotide polymorphism, Bioinformatics, Polymorphism, Single Nucleotide, Coronary artery disease, iron, Predictive Value of Tests, Epidemiology, Mendelian randomization, medicine, Humans, Aged, heart diseases, business.industry, Incidence (epidemiology), Confounding, General Medicine, Iron deficiency, Mendelian Randomization Analysis, medicine.disease, incidence, Female, business, Biomarkers, coronary artery disease
Abstract: The observation that premenopausal women have a relatively low incidence of heart disease led in the nineteen eighties to the hypothesis that iron deficiency protects against heart diseases. These early observations were followed-up by conflicting epidemiological data. To confer causal relationships from epidemiological data is challenging as results can be influenced by residual confounding or reverse causation. For bias reduction, an alternative analysis strategy utilizing single-nucleotide polymorphisms (SNPs) as instrumental variables (Mendelian Randomization) has been developed. A recent study using 3 iron status associated SNPs suggested a protective effect of a higher iron status on the development of CAD.3 With a larger set of SNPs covering different components of iron metabolism, we aimed to provide a reliable answer to this lingering question.
Published: 2020

26. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author: Dennis O. Mook-Kanamori, Yalda Jamshidi, Peter K. Joshi, Seung Hoan Choi, Henry J. Lin, Rebecca D. Jackson, Alison D. Murray, May E. Montasser, Veikko Salomaa, Charles Kooperberg, Moritz F. Sinner, Gianfranco Sinagra, Luisa Foco, James G. Wilson, Johan Sundström, Kathleen A. Ryan, Eric A. Whitsel, Bruno H. Stricker, Sandosh Padmanabhan, Christopher Newton-Cheh, Ozren Polasek, Unnur Thorsteinsdottir, Niek Verweij, Pier D. Lambiase, Nathan R. Tucker, Stefan Kääb, Jun Ding, Stefan Weiss, Daniel F. Gudbjartsson, David Conen, Lars Lind, Ivana Kolcic, Lu-Chen Weng, J. Wouter Jukema, Kirill V. Tarasov, Xiuqing Guo, Stella Trompet, Patricia B. Munroe, Albert V. Smith, Elsayed Z. Soliman, Andrew Tinker, Antti Jula, J. Gustav Smith, Alexander P. Reiner, Sébastien Thériault, Kathryn L. Lunetta, Vilmundur Gudnason, Mika Kähönen, Massimo Mangino, Raymond Noordam, Joshua C. Bis, Alan R. Shuldiner, Tim D. Spector, Borbala Mifsud, Stefan van Duijvenboden, Jeffrey R. O'Connell, Emelia J. Benjamin, M. Benjamin Shoemaker, Stephan B. Felix, Peter W. Macfarlane, Lorenz Risch, Uwe Völker, Stephanie M. Gogarten, Maria Fernanda Lima-Costa, Julia Ramirez, Morten S. Olesen, Konstantin Strauch, Annette Peters, Aaron Isaacs, Steven A. Lubitz, Eric Boerwinkle, Carolina Roselli, James H. Cartwright, Nathalia M. Araujo, Ruth J. F. Loos, Diane Fatkin, Harry Campbell, Blair H. Smith, Thomas Meitinger, André G. Uitterlinden, Paul L. Huang, Tamara B. Harris, Kathleen F. Kerr, David J. Porteous, Martina Müller-Nurasyid, Francesco Cucca, Michiel Rienstra, Davíð O. Arnar, Amanda A. Seyerle, Caroline Hayward, M. Abdullah Said, Catriona L. K. Barnes, Kent D. Taylor, Nona Sotoodehnia, Nina Mononen, Dan M. Roden, Jonathan Marten, Terho Lehtimäki, Dan E. Arking, Anna F. Dominiczak, Jan A. Kors, Olli T. Raitakari, Igor Rudan, Yordi J. van de Vegte, Christopher P. Nelson, Erik Ingelsson, Ulrike Peters, Girish N. Nadkarni, Eduardo Tarazona-Santos, Edward G. Lakatta, Nina Hutri-Kähönen, Bruce M. Psaty, Patrick T. Ellinor, Christian Fuchsberger, Katharina Schramm, Amelia W. Hall, M. Yldau van der Ende, Alvaro Alonso, James F. Wilson, Sheila Ulivi, Rosa B. Thorolfsdottir, Stefanie Aeschbacher, Mary L. Biggs, Marten E. van den Berg, Nilesh J. Samani, Thibaud Boutin, Vilmantas Giedraitis, Honghuang Lin, Kjell Nikus, Helen R. Warren, Arie C. Maan, James J. Cranley, Adolfo Correa, Martin Gögele, Ian Ford, Katri Sääksjärvi, Georg Ehret, Michele Orini, Susan R. Heckbert, Cecilia M. Lindgren, Jie Yao, Maria Pina Concas, Pim van der Harst, Ioanna Ntalla, Jeffrey Haessler, Jerome I. Rotter, Pashupati P. Mishra, Michael J. Cutler, Erwin P. Bottinger, Cornelia M. van Duijn, Jennifer A. Brody, Paolo Gasparini, Lenore J. Launer, Andrew P. Morris, Renée de Mutsert, Aki S. Havulinna, James P. Cook, Hilma Holm, Patrick Sulem, Alessandro De Grandi, Cristian Pattaro, Gardar Sveinbjornsson, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Gudmar Thorleifsson, Marcus Dörr, Muhammad B. Riaz, Peter P. Pramstaller, Yong Qian, Anubha Mahajan, Cathy C. Laurie, Kenneth Rice, Mark Chaffin, Kari Stefansson, Andrew A. Hicks, Solmaz Assa, Hao Mei, Leo-Pekka Lyytikäinen, Fabiola Del Greco M, Renan P. Souza, Michael Preuss, Adrienne M. Stilp, Barry London, Melanie Waldenberger, Christy L. Avery, Daniel Levy, Michael R. Barnes, Medical Informatics, Epidemiology, Internal Medicine, Weng, Lu-Chen [0000-0003-1475-4930], Hall, Amelia Weber [0000-0002-7915-0313], Tucker, Nathan R [0000-0002-5071-4218], Chaffin, Mark D [0000-0002-1234-5562], Roselli, Carolina [0000-0001-5267-6756], Barnes, Michael R [0000-0001-9097-7381], Mifsud, Borbala [0000-0003-3429-3094], Hayward, Caroline [0000-0002-9405-9550], Concas, Maria Pina [0000-0003-3598-2537], Boutin, Thibaud [0000-0003-4754-1675], Kolcic, Ivana [0000-0001-7918-6052], Rudan, Igor [0000-0001-6993-6884], Souza, Renan P [0000-0002-9479-4432], Giedraitis, Vilmantas [0000-0003-3423-2021], Ingelsson, Erik [0000-0003-2256-6972], Mahajan, Anubha [0000-0001-5585-3420], Morris, Andrew P [0000-0002-6805-6014], Hicks, Andrew A [0000-0001-6320-0411], Sundström, Johan [0000-0003-2247-8454], Nelson, Christopher P [0000-0001-8025-2897], Riaz, Muhammad B [0000-0002-5512-1745], Sinagra, Gianfranco [0000-0003-2700-8478], Mishra, Pashupati P [0000-0001-5177-3431], Caulfield, Mark J [0000-0001-9295-3594], Dominiczak, Anna [0000-0003-4913-3608], Risch, Lorenz [0000-0003-2692-6699], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Isaacs, Aaron [0000-0001-5037-4834], van Duijn, Cornelia M [0000-0002-2374-9204], Gudnason, Vilmundur [0000-0001-5696-0084], Smith, Albert V [0000-0003-1942-5845], Loos, Ruth JF [0000-0002-8532-5087], Preuss, Michael H [0000-0001-5266-8465], Correa, Adolfo [0000-0002-9501-600X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Waldenberger, Melanie [0000-0003-0583-5093], Mangino, Massimo [0000-0002-2167-7470], Rienstra, Michiel [0000-0002-2581-070X], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Fatkin, Diane [0000-0002-9010-9856], Brody, Jennifer A [0000-0001-8509-148X], Rice, Kenneth [0000-0002-3071-7278], Pattaro, Cristian [0000-0002-4119-0109], Wouter Jukema, J [0000-0002-3246-8359], Weiss, Stefan [0000-0002-3553-4315], Havulinna, Aki S [0000-0002-4787-8959], Sääksjärvi, Katri [0000-0002-5061-4911], Salomaa, Veikko [0000-0001-7563-5324], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Lakatta, Edward G [0000-0002-4772-0035], Lin, Honghuang [0000-0003-3043-3942], Lunetta, Kathryn L [0000-0002-9268-810X], Murray, Alison D [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Smith, Blair H [0000-0002-5362-9430], Uitterlinden, André [0000-0002-7276-3387], Peters, Ulrike [0000-0001-5666-9318], Alonso, Alvaro [0000-0002-2225-8323], Ehret, Georg B [0000-0002-5730-0675], Soliman, Elsayed Z [0000-0001-5632-8150], Gogarten, Stephanie M [0000-0002-7231-9745], Kerr, Kathleen F [0000-0002-6438-9583], Abdullah Said, M [0000-0003-2920-7745], Orini, Michele [0000-0001-5773-0344], Ramirez, Julia [0000-0003-4130-5866], Van Duijvenboden, Stefan [0000-0001-8897-558X], Gudbjartsson, Daniel F [0000-0002-5222-9857], Sulem, Patrick [0000-0001-7123-6123], Thorolfsdottir, Rosa B [0000-0001-7475-0398], Benjamin, Emelia J [0000-0003-4076-2336], Stefansson, Kari [0000-0003-1676-864X], Ellinor, Patrick T [0000-0002-2067-0533], Jamshidi, Yalda [0000-0003-0151-6482], Lubitz, Steven A [0000-0002-9599-4866], Munroe, Patricia B [0000-0002-4176-2947], Apollo - University of Cambridge Repository, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Cardiovascular Centre (CVC), Ntalla, I., Weng, L. -C., Cartwright, J. H., Hall, A. W., Sveinbjornsson, G., Tucker, N. R., Choi, S. H., Chaffin, M. D., Roselli, C., Barnes, M. R., Mifsud, B., Warren, H. R., Hayward, C., Marten, J., Cranley, J. J., Concas, M. P., Gasparini, P., Boutin, T., Kolcic, I., Polasek, O., Rudan, I., Araujo, N. M., Lima-Costa, M. F., Ribeiro, A. L. P., Souza, R. P., Tarazona-Santos, E., Giedraitis, V., Ingelsson, E., Mahajan, A., Morris, A. P., Del Greco M, F., Foco, L., Gogele, M., Hicks, A. A., Cook, J. P., Lind, L., Lindgren, C. M., Sundstrom, J., Nelson, C. P., Riaz, M. B., Samani, N. J., Sinagra, G., Ulivi, S., Kahonen, M., Mishra, P. P., Mononen, N., Nikus, K., Caulfield, M. J., Dominiczak, A., Padmanabhan, S., Montasser, M. E., O'Connell, J. R., Ryan, K., Shuldiner, A. R., Aeschbacher, S., Conen, D., Risch, L., Theriault, S., Hutri-Kahonen, N., Lehtimaki, T., Lyytikainen, L. -P., Raitakari, O. T., Barnes, C. L. K., Campbell, H., Joshi, P. K., Wilson, J. F., Isaacs, A., Kors, J. A., van Duijn, C. M., Huang, P. L., Gudnason, V., Harris, T. B., Launer, L. J., Smith, A. V., Bottinger, E. P., Loos, R. J. F., Nadkarni, G. N., Preuss, M. H., Correa, A., Mei, H., Wilson, J., Meitinger, T., Muller-Nurasyid, M., Peters, A., Waldenberger, M., Mangino, M., Spector, T. D., Rienstra, M., van de Vegte, Y. J., van der Harst, P., Verweij, N., Kaab, S., Schramm, K., Sinner, M. F., Strauch, K., Cutler, M. J., Fatkin, D., London, B., Olesen, M., Roden, D. M., Benjamin Shoemaker, M., Gustav Smith, J., Biggs, M. L., Bis, J. C., Brody, J. A., Psaty, B. M., Rice, K., Sotoodehnia, N., De Grandi, A., Fuchsberger, C., Pattaro, C., Pramstaller, P. P., Ford, I., Wouter Jukema, J., Macfarlane, P. W., Trompet, S., Dorr, M., Felix, S. B., Volker, U., Weiss, S., Havulinna, A. S., Jula, A., Saaksjarvi, K., Salomaa, V., Guo, X., Heckbert, S. R., Lin, H. J., Rotter, J. I., Taylor, K. D., Yao, J., de Mutsert, R., Maan, A. C., Mook-Kanamori, D. O., Noordam, R., Cucca, F., Ding, J., Lakatta, E. G., Qian, Y., Tarasov, K. V., Levy, D., Lin, H., Newton-Cheh, C. H., Lunetta, K. L., Murray, A. D., Porteous, D. J., Smith, B. H., Stricker, B. H., Uitterlinden, A., van den Berg, M. E., Haessler, J., Jackson, R. D., Kooperberg, C., Peters, U., Reiner, A. P., Whitsel, E. A., Alonso, A., Arking, D. E., Boerwinkle, E., Ehret, G. B., Soliman, E. Z., Avery, C. L., Gogarten, S. M., Kerr, K. F., Laurie, C. C., Seyerle, A. A., Stilp, A., Assa, S., Abdullah Said, M., Yldau van der Ende, M., Lambiase, P. D., Orini, M., Ramirez, J., Van Duijvenboden, S., Arnar, D. O., Gudbjartsson, D. F., Holm, H., Sulem, P., Thorleifsson, G., Thorolfsdottir, R. B., Thorsteinsdottir, U., Benjamin, E. J., Tinker, A., Stefansson, K., Ellinor, P. T., Jamshidi, Y., Lubitz, S. A., Munroe, P. B., Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Arrhythmias, Genome-wide association studies, CALCINEURIN, Electrocardiography, 0302 clinical medicine, Cardiovascular Disease, Multi-ancestry GWAS, ELEMENTS, Medicine, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, RISK, DECREASE, education.field_of_study, Multidisciplinary, Kardiologi, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, Atrial fibrillation, 3142 Public health care science, environmental and occupational health, 3. Good health, Endophenotype, Arrhythmias, Cardiac, Cardiovascular Diseases, Endophenotypes, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Quantitative Trait Loci, cardiovascular system, Cardiology, medicine.symptom, Erfðarannsóknir, Cardiac, Medical Genetics, Human, Bradycardia, medicine.medical_specialty, Science, GENOME-WIDE ASSOCIATION, ATRIAL-FIBRILLATION, MUTATIONS, DURATION, CARDIOMYOPATHY, BRADYCARDIA, Population, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Cardiac conduction, PR interval, education, Medicinsk genetik, business.industry, Cardiovascular genetics, General Chemistry, Arfgengi, medicine.disease, 030104 developmental biology, lcsh:Q, business
Abstract: Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.
Published: 2020
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27. Contributions of Interactions Between Lifestyle and Genetics on Coronary Artery Disease Risk

Author: Muhammad Zafar, Niek Verweij, Yordi J. van de Vegte, M. Abdullah Said, M. Yldau van der Ende, Pim van der Harst, and Ghazala Kaukab Raja
Subjects: Candidate gene, Heart disease, ALCOHOL-CONSUMPTION, Coronary Artery Disease Risk, Psychological intervention, CAD, Genome-wide association study, HEART-DISEASE, Coronary Artery Disease, Disease, 030204 cardiovascular system & hematology, Bioinformatics, Genome-wide association studies, Polymorphism, Single Nucleotide, TERM COFFEE CONSUMPTION, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Life Style, Genetic lifestyle interactions, business.industry, ASSOCIATION, Lifestyle, medicine.disease, INDIVIDUALS, PHYSICAL-ACTIVITY, MYOCARDIAL-INFARCTION, CARDIOVASCULAR-DISEASE, Lipid Abnormalities and Cardiovascular Prevention (G De Backer, Section Editor), Genetic risk scores, Gene-Environment Interaction, DOSE-RESPONSE METAANALYSIS, CIGARETTE-SMOKING, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract: Purpose of the Review To summarize current knowledge on interactions between genetic variants and lifestyle factors (G×L) associated with the development of coronary artery disease (CAD) and prioritize future research. Recent Findings Genetic risk and combined lifestyle factors and behaviors have a log-additive effect on the risk of developing CAD. Summary First, we describe genetic and lifestyle factors associated with CAD and then focus on G×L interactions. The majority of G×L interaction studies are small-scale candidate gene studies that lack replication and therefore provide spurious results. Only a few studies, of which most use genetic risk scores or genome-wide approaches to test interactions, are robust in number and analysis strategy. These studies provide evidence for the existence of G×L interactions in the development of CAD. Further G×L interactions studies are important as they contribute to our understanding of disease pathophysiology and possibly provide insights for improving interventions or personalized recommendations.
Published: 2019
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28. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Author: Lorenz Risch, Igor Rudan, Hilma Holm, Christopher P. Nelson, Jan A. Kors, Stefanie Aeschbacher, Stefan Kääb, Peter W. Macfarlane, Lars Lind, Amanda A. Seyerle, Ozren Polasek, Daniel F. Gudbjartsson, Xiuqing Guo, Nilesh J. Samani, Bruce M. Psaty, Rosa B. Thorolfsdottir, Elsayed Z. Soliman, Yong Qian, Mary L. Biggs, Antti Jula, Vilmundur Gudnason, Paul L. Huang, Tamara B. Harris, Gianfranco Sinagra, Luisa Foco, Anubha Mahajan, Mika Kähönen, Lu-Chen Weng, Borbala Mifsud, Stefan van Duijvenboden, Terho Lehtimäki, Jennifer A. Brody, Paolo Gasparini, Kathleen A. Ryan, Marten E. van den Berg, James J. Cranley, Eric Boerwinkle, Cathy C. Laurie, Annette Peters, Joshua C. Bis, Raymond Noordam, Andrew P. Morris, Johan Sundström, Lenore J. Launer, Stefan Weiss, Rebecca D. Jackson, Alison D. Murray, Jeffrey R. O'Connell, Aki S. Havulinna, Dennis O. Mook-Kanamori, Sheila Ulivi, Renée de Mutsert, Eric A. Whitsel, Adrienne M. Stilp, James P. Cook, Nona Sotoodehnia, Antonio Luiz Pinho Ribeiro, Seung Hoan Choi, Mark J. Caulfield, Sébastien Thériault, Henry J. Lin, Dan M. Roden, J. Wouter Jukema, James F. Wilson, Veikko Salomaa, Honghuang Lin, Andrew A. Hicks, Christy L. Avery, Nina Mononen, Dan E. Arking, Ruth J. F. Loos, Yalda Jamshidi, André G. Uitterlinden, Nina Hutri-Kähönen, Andrew Tinker, Gudmar Thorleifsson, Daniel Levy, Martina Müller-Nurasyid, Alexander P. Reiner, Bruno H. Stricker, Caroline Hayward, Yordi J. van de Vegte, Ioanna Ntalla, Tim D. Spector, Niek Verweij, Michael R. Barnes, Martin Gögele, Nathan R. Tucker, Arie C. Maan, Eduardo Tarazona-Santos, Katri Sääksjärvi, Maria Pina Concas, Pim van der Harst, Georg Ehret, Cecilia M. Lindgren, David Conen, Cornelia M. van Duijn, Muhammad B. Riaz, Leo-Pekka Lyytikäinen, Amelia W. Hall, Peter P. Pramstaller, Maria Fernanda Lima-Costa, Vilmantas Giedraitis, Emelia J. Benjamin, M. Fabiola Del Greco, Thomas Meitinger, Erwin P. Bottinger, Francesco Cucca, Aaron Isaacs, Carolina Roselli, James H. Cartwright, Massimo Mangino, Adolfo Correa, Patrick Sulem, Thibaud Boutin, Michiel Rienstra, Stephan B. Felix, Julia Ramirez, Kathleen F. Kerr, Jonathan Marten, David J. Porteous, Kent D. Taylor, Patrick T. Ellinor, Michele Orini, Susan R. Heckbert, Olli T. Raitakari, Girish N. Nadkarni, Edward G. Lakatta, Anna F. Dominiczak, Jie Yao, Erik Ingelsson, Christopher Newton-Cheh, Katharina Schramm, Jerome I. Rotter, Michael J. Cutler, Pashupati P. Mishra, Diane Fatkin, Marcus Dörr, Ulrike Peters, Solmaz Assa, Christian Fuchsberger, M. Abdullah Said, Catriona L. K. Barnes, Peter K. Joshi, M. Yldau van der Ende, Alvaro Alonso, James G. Wilson, Jun Ding, Kathryn L. Lunetta, Kjell Nikus, Helen R. Warren, Charles Kooperberg, Moritz F. Sinner, Sandosh Padmanabhan, Patricia B. Munroe, Jeffrey Haessler, Albert V. Smith, Alan R. Shuldiner, Morten S. Olesen, Konstantin Strauch, Steven A. Lubitz, J. Gustav Smith, Renan P. Souza, Michael Preuss, Kirill V. Tarasov, M. Benjamin Shoemaker, Barry London, Melanie Waldenberger, Cristian Pattaro, David O. Arnar, Gardar Sveinbjornsson, Alessandro De Grandi, Ian Ford, Kenneth Rice, Mark Chaffin, Kari Stefansson, Hao Mei, Uwe Völker, Blair H. Smith, Nathalia M. Araujo, Harry Campbell, Pier D. Lambiase, Stephanie M. Gogarten, May E. Montasser, Unnur Thorsteinsdottir, Ivana Kolcic, and Stella Trompet
Subjects: 0303 health sciences, medicine.medical_specialty, education.field_of_study, business.industry, Population, Cardiomyopathy, Atrial fibrillation, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Endophenotype, Cardiac conduction, medicine, Cardiology, PR interval, business, education, 030304 developmental biology
Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
Published: 2019
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29. Smoking does not accelerate leucocyte telomere attrition

Author: Brenda W.J.H. Penninx, Gillian Pepper, Carlos Labat, Børge G. Nordestgaard, M. Abdullah Said, Carmen Martin-Ruiz, Peter Willeit, Yoav Ben-Shlomo, William Murray Thomson, Sara Hägg, Dóra Révész, Stig E. Bojesen, Daniel Nettle, Melissa Bateson, Yiqiang Zhan, Craig Meyer, John M. Starr, Mary A. Whooley, Holly E. Syddall, Cyrus Cooper, Abraham Aviv, Laila Bendix, Ian J. Deary, Diana Kuh, Pim van der Harst, Jeremy D. Kark, Rachel Cooper, Athanase Benetos, Sarah E. Harris, Thomas von Zglinicki, Florian Kronenberg, Cardiovascular Centre (CVC), Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Newcastle University [Newcastle], Center of Human Development and Aging, New Jersey Medical School, Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Odense University Hospital, Odense, Service de Gériatrie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), University of Bristol [Bristol], Department of Clinical Biochemistry, University of Copenhagen = Københavns Universitet (KU)-Copenhagen University Hospital-Herlev and Gentofte Hospital, MRC Epidemiology Resource Centre, University of Southampton, University College of London [London] (UCL), University of Edinburgh, Karolinska Institutet [Stockholm], Hadassah School of Public Health and Community Medicine, The Hebrew University of Jerusalem (HUJ), Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, 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), University of California [San Francisco] (UCSF), University of California, VU University Medical Center [Amsterdam], Maastricht University [Maastricht], University Medical Center Groningen [Groningen] (UMCG), University of Otago [Dunedin, Nouvelle-Zélande], University of Groningen [Groningen], University of Innsbruck, LBC1921, CCS, HAS and NSHD—New Dynamics of Ageing via the HALCyon cross-cohort collaborative programme (RES-353-25-0001), LBC1921—UK Biotechnology and Biological Sciences Research Council (BBSRC), JLRCS—US-Israel Binational Science Foundation, the Israel Science Foundation and the National Institutes of Health (AG030678 and AG201320), DMHDS—US National Institute on Aging (AG032282) and the UK Medical Research Council (MR/K00381X and MR/P005918), NESDA—The Netherlands Organisation for Health Research and Development (10-000-1002), VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum, National Centre for the Replacement Refinement and Reduction of Animals in Research (NC/ K000802/1), European Research Council (AdG 666669), National Institutes of Health (R01HL116446, R01HD071180, R01HL13840), Karolinska Institutet Delfinansiering, the Swedish Research Council (2015-03255), the Loo & Hans Osterman Foundation, the Foundation for Geriatric Diseases, the Magnus Bergwall Foundation, the Erik Rönnberg award for aging studies and the Strategic Research Program in Epidemiology at Karolinska Institutet, UK Medical Research Council and University of Southampton, UK Medical Research Council (G0601333), Centre for Cognitive Ageing and Cognitive Epidemiology, which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1), The Royal Society, and The Chief Scientist Office of the Scottish Government, Lifelong Health and Wellbeing Initiative (MR/K026992/1), LBC1936—Age UK (Disconnected Mind Project), NSHD—UK Medical Research Council, DE CARVALHO, Philippe, Copenhagen University Hospital-Herlev and Gentofte Hospital-University of Copenhagen = Københavns Universitet (UCPH), University of California [San Francisco] (UC San Francisco), University of California (UC), Leopold Franzens Universität Innsbruck - University of Innsbruck, Epidemiologie, and RS: FHML non-thematic output
Subjects: longitudinal, Biological age, [SDV]Life Sciences [q-bio], CHILDHOOD, DETERMINANTS, INCREASE, smoking, 03 medical and health sciences, 0302 clinical medicine, Cigarette smoking, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, telomere length, Medicine, Attrition, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, OXIDATIVE STRESS, lcsh:Science, LENGTH DYNAMICS, 030304 developmental biology, Reduced longevity, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, business.industry, MORTALITY, Causal effect, Biology (Whole Organism), C400, medicine.disease, EXPERIENCES, telomere attrition, Telomere, biological age, [SDV] Life Sciences [q-bio], LIFE, Meta-analysis, Biomarker (medicine), lcsh:Q, CIGARETTE-SMOKING, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article, SMOKERS, Demography
Abstract: Smoking is associated with shorter leucocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking causes accelerated LTL attrition in adulthood, but the evidence for this is inconsistent. We analysed the association between smoking and LTL dynamics in 18 longitudinal cohorts. The dataset included data from 12 579 adults (4678 current smokers and 7901 non-smokers) over a mean follow-up interval of 8.6 years. Meta-analysis confirmed a cross-sectional difference in LTL between smokers and non-smokers, with mean LTL 84.61 bp shorter in smokers (95% CI: 22.62 to 146.61). However, LTL attrition was only 0.51 bp yr −1 faster in smokers than in non-smokers (95% CI: −2.09 to 1.08), a difference that equates to only 1.32% of the estimated age-related loss of 38.33 bp yr −1 . Assuming a linear effect of smoking, 167 years of smoking would be required to generate the observed cross-sectional difference in LTL. Therefore, the difference in LTL between smokers and non-smokers is extremely unlikely to be explained by a linear, causal effect of smoking. Selective adoption, whereby individuals with short telomeres are more likely to start smoking, needs to be considered as a more plausible explanation for the observed pattern of telomere dynamics.
Published: 2019
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30. Effects of Calcium, Magnesium, and Potassium concentrations on ventricular repolarization in unselected individuals

Author: Pedro Guatimosim Vidigal, Yongmei Liu, Alice Stanton, Kent D. Taylor, Thomas Meitinger, Vilmundur Gudnason, Massimo Mangino, Mario Pirastu, Nilesh J. Samani, Christopher Newton-Cheh, Xiuqing Guo, Bruno H. Stricker, Mortiz F. Sinner, Steven R. Cummings, Jennifer A. Brody, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Bryan Kestenbaum, Dennis O. Mook-Kanamori, Jørgen K. Kanters, Kirill V. Tarasov, Martina Müller-Nurasyid, Luana Giatti, Elsayed Z. Soliman, Christian R. Juhl, Nuno R. Zilhão, Harold Snieder, Eric Campana, Mika Kähönen, Ginevra Biino, Raymond Noordam, Jun Ding, Chris H. L. Thio, Jerome I. Rotter, Torben Hansen, M. Abdullah Said, Francesco Cucca, Allan Linneberg, Nona Sotoodehnia, Niels Grarup, Peter S. Sever, James F. Wilson, André G. Uitterlinden, Xia Shen, Luisa Foco, Yong Qian, Christina Ellervik, Diana van Heemst, Antonietta Robino, Henry J. Lin, Konstantin Strauch, Patricia B. Munroe, Nabi Shah, Claus Graff, Daniel S. Evans, Peter J. van der Most, Stefan Weiss, Maria Pina Concas, Reem Salman, Hao Mei, Linda Repetto, Helen R. Warren, Peter K. Joshi, Susan R. Heckbert, Tim D. Spector, Sandhi Maria Barreto, Jie Yao, Marcus Dörr, Eulalia Catamo, Anna F. Dominiczak, Leo-Pekka Lyytikäinen, Giorgia Girotto, Peter P. Pramstaller, Gudny Eiriksdottir, J. Wouter Jukema, Paulo A. Lotufo, Colin N. A. Palmer, Andrew Tinker, James G. Wilson, Mary L. Biggs, Astrid Petersmann, Arie C. Maan, Peter S. Braund, Maria Fernanda Lima-Costa, Paraskevi Christofidou, Sandosh Padmanabhan, Adolfo Correa, Melanie Waldenberger, Alessandro De Grandi, Stefan Kääb, Cristian Pattaro, Annette Peters, William J Young, Alex S. F. Doney, Katharina Schramm, Terho Lehtimäki, Christopher P. Nelson, Martin Gögele, Marten E. van den Berg, Marco Brumat, Pim van der Harst, Niek Verweij, Simona Vaccargiu, Noordam, R, Young, Wj, Salman, R, Kanters, Jk, van den Berg, Me, van Heemst, D, Lin, Hj, Barreto, Sm, Biggs, Ml, Biino, G, Catamo, E, Concas, Mp, Ding, J, Evans, D, Foco, L, Grarup, N, Lyytikäinen, Lp, Mangino, M, Mei, H, van der Most, Pj, Müller-Nurasyid, M, Nelson, Cp, Qian, Y, Repetto, L, Said, Ma, Shah, N, Schramm, K, Vidigal, Pg, Weiss, S, Yao, J, Zilhao, Nr, Brody, Ja, Braund, P, Brumat, M, Campana, E, Christofidou, P, Caulfield, Mj, De Grandi, A, Dominiczak, Af, Doney, Asf, Eiriksdottir, G, Ellervik, C, Giatti, L, Gögele, M, Graff, C, Guo, X, van der Harst, P, Joshi, Pk, Kähönen, M, Kestenbaum, B, Lima-Costa, Mf, Linneberg, A, Maan, Ac, Meitinger, T, Padmanabhan, S, Pattaro, C, Peters, A, Petersmann, A, Sever, P, Sinner, Mf, Shen, X, Stanton, A, Strauch, K, Soliman, Ez, Tarasov, Kv, Taylor, Kd, Thio, Chl, Uitterlinden, Ag, Vaccargiu, S, Waldenberger, M, Robino, A, Correa, A, Cucca, F, Cummings, Sr, Dörr, M, Girotto, G, Gudnason, V, Hansen, T, Heckbert, Sr, Juhl, Cr, Kääb, S, Lehtimäki, T, Liu, Y, Lotufo, Pa, Palmer, Cna, Pirastu, M, Pramstaller, Pp, Ribeiro, Alp, Rotter, Ji, Samani, Nj, Snieder, H, Spector, Td, Stricker, Bh, Verweij, N, Wilson, Jf, Wilson, Jg, Jukema, Jw, Tinker, A, Newton-Cheh, Ch, Sotoodehnia, N, Mook-Kanamori, Do, Munroe, Pb, Warren, Hr., Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), and Epidemiology
Subjects: Male, Cardiac & Cardiovascular Systems, 030204 cardiovascular system & hematology, ELECTROCARDIOGRAM, Electrocardiography, 0302 clinical medicine, cohort studies, Risk Factors, Medicine, Magnesium, 030212 general & internal medicine, Correlation of Data, 1102 Cardiorespiratory Medicine and Haematology, RISK, education.field_of_study, medicine.diagnostic_test, ACTION-POTENTIAL DURATION, ASSOCIATION, Middle Aged, COUNCIL, electrocardiographic intervals, Cardiovascular Diseases, Cardiology, Female, epidemiology, Electrical conduction system of the heart, Cardiology and Cardiovascular Medicine, Electrophysiologic Techniques, Cardiac, Life Sciences & Biomedicine, medicine.medical_specialty, Population, electrolytes epidemiology, meta-analysis, chemistry.chemical_element, electrolytes, Calcium, QT interval, 1117 Public Health and Health Services, 03 medical and health sciences, QRS complex, DISPERSION, Heart Conduction System, Internal medicine, Humans, PR interval, education, Science & Technology, Cohort Studies, Electrocardiographic Intervals, Electrolytes, Epidemiology, Meta-analysis, business.industry, QT INTERVAL, RESTING HEART-RATE, Confidence interval, REDUCTION, chemistry, Cardiovascular System & Hematology, CONDUCTION, Asymptomatic Diseases, Potassium, Cardiovascular System & Cardiology, electrocardiographic interval, business, cohort studie
Abstract: BACKGROUND Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.OBJECTIVES This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.METHODS Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 +/- 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.RESULTS Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.CONCLUSIONS The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms. (C) 2019 by the American College of Cardiology Foundation.
Published: 2019
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31. Search for a Functional Genetic Variant Mimicking the Effect of SGLT2 Inhibitor Treatment

Author: Niek Verweij, Chris H. L. Thio, Hilde E. Groot, M. Abdullah Said, Harold Snieder, Peter J. van der Most, Yordi J. van de Vegte, Pim van der Harst, Siqi Wang, Life Course Epidemiology (LCE), and Cardiovascular Centre (CVC)
Subjects: Adult, Male, 0301 basic medicine, Untranslated region, UK Biobank, Quantitative Trait Loci, heart failure, Single-nucleotide polymorphism, QH426-470, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, CARDIOVASCULAR OUTCOMES, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, HBA1C, Genetics, Humans, Missense mutation, Sodium-Glucose Transporter 2 Inhibitors, Gene, Genetics (clinical), Glycated Hemoglobin, RISK, genetic variants, EMPAGLIFLOZIN, Genetic Variation, SGLT2 inhibitor, ASSOCIATION, Middle Aged, POTASSIUM, Renal glucose reabsorption, SODIUM, Minor allele frequency, 030104 developmental biology, chemistry, Female, Glycated hemoglobin, SGLT2 Inhibitor
Abstract: SGLT2 inhibitors (SGLT2i) block renal glucose reabsorption. Due to the unexpected beneficial observations in type 2 diabetic patients potentially related to increased natriuresis, SGLT2i are also studied for heart failure treatment. This study aimed to identify genetic variants mimicking SGLT2i to further our understanding of the potential underlying biological mechanisms. Using the UK Biobank resource, we identified 264 SNPs located in the SLC5A2 gene or within 25kb of the 5′ and 3′ flanking regions, of which 91 had minor allele frequencies &gt, 1%. Twenty-seven SNPs were associated with glycated hemoglobin (HbA1c) after Bonferroni correction in participants without diabetes, while none of the SNPs were associated with sodium excretion. We investigated whether these variants had a directionally consistent effect on sodium excretion, HbA1c levels, and SLC5A2 expression. None of the variants met these criteria. Likewise, we identified no common missense variants, and although four SNPs could be defined as 5′ or 3′ prime untranslated region variants of which rs45612043 was predicted to be deleterious, these SNPs were not annotated to SLC5A2. In conclusion, no genetic variant was found mimicking SGLT2i based on their location near SLC5A2 and their association with sodium excretion or HbA1c and SLC5A2 expression or function.
Published: 2021
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32. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author: Chris Finan, Yoav Ben-Shlomo, Eric B. Larson, Tine Jess, Richard W Morris, Daniel I. Chasman, Fernando Pires Hartwig, Catherine Welch, Rodney J. Scott, Helen E. Speedy, Andrzej Pajak, Raha Pazoki, André G. Uitterlinden, Torben Hansen, Marc Sanson, Hakon Hakonarson, Claudia Langenberg, Joey Ward, John Wright, Dorothée Thuillier, Ben Kinnersley, Diederick E. Grobbee, Yvonne T. van der Schouw, Pieter Sonneveld, Michiel L. Bots, Harold Snieder, Karim Labreche, Dan M. Roden, Archie Campbell, Melissa C. Smart, Christine Power, Pim van der Harst, Amélie Bonnefond, Ingrid E. Christophersen, Riyaz S. Patel, Uwe Völker, Stephen Hancock, Niels Grarup, Dennis O. Mook-Kanamori, Mariza de Andrade, Caroline Dale, N. Charlotte Onland-Moret, David R. Crosslin, Meena Kumari, Erik Ingelsson, Michael V. Holmes, Spiros Denaxas, Sudha Seshadri, Kees Hovingh, Marcus Dörr, Paul M. Ridker, Stefan Coassin, Albert Hofman, Andrew N. Nicolaides, Oluf Pedersen, Philippe Froguel, Simonetta Guarrera, Murray H. Brilliant, Sara E. Dobbins, Salim Yusuf, Kari Hemminki, Erik P A Van Iperen, Abbas Dehghan, Jill P. Pell, Alexander Teumer, Peter W. Schofield, Aroon D. Hingorani, Dan Mason, Amand F. Schmidt, Rui Bebiano Da Providencia E Costa, James M. Allan, Leslie A. Lange, Niels Weinhold, Stefan Gustafsson, Jackie F. Price, Mika Kivimäki, Hynek Pikhart, Kirchner H. Lester, Lars Lind, Philip J. Law, Cara L. Carty, David Preiss, Richard S. Houlston, Robin Young, Tom W. Meade, Martin O'Donnell, Alexander P. Reiner, Ni Li, Oscar H. Franco, Zammy Fairhurst-Hunter, Ronan Roussel, Tim Christen, Ilja Demuth, David Carrell, Catherine A. McCarty, Juan P. Casas, Johann Willeit, Peter H. Whincup, Stela McLachlan, Adelaida Sanchez-Galvez, Hartmut Goldschmidt, Guillaume Paré, Harry Hemingway, Anubha Mahajan, Elisabeth Steinhagen-Thiessen, Elizabeth G. Holliday, Giuseppe Matullo, Henry Völzke, Ian Ford, Martin Bobak, Pedro Marques-Vidal, Bertrand Cariou, Bernardo L. Horta, Melissa L. Bondy, Goya Wanamethee, Naveed Sattar, Steve E. Humphries, Marylyn D. Ritchie, Kristina Norman, Carlotta Sacerdote, Giovanni Fiorito, Sebastian E. Baumeister, Amit Sud, Dennis Valentine, Andreas Engert, Juri Demuth, Rupert Faraway, Abdonas Tamosiunas, Andrie G. Panayiotou, Terrie Kitchner, Lars Bertram, Sandosh Padmanabhan, Sofia Malyutina, Anke H. Maitland-van der Zee, Alex J. Cornish, Joshua C. Denny, Jian'an Luan, Robert A. Scott, Daniel I. Swerdlow, John Attia, Karin Willeit, Gareth J. Morgan, Michael Chong, Ruben N. Eppinga, Elina Hyppönen, Ekaterina V. Baranova, Jackie A. Cooper, Ghazaleh Fatemifar, Niek Verweij, Max Moldovan, Brendan J. Keating, M. Abdullah Said, Markus M. Lerch, Christina M. Lill, Markus Hansson, Jemma C. Hopewell, Björn Nilsson, Folkert W. Asselbergs, Ruzena Kubinova, Molly Went, Nicholas J. Wareham, Stefan Kiechl, Yanchun Bao, Allan Linneberg, Matthias Simon, Epidemiology and Data Science, Pulmonology, Paediatric Pulmonology, APH - Personalized Medicine, AII - Inflammatory diseases, AII - Cancer immunology, CCA - Cancer biology and immunology, Ear, Nose and Throat, Schmidt, Amand F, Holmes, Michael V, Preiss, David, Swerdlow, Daniel I, Hypponen, Elina, Dehghan, Abbas, Schmidt, Amand F [0000-0003-1327-0424], Apollo - University of Cambridge Repository, Lifelines Cohort, ICBP Consortium, METASTROKE Consortium of the ISGC, PharmacoTherapy, -Epidemiology and -Economics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Schmidt, Amand F. [0000-0003-1327-0424], Epidemiology, and Hematology
Subjects: Oncology, lcsh:Diseases of the circulatory (Cardiovascular) system, Genetic association studies, Proprotein Convertase 9/genetics, Apolipoprotein B, Anticholesteremic Agents/adverse effects, Myocardial Infarction, Blood lipids, Genome-wide association study, 030204 cardiovascular system & hematology, Coronary artery disease, Gastroenterology, Medical and Health Sciences, Stroke/epidemiology, Brain Ischemia, 0302 clinical medicine, Risk Factors, Dyslipidemias/blood, Medicine, LDL-cholesterol, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, Myocardial infarction, Mendelian randomisation, 1102 Cardiorespiratory Medicine and Haematology, Randomized Controlled Trials as Topic, Kardiologi, biology, Anticholesteremic Agents, PCSK9 Inhibitors, Single Nucleotide, 16. Peace & justice, LDL/blood, 3. Good health, Stroke, Cholesterol, Treatment Outcome, Cholesterol, LDL/blood, ICBP Consortium, Phenome-wide association scan, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Research Article, medicine.medical_specialty, Serine Proteinase Inhibitors, Down-Regulation, 610 Medicine & health, Single-nucleotide polymorphism, Placebo, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, Internal medicine, Genetic variation, Myocardial Infarction/epidemiology, Humans, Serine Proteinase Inhibitors/adverse effects, Polymorphism, Dyslipidemias, Genetic association, Lifelines Cohort authors, METASTROKE Consortium of the ISGC, business.industry, PCSK9, Cholesterol, LDL, Odds ratio, medicine.disease, Cardiovascular System & Hematology, lcsh:RC666-701, biology.protein, Brain Ischemia/epidemiology, Clinical Medicine, business, Biomarkers, Biomarkers/blood, Genome-Wide Association Study
Abstract: BackgroundWe characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.MethodsPublished and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Fourteen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentrationResultsThe PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95%CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95%CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95%CI 0.57; 1.22) for the GS, compared to 0.85 (95%CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95%CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable.ConclusionsGenetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. Apparent discordance between genetic associations and trial outcome for T2DM might be explained lack by a of statistical precision, or differences in the nature and duration of genetic versus pharmacological perturbation of PCSK9.FundingThis research was funded by the British Heart Foundation (SP/13/6/30554, RG/10/12/28456, FS/18/23/33512), UCL Hospitals NIHR Biomedical Research Centre, by the Rosetrees and Stoneygate Trusts.Condensed abstractEvidence on the long-term efficacy and safety of therapeutic inhibition of PCSK9 is lacking. To explore potential long-term effects of PCSK9 inhibition, we characterised the phenotypic consequence of LDL-cholesterol lowering variants at the PCSK9 locus. A PCSK9 gene score comprising 4 SNPs recapitulated the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and risk of myocardial infarction, and was associated with an increased risk of type 2 diabetes. No associations with safety outcomes such as cancer, COPD, Alzheimer’s disease or atrial fibrillation were identified. Our findings suggest PCSK9 inhibition may be safe and effective during prolonged use.
Published: 2019
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33. Supplementary tables and figures from Smoking does not accelerate leucocyte telomere attrition: a meta-analysis of 18 longitudinal cohorts

Author: Bateson, Melissa, Aviv, Abraham, Bendix, Laila, Benetos, Athanase, Ben-Shlomo, Yoav, Bojesen, Stig E., Cooper, Cyrus, Cooper, Rachel, Deary, Ian J., Hägg, Sara, Harris, Sarah E., Kark, Jeremy D., Kronenberg, Florian, Kuh, Diana, Labat, Carlos, Martin-Ruiz, Carmen M., Meyer, Craig, Nordestgaard, Børge G., Penninx, Brenda W. J. H., Pepper, Gillian V., Révész, Dóra, M. Abdullah Said, Starr, John M., Syddall, Holly, Thomson, William Murray, Harst, Pim Van Der, Whooley, Mary, Zglinicki, Thomas Von, Willeit, Peter, Yiqiang Zhan, and Nettle, Daniel
Abstract: Supplementary tables and figures
Published: 2019
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34. Lipidomics, Atrial Conduction, and Body Mass Index Evidence From Association, Mediation, and Mendelian Randomization Models

Author: Pim van der Harst, Andrew A. Hicks, Marcus Dörr, Peter P. Pramstaller, Luisa Foco, Niek Verweij, Maik Pietzner, Viviana Meraviglia, James F. Wilson, Harold Snieder, Alessandra Rossini, Werner Rauhe, Roberto Melotti, Peter K. Joshi, Harry Campbell, M. Abdullah Said, Yordi J. van de Vegte, Giuseppe Paglia, Stephan B. Felix, Alexander Teumer, Vladimir Vukovic, Alan F. Wright, Fabiola Del Greco M, Ayse Demirkan, Cristian Pattaro, Erasmus MC other, Epidemiology, Del Greco M, F, Foco, L, Teumer, A, Verweij, N, Paglia, G, Meraviglia, V, Melotti, R, Vukovic, V, Rauhe, W, Joshi, P, Demirkan, A, Felix, S, Pietzner, M, Said, M, van de Vegte, Y, van der Harst, P, Wright, A, Hicks, A, Campbell, H, Dorr, M, Snieder, H, Wilson, J, Pramstaller, P, Rossini, A, and Pattaro, C
Subjects: 0301 basic medicine, medicine.medical_specialty, Population, Genome-wide association study, body mass index, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Lipidomics, Mendelian randomization, medicine, phosphatidylcholine 38:3, education, Genetic association, mass spectrometry, Mendelian randomization analysi, education.field_of_study, genome-wide association study, Cholesterol, business.industry, Mendelian Randomization Analysis, General Medicine, 030104 developmental biology, chemistry, Cardiology, business, Body mass index
Abstract: Background: Lipids are increasingly involved in cardiovascular risk prediction as potential proarrhythmic influencers. However, knowledge is limited about the specific mechanisms connecting lipid alterations with atrial conduction. Methods: To shed light on this issue, we conducted a broad assessment of 151 sphingo- and phospholipids, measured using mass spectrometry, for association with atrial conduction, measured by P wave duration (PWD) from standard electrocardiograms, in the MICROS study (Microisolates in South Tyrol) (n=839). Causal pathways involving lipidomics, body mass index (BMI), and PWD were assessed using 2-sample Mendelian randomization analyses based on published genome-wide association studies of lipidomics (n=4034) and BMI (n=734 481), and genetic association analysis of PWD in 5 population-based studies (n=24 236). Results: We identified an association with relative phosphatidylcholine 38:3 (%PC 38:3) concentration, which was replicated in the ORCADES (Orkney Complex Disease Study; n=951), with a pooled association across studies of 2.59 (95% CI, 1.3–3.9; P =1.1×10 −4 ) ms PWD per mol% increase. While being independent of cholesterol, triglycerides, and glucose levels, the %PC 38:3-PWD association was mediated by BMI. Results supported a causal effect of BMI on both PWD ( P =8.3×10 −5 ) and %PC 38:3 ( P =0.014). Conclusions: Increased %PC 38:3 levels are consistently associated with longer PWD, partly because of the confounding effect of BMI. The causal effect of BMI on PWD reinforces evidence of BMI’s involvement into atrial electrical activity.
Published: 2019
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35. Relationship of Arterial Stiffness Index and Pulse Pressure With Cardiovascular Disease and Mortality

Author: Niek Verweij, Erik Lipsic, Pim van der Harst, M. Abdullah Said, Ruben N. Eppinga, and Cardiovascular Centre (CVC)
Subjects: Male, Aging, Time Factors, Epidemiology, PREDICTION, Blood Pressure, Disease, 030204 cardiovascular system & hematology, 0302 clinical medicine, Risk Factors, cardiovascular disease, Cause of Death, FAILURE, 030212 general & internal medicine, Myocardial infarction, Stroke, Original Research, Age Factors, Middle Aged, Prognosis, 3. Good health, Pulse pressure, arterial stiffness, Cardiovascular Diseases, Cardiology, Female, Mortality/Survival, Cardiology and Cardiovascular Medicine, STROKE, Adult, UK Biobank, medicine.medical_specialty, Risk Assessment, EVENTS, WAVE VELOCITY, 03 medical and health sciences, Vascular Stiffness, RISK-FACTOR, Photoplethysmogram, Internal medicine, medicine, Humans, CORONARY-HEART-DISEASE, Risk factor, Photoplethysmography, Aged, HYPERTENSION, business.industry, pulse pressure, medicine.disease, mortality, United Kingdom, cardiovascular outcomes, Blood pressure, MYOCARDIAL-INFARCTION, Arterial stiffness, business, SYSTOLIC BLOOD-PRESSURE
Abstract: Background Vascular aging results in stiffer arteries and may have a role in the development of cardiovascular disease ( CVD ). Arterial stiffness index ( ASI ), measured by finger photoplethysmography, and pulse pressure ( PP ) are 2 independent vascular aging indices. We investigated whether ASI or PP predict new‐onset CVD and mortality in a large community‐based population. Methods and Results We studied 169 613 UK Biobank participants (mean age 56.8 years; 45.8% males) who underwent ASI measurement and blood pressure measurement for PP calculation. Mean± SD ASI was 9.30±3.1 m/s and mean± SD PP was 50.98±13.2 mm Hg. During a median disease follow‐up of 2.8 years (interquartile range 1.4–4.0), 18 190 participants developed CVD , of which 1587 myocardial infarction ( MI ), 4326 coronary heart disease, 1192 heart failure, and 1319 stroke. During a median mortality follow‐up of 6.1 years (interquartile range 5.8–6.3), 3678 participants died, of which 1180 of CVD . Higher ASI was associated with increased risk of overall CVD (unadjusted hazard ratio 1.27; 95% confidence interval [ CI ], 1.25–1.28), myocardial infarction (1.38; 95% CI , 1.32–1.44), coronary heart disease (1.31; 95% CI , 1.27–1.34), and heart failure (1.31; 95% CI 1.24–1.37). ASI also predicted mortality (all‐cause, CVD , other). Higher PP was associated with overall CVD (1.57; 95% CI , 1.55–1.59), myocardial infarction (1.48; 95% CI , 1.42–1.54), coronary heart disease (1.47; 95% CI , 1.43–1.50), heart failure (1.47; 95% CI , 1.40–1.55), and CVD mortality (1.47; 95% CI , 1.40–1.55). PP improved risk reclassification of CVD in a non–laboratory‐based Framingham Risk Score by 5.4%, ASI by 2.3%. Conclusions ASI and PP are independent predictors of CVD and mortality outcomes. Although both improved risk prediction for new‐onset disease, PP appears to have a larger clinical value than ASI .
Published: 2018
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36. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

Author: Rico Rueedi, Yuri Milaneschi, Brenda W.J.H. Penninx, Neil Poulter, Karen Schwander, Marco Brumat, Kenneth Rice, Yize Li, Veronique Vitart, Ioanna Ntalla, Michele K. Evans, Jeffrey R. O'Connell, Nilesh J. Samani, Colleen M. Sitlani, W. James Gauderman, Xuan Deng, Paul M. Ridker, Yun J. Sung, Yukihide Momozawa, Archie Campbell, Tin Louie, Nona Sotoodehnia, Yii-Der Ida Chen, Cornelia M. van Duijn, Tanika N. Kelly, Peter S. Sever, André G. Uitterlinden, Brigitte Kühnel, John M. Starr, Lawrence F. Bielak, Christopher P. Nelson, Wanqing Wen, Stephan B. Felix, Stefan Weiss, Daniel Levy, Nicholette D. Palmer, Alisa K. Manning, Salman M. Tajuddin, Jill M. Norris, Marie Loh, M. Abdullah Said, Alena Stančáková, Anuradhani Kasturiratne, John M. C. Connell, Jian'an Luan, Tuomas O. Kilpeläinen, Amy R. Bentley, Stephen Sidney, Alan B. Zonderman, Karin Leander, David J. Porteous, Jianjun Liu, Tin Aung, Charles B. Eaton, Sharon L.R. Kardia, Rajkumar Dorajoo, Stephen Turner, Michael Boehnke, Diane M. Becker, Cora E. Lewis, Ozren Polasek, Mickaël Canouil, Kurt Lohman, Georg Ehret, Sarah E. Harris, Robert A. Scott, Claude Bouchard, Lynne E. Wagenknecht, Mohsen Ghanbari, Stephen B. Kritchevsky, Jin-Fang Chai, Gregory L. Burke, Jiang He, Federica Laguzzi, Michael R. Brown, Walter Palmas, Lili Milani, Thomas T. Perls, Tibor V. Varga, José Eduardo Krieger, Erin B. Ware, Tamara B. Harris, Tomohiro Katsuya, Nicole Schupf, Mika Kähönen, Nana Matoba, Hugues Aschard, Ilaria Gandin, Jennifer A. Smith, Traci M. Bartz, James Scott, Tuomo Rankinen, Yuan Shi, Meian He, Timo A. Lakka, Helen R. Warren, Mike A. Nalls, Kent D. Taylor, Woon-Puay Koh, Ya Xing Wang, Muhammad Riaz, Sandosh Padmanabhan, Mary F. Feitosa, Jost B. Jonas, Paul Elliott, Christian Gieger, Terho Lehtimäki, Kaare Christensen, Maris Alver, Pirjo Komulainen, Pamela J. Schreiner, M. Arfan Ikram, David R. Weir, Charles Kooperberg, Oscar H. Franco, Yongmei Liu, Lisa de las Fuentes, Nancy L. Pedersen, Thomas W. Winkler, Bruna Gigante, Göran Hallmans, Ingrid B. Borecki, Shiow Lin, Ian J. Deary, Wei Zheng, Yajuan Wang, Bernardo L. Horta, Heather M. Stringham, Bruce M. Psaty, Paul W. Franks, Weihua Zhang, Nora Franceschini, Adolfo Correa, Nita G. Forouhi, Xiuqing Guo, Fumihiko Takeuchi, L. Adrienne Cupples, William R. Scott, Zoltán Kutalik, He Gao, Nicholas J. Wareham, E. Shyong Tai, Aravinda Chakravarti, C. Charles Gu, Paolo Gasparini, Albertine J. Oldehinkel, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Colin A. McKenzie, Qing Duan, Aldi T. Kraja, Carsten Oliver Schmidt, Bamidele O. Tayo, Xiaofeng Zhu, Thomas Meitinger, Mary K. Wojczynski, Markku Laakso, Mark J. Caulfield, Carl D. Langefeld, Jingzhong Ding, Yechiel Friedlander, Tien Yin Wong, Virginia Fisher, Raymond Noordam, Caizheng Yu, Pim van der Harst, Yik Ying Teo, Ervin R. Fox, Sabanayagam Charumathi, Jonathan Marten, Nicholas Y.Q. Tan, Jerome I. Rotter, Harold Snieder, Karen L. Mohlke, Christine Williams, Olli T. Raitakari, Renée de Mutsert, Lihua Wang, Kathryn Roll, Jingmin Liu, Dongfeng Gu, Wei Zhao, Lynda M. Rose, Michael A. Province, Fernando Pires Hartwig, Rob M. van Dam, Barry I. Freedman, Andres Metspalu, Donald W. Bowden, Andrea R. V. R. Horimoto, Martin Farrall, Frits R. Rosendaal, Rainer Rauramaa, Konstantin Strauch, Albert V. Smith, Yanick Hagemeijer, Michiaki Kubo, Ilja M. Nolte, Tõnu Esko, Yih Chung Tham, Cathy C. Laurie, Antonietta Robino, Anne U. Jackson, Chuan Gao, Dabeeru C. Rao, Xiao-Ou Shu, H. Janaka de Silva, Morris J. Brown, Alanna C. Morrison, Peter J. van der Most, Jian-Min Yuan, Melanie Waldenberger, Leslie J. Raffel, Ulrich John, Fang-Chi Hsu, Reedik Mägi, Solomon K. Musani, Chiea Chuen Khor, Mario Sims, Ruben N. Eppinga, Melissa A. Richard, Yoichiro Kamatani, Changwei Li, Qiuyin Cai, Daniel I. Chasman, Mathilde Boissel, Claudia Langenberg, Sami Heikkinen, Jasmin Divers, Saima Afaq, Wen Bin Wei, Jaspal S. Kooner, Terrence Forrester, Hua Tang, Charles N. Rotimi, Anuj Goel, Annette Peters, Tangchun Wu, Dennis O. Mook-Kanamori, Caroline Hayward, Ching-Yu Cheng, Lisa R. Yanek, Ananda R. Wickremasinghe, Chew-Kiat Heng, Myriam Fornage, Dina Vojinovic, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Jing Hua Zhao, Barbara V. Howard, Vilmundur Gudnason, Ulrich Broeckel, Eric Boerwinkle, Saskia P. Hagenaars, Dan E. Arking, Peter Vollenweider, Alexandre C. Pereira, Jie Yao, Makoto Hirata, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Marzyeh Amini, Benjamin Lehne, Epidemiology, Erasmus MC other, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), University of Regensburg, Queen Mary University of London (QMUL), Harbor UCLA Medical Center [Torrance, Ca.], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Northwestern Polytechnical University [Xi'an] (NPU), Centre for Molecular Epidemiology, National University of Singapore (NUS), Harvard School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), National Institutes of Health [Bethesda] (NIH), The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., AGES (Age Gene/Environment Susceptibility Reykjavik Study) is approved by the Icelandic National Bioethics Committee, VSN: 00–063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC (Atherosclerosis Risk in Communities): The authors thank the staff and participants of the ARIC study for their important contributions. CARDIA (Coronary Artery Risk Development in Young Adults): This manuscript has been reviewed and approved by CARDIA for scientific content. CHS (Cardiovascular Health Study): A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. IGMM (Institute of Genetics and Molecular Medicine): CROATIA-Korcula: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools and the Croatian Institute for Public Health. We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the participants. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. CROATIA-Vis: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. GS:SFHS: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland. ERF (Erasmus Rucphen Family study): We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work, P. Snijders for his help in data collection and E.M. van Leeuwen for genetic imputation. GENOA (Genetic Epidemiology Network of Arteriopathy): Genotyping was performed at the Mayo Clinic (Stephen T. Turner, MD, Mariza de Andrade PhD, Julie Cunningham, PhD). We thank Eric Boerwinkle, PhD and Megan L. Grove from the Human Genetics Center and Institute of Molecular Medicine and Division of Epidemiology, University of Texas Health Science Center, Houston, Texas, USA for their help with genotyping. We would also like to thank the families that participated in the GENOA study. HANDLS (Healthy Aging in Neighborhoods of Diversity across the Life Span): Data analyses for the HANDLS study utilized the high-performance computational resources of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. http://hpc.nih.gov HUFS (Howard University Family Study): We thank the participants of the study. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. HyperGEN (Hypertension Genetic Epidemiology Network): The study involves: University of Utah: (Network Coordinating Center, Field Center, and Molecular Genetics Lab), Univ. of Alabama at Birmingham: (Field Center and Echo Coordinating and Analysis Center), Medical College of Wisconsin: (Echo Genotyping Lab), Boston University: (Field Center), University of Minnesota: (Field Center and Biochemistry Lab), University of North Carolina: (Field Center), Washington University: (Data Coordinating Center), Weil Cornell Medical College: (Echo Reading Center), National Heart, Lung, & Blood Institute. For a complete list of HyperGEN Investigators: http://www.biostat.wustl.edu/hypergen/Acknowledge.html JHS (Jackson Heart Study): The authors wish to thank the staffs and participants of the JHS. MESA (Multi-Ethnic Study of Atherosclerosis): MESA and the MESA SHARe project are conducted in collaboration with MESA investigators. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. NEO (The Netherlands Epidemiology of Obesity study): The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group, Petra Noordijk, Pat van Beelen and Ingeborg de Jonge for the coordination, lab and data management of the NEO study. RS (Rotterdam Study) was funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters and Carolina Medina-Gomez for their help in creating the GWAS database, and Karol Estrada, Yurii Aulchenko and Carolina Medina-Gomez for the creation and analysis of imputed data. WHI (Women’s Health Initiative): The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf Replication: AA-DHS (African American Diabetes Heart Study): The investigators acknowledge the cooperation of our Diabetes Heart Study (DHS) and AA-DHS participants. ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial): We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular, we thank Clare Muckian and David Toomey for their help in DNA extraction, storage, and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome chip array. P.B.M, M.J.C and H.R.W wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Centre at Barts and Queen Mary University of London, UK. BBJ (Biobank Japan Project): We thank all the participants, medical coordinators of the cooperating hospitals for collecting samples and clinical information in the project. BRIGHT (British Genetics of Hypertension): The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. P.B.M, M.J.C and H.R.W wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Centre at Barts and Queen Mary University of London, UK. CoLaus (Cohorte Lausannoise Study): The authors would like to thank all the people who participated in the recruitment of the participants, data collection and validation, particularly Nicole Bonvin, Yolande Barreau, Mathieu Firmann, François Bastardot, Julien Vaucher, Panagiotis Antiochos and Cédric Gubelmann. DESIR (Data from an Epidemiological Study on the Insulin Resistance): The DESIR Study Group is composed of Inserm-U1018 (Paris: B. Balkau, P. Ducimetière, E. Eschwège), Inserm-U367 (Paris: F. Alhenc-Gelas), CHU d’Angers (A. Girault), Bichat Hospital (Paris: F. Fumeron, M. Marre, R. Roussel), CHU de Rennes (F. Bonnet), CNRS UMR-8199 (Lille: A. Bonnefond, P. Froguel), Medical Examination Services (Alençon, Angers, Blois, Caen, Chartres, Chateauroux, Cholet, LeMans, Orléans and Tours), Research Institute for General Medicine (J. Cogneau), the general practitioners of the region and the Cross- Regional Institute for Health (C. Born, E. Caces, M. Cailleau, N. Copin, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol). DHS (Diabetes Heart Study): The authors thank the investigators, staff, and participants of the DHS for their valuable contributions. EGCUT Estonian Genome Center—University of Tartu (Estonian Biobank): Data analyzes were carried out in part in the High Performance Computing Center of University of Tartu. EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk: We thank all EPIC participants and staff for their contribution to the study. FENLAND (The Fenland Study): We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. We further acknowledge support from the Medical research council (MC_UU_12015/1). GeneSTAR (Genetic Studies of Atherosclerosis Risk): We are very grateful to all of our participants for their long-term involvement. GLACIER (Gene x Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk): We thank the participants, health professionals and data managers involved in the Västerbottens Intervention Project. We are also grateful to the staff of the Northern Sweden Biobank for preparing materials and to K Enqvist and T Johansson (Västerbottens County Council, Umeå, Sweden) for DNA preparation. HCHS/SOL (Hispanic Community Health Study/Study of Latinos): We thank the participants and staff of the HCHS/SOL study for their contributions to this study. HRS (Health & Retirement Study): Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington. HyperGEN-AXIOM (Hypertension Genetic Epidemiology Network—Axiom Chip GWAS): We thank the study investigators, staff and participants for their value contributions. INGI (Italian Network Genetic Isolate): We thank all the inhabitants who participated to the projects. InterAct (The EPIC-InterAct Case-Cohort Study): We thank all EPIC participants and staff for their contribution to the study. IRAS (Insulin Resistance Atherosclerosis Study): The authors thank study investigators, staff, and participants for their valuable contributions. KORA (Cooperative Health Research in the Augsburg Region): We thank all KORA participants and staff for their contribution to the study. LBC1921 (Lothian Birth Cohort 1921): We thank the LBC1921 cohort participants and team members who contributed to these studies. Funding from the Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. LBC1936 (Lothian Birth Cohort 1936): We thank the LBC1936 cohort participants and team members who contributed to these studies. Funding from the Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. LifeLines (Lifelines Cohort Study): The authors wish to acknowledge the services of the Lifelines, the contributing research centers delivering data to Lifelines, and all the study participants. The authors wish to acknowledge the services of the Lifelines, the contributing research centers delivering data to Lifelines, and all the study participants. Also, Lifelines acknowledges the contributions from Behrooz Z Alizadeh (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), H Marike Boezen (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), Lude Franke (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands), Pim van der Harst (Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands), Gerjan Navis (Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands), Marianne Rots (Department of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands), Harold Snieder (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), Morris Swertz (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands), Bruce HR Wolffenbuttel (Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands), Cisca Wijmenga (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands). LLFS (Long Life Family Study): The LLFS would like to thank the participants and research staff who make the study possible. LOLIPOP (London Life Sciences Prospective Population Study): We acknowledge support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR or the Department of Health. We thank the participants and research staff who made the study possible. PROCARDIS (Precocious Coronary Artery Disease): The PROCARDIS researchers thank the patients for their selfless participation in this project. RHS (Ragama Health Study): The RHS was supported by the Grant of National Center for Global Health and Medicine (NCGM), Japan. SWHS/SMHS (Shanghai Women's Health Study/ Shanghai Men's Health Study): We thank all the individuals who took part in these studies and all the researchers who have enabled this work to be carried out. TRAILS (TRacking Adolescents’ Individual Lives Survey): TRAILS is a collaborative project involving various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. We are grateful to all adolescents who participated in this research and to everyone who worked on this project and made it possible. UKB (United Kingdom Biobank, www.ukbiobank.ac.uk): This research has been conducted using the UK Biobank Resource. The UK Biobank data were analyzed from the data set corresponding to UK Biobank access application no. 236, application title 'Genome-wide association study of blood pressure', with Paul Elliott as the PI/applicant. This work was supported by the UK-CMC and the BP working group., InterAct Consortium, Marten, Jonathan [0000-0001-6916-2014], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Lee Kong Chian School of Medicine (LKCMedicine), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Feitosa, Mary F., Kraja, Aldi T., Chasman, Daniel I., Sung, Yun J., Winkler, Thomas W., Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Bentley, Amy R., Brown, Michael R., Schwander, Karen, Richard, Melissa A., Noordam, Raymond, Aschard, Hugue, Bartz, Traci M., Bielak, Lawrence F., Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P., Horimoto, Andrea R. V. R., Lohman, Kurt K., Manning, Alisa K., Rankinen, Tuomo, Smith, Albert V., Tajuddin, Salman M., Wojczynski, Mary K., Alver, Mari, Boissel, Mathilde, Cai, Qiuyin, Campbell, Archie, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Jackson, Anne U., Kähönen, Mika, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Luan, Jian'An, Matoba, Nana, Nolte, Ilja M., Padmanabhan, Sandosh, Riaz, Muhammad, Rueedi, Rico, Robino, Antonietta, Said, M. Abdullah, Scott, Robert A., Sofer, Tamar, Stančáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O., Van Der Most, Peter J., Varga, Tibor V., Vitart, Veronique, Wang, Yajuan, Ware, Erin B., Warren, Helen R., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E., Aung, Tin, Boerwinkle, Eric, Borecki, Ingrid, Broeckel, Ulrich, Brown, Morri, Brumat, Marco, Burke, Gregory L., Canouil, Mickaël, Chakravarti, Aravinda, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M., Correa, Adolfo, De Las Fuentes, Lisa, De Mutsert, Renée, De Silva, H. Janaka, Deng, Xuan, Ding, Jingzhong, Duan, Qing, Eaton, Charles B., Ehret, Georg, Eppinga, Ruben N., Evangelou, Evangelo, Faul, Jessica D., Felix, Stephan B., Forouhi, Nita G., Forrester, Terrence, Franco, Oscar H., Friedlander, Yechiel, Gandin, Ilaria, Gao, He, Ghanbari, Mohsen, Gigante, Bruna, Gu, C. Charle, Gu, Dongfeng, Hagenaars, Saskia P., Hallmans, Göran, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Howard, Barbara V., Ikram, M. Arfan, John, Ulrich, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Krieger, José E., Kritchevsky, Stephen B., Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lin, Shiow, Liu, Jianjun, Liu, Jingmin, Loh, Marie, Louie, Tin, Mägi, Reedik, Mckenzie, Colin A., Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L., Momozawa, Yukihide, Nalls, Mike A., Nelson, Christopher P., Sotoodehnia, Nona, Norris, Jill M., O'Connell, Jeff R., Palmer, Nicholette D., Perls, Thoma, Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Poulter, Neil, Raffel, Leslie J., Raitakari, Olli T., Roll, Kathryn, Rose, Lynda M., Rosendaal, Frits R., Rotter, Jerome I., Schmidt, Carsten O., Schreiner, Pamela J., Schupf, Nicole, Scott, William R., Sever, Peter S., Shi, Yuan, Sidney, Stephen, Sims, Mario, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Stringham, Heather M., Tan, Nicholas Y. Q., Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Turner, Stephen T., Uitterlinden, André G., Vollenweider, Peter, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Williams, Christine, Yao, Jie, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Deary, Ian J., Esko, Tõnu, Farrall, Martin, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Jonas, Jost Bruno, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S., Kutalik, Zoltán, Laakso, Markku, Laurie, Cathy C., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K. E., Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Polasek, Ozren, Porteous, David J., Rauramaa, Rainer, Samani, Nilesh J., Scott, Jame, Shu, Xiao-Ou, Van Der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Bouchard, Claude, Christensen, Kaare, Evans, Michele K., Gudnason, Vilmundur, Horta, Bernardo L., Kardia, Sharon L. R., Liu, Yongmei, Pereira, Alexandre C., Psaty, Bruce M., Ridker, Paul M., Van Dam, Rob M., Gauderman, W. Jame, Zhu, Xiaofeng, Mook-Kanamori, Dennis O., Fornage, Myriam, Rotimi, Charles N., Cupples, L. Adrienne, Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, Van Duijn, Cornelia M., Tai, E. Shyong, Wong, Tien Yin, Kooperberg, Charle, Palmas, Walter, Rice, Kenneth, Morrison, Alanna C., Elliott, Paul, Caulfield, Mark J., Munroe, Patricia B., Rao, Dabeeru C., Province, Michael A., Levy, Daniel, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Surgery, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, and Ehret, Georg Benedikt
Subjects: Genetics and Molecular Biology (all), Male, Erfðagreining, Áfengissýki, LOCI, Social Sciences, Blood Pressure, Genome-wide association study, Biochemistry, Vascular Medicine, TRANSCRIPTION FACTOR GATA4, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), DEPENDENCE, HEPATOCELLULAR-CARCINOMA, 80 and over, Psychology, Public and Occupational Health, Alcohol consumption, Cardiac and Cardiovascular Systems, Gene–environment interaction, ddc:616, Aged, 80 and over, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, Kardiologi, MESH: Polymorphism, Single Nucleotide, Áfengisneysla, MESH: Gene-Environment Interaction, COMMON VARIANTS, Genomics, MESH: Blood Pressure, Pedigree, 3. Good health, Näringslära, MESH: Young Adult, Physical Sciences, Medicine, Medical genetics, Erfðarannsóknir, Statistics (Mathematics), medicine.medical_specialty, Blood Pressure/genetics, Alcohol Drinking, MESH: Pedigree, Science, Genetic loci, ta3111, Genome Complexity, 03 medical and health sciences, Gene mapping, Genetics, Humans, Polymorphism, Statistical Methods, GENOME-WIDE ASSOCIATION, Molecular Biology Techniques, Molecular Biology, Alleles, Aged, MESH: Adolescent, MESH: Humans, Adolescent, Adult, Alcohol Drinking/epidemiology, Alcohol Drinking/genetics, Cohort Studies, Continental Population Groups/genetics, Continental Population Groups/statistics & numerical data, Female, Gene-Environment Interaction, Genetic Predisposition to Disease/epidemiology, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Hypertension/epidemiology, Hypertension/genetics, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Gene Mapping, Racial Groups, ta1182, Biology and Life Sciences, Computational Biology, MESH: Adult, Meta-analysis, 030104 developmental biology, Genetic Loci, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Female, Mathematics, MESH: Alcohol Drinking, Meta-Analysis, 0301 basic medicine, MESH: Continental Population Groups, MESH: Hypertension, Mathematical and Statistical Techniques, MESH: Aged, 80 and over, Polymorphism (computer science), Medicine and Health Sciences, FUNCTIONAL VARIATION, MESH: Cohort Studies, MESH: Aged, Alcohol Consumption, Multidisciplinary, Nutrition and Dietetics, MESH: Genetic Predisposition to Disease, Genetic Predisposition to Disease/epidemiology/genetics, Single Nucleotide, Blóðþrýstingur, ENVIRONMENT INTERACTION, PTP4A1-PHF3-EYS VARIANTS, Alcoholism, ANCESTRAIS, Háþrýstingur, Hypertension, Blood pressure, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Medical Genetics, Research Article, Substance-Related Disorders, Addiction, RISK, METAANALYSIS, Research and Analysis Methods, Mental Health and Psychiatry, medicine, Medicine [Science], Genetic Predisposition to Disease, Allele, Hypertension/epidemiology/genetics, Nutrition, Medicinsk genetik, Continental Population Groups/genetics/statistics & numerical data, business.industry, Alcohol Drinking/epidemiology/genetics, Genetic architecture, MESH: Male, Introns, Diet, BODY-MASS INDEX, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Publisher's version (útgefin grein)., Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension., The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2018
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37. Genetically Determined Physical Activity and Its Association with Circulating Blood Cells

Author: Niek Verweij, Yordi J. van de Vegte, Femke M. Prins, Pim van der Harst, Hilde E. Groot, M. Abdullah Said, and Cardiovascular Centre (CVC)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, lcsh:QH426-470, Physical activity, physical activity, Inflammation, Single-nucleotide polymorphism, Disease, Systemic inflammation, Polymorphism, Single Nucleotide, Article, single nucleotide polymorphisms, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Eosinophilia, Mendelian randomization, Genetics, medicine, Humans, Exercise, Genetics (clinical), Aged, business.industry, Mendelian Randomization Analysis, Middle Aged, Blood Cell Count, blood cell counts, lcsh:Genetics, 030104 developmental biology, Increased risk, Endocrinology, inflammation, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Lower levels of physical activity (PA) have been associated with increased risk of cardiovascular disease. Worldwide, there is a shift towards a lifestyle with less PA, posing a serious threat to public health. One of the suggested mechanisms behind the association between PA and disease development is through systemic inflammation, in which circulating blood cells play a pivotal role. In this study we investigated the relationship between genetically determined PA and circulating blood cells. We used 68 single nucleotide polymorphisms associated with objectively measured PA levels to perform a Mendelian randomization analysis on circulating blood cells in 222,645 participants of the UK Biobank. For inverse variance fixed effects Mendelian randomization analyses, p &lt, 1.85 &times, 10&minus, 3 (Bonferroni-adjusted p-value of 0.05/27 tests) was considered statistically significant. Genetically determined increased PA was associated with decreased lymphocytes (&beta, = &ndash, 0.03, SE = 0.008, p = 1.35 &times, 3) and decreased eosinophils (&beta, 0.008, SE = 0.002, p = 1.36 &times, 3). Although further mechanistic studies are warranted, these findings suggest increased physical activity is associated with an improved inflammatory state with fewer lymphocytes and eosinophils.
Published: 2019
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38. Telomere Length and Risk of Cardiovascular Disease and Cancer

Author: Pim van der Harst, M. Abdullah Said, Yanick Hagemeijer, Niek Verweij, Ruben N. Eppinga, and Cardiovascular Centre (CVC)
Subjects: Male, Letter, Cell division, Disease, 030204 cardiovascular system & hematology, medicine.disease_cause, Risk Assessment, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Neoplasms, Databases, Genetic, Prevalence, medicine, Humans, Mortality, business.industry, Telomere Homeostasis, Cancer, Mendelian Randomization Analysis, Middle Aged, Telomere, medicine.disease, United Kingdom, Cell biology, chemistry, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Female, Cardiology and Cardiovascular Medicine, business, Sequence Analysis, Oxidative stress, DNA
Abstract: Telomeres are DNA repeat structures with protein complexes capping the ends of chromosomes important for chromosomal stability and cellular integrity [(1)][1]. Telomeres shorten with each cell division and under environmental conditions such as oxidative stress. Therefore, telomere length (TL) has
Published: 2017
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39. Associations of Combined Genetic and Lifestyle Risks With Incident Cardiovascular Disease and Diabetes in the UK Biobank Study

Author: Niek Verweij, M. Abdullah Said, Pim van der Harst, and Cardiovascular Centre (CVC)
Subjects: Adult, Male, 0301 basic medicine, Health Behavior, Population, Coronary Artery Disease, Type 2 diabetes, Disease, 030204 cardiovascular system & hematology, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Diabetes mellitus, Atrial Fibrillation, medicine, Humans, Genetic Predisposition to Disease, education, Exercise, Life Style, Aged, Biological Specimen Banks, Proportional Hazards Models, Original Investigation, education.field_of_study, Proportional hazards model, business.industry, Incidence, Smoking, Hazard ratio, Middle Aged, medicine.disease, United Kingdom, Diet, Stroke, 030104 developmental biology, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Hypertension, Female, Gene-Environment Interaction, Cardiology and Cardiovascular Medicine, business, Demography, Cohort study
Abstract: Importance: Genetic and lifestyle factors both contribute to the risk of developing cardiovascular disease, but whether poor health behaviors are associated with similar increases in risk among individuals with low, intermediate, or high genetic risk is unknown.Objective: To investigate the association of combined health behaviors and factors within genetic risk groups with coronary artery disease, atrial fibrillation, stroke, hypertension, and type 2 diabetes as well as to investigate the interactions between genetic risk and lifestyle.Design, Setting, and Participants: The UK Biobank cohort study includes more than 500 000 participants aged 40 to 70 years who were recruited from 22 assessment centers across the United Kingdom from 2006 to 2010. A total of 339 003 unrelated individuals of white British descent with available genotype and matching genetic data and reported sex were included in this study from the UK Biobank population-based sample. Individuals were included in the analyses of 1 or more new-onset diseases. Data were analyzed from April 2006 to March 2015.Main Outcomes and Measures: Risks of new-onset cardiovascular disease and diabetes associated with genetic risk and combined health behaviors and factors. Genetic risk was categorized as low (quintile 1), intermediate (quintiles 2-4), or high (quintile 5). Within each genetic risk group, the risks of incident events associated with ideal, intermediate, or poor combined health behaviors and factors were investigated and compared with low genetic risk and ideal lifestyle.Results: Of 339 003 individuals, 181 702 (53.6%) were female, and the mean (SD) age was 56.86 (7.99) years. During follow-up, 9771 of 325 133 participants (3.0%) developed coronary artery disease, 7095 of 333 637 (2.1%) developed atrial fibrillation, 3145 of 332 971 (0.9%) developed stroke, 11 358 of 234 651 (4.8%) developed hypertension, and 4379 of 322 014 (1.4%) developed diabetes. Genetic risk and lifestyle were independent predictors of incident events, and there were no interactions for any outcome. Compared with ideal lifestyle in the low genetic risk group, poor lifestyle was associated with a hazard ratio of up to 4.54 (95% CI, 3.72-5.54) for coronary artery disease, 5.41 (95% CI, 4.29-6.81) for atrial fibrillation, 4.68 (95% CI, 3.85-5.69) for hypertension, 2.26 (95% CI, 1.63-3.14) for stroke, and 15.46 (95% CI, 10.82-22.08) for diabetes in the high genetic risk group.Conclusions and Relevance: In this large contemporary population, genetic composition and combined health behaviors and factors had a log-additive effect on the risk of developing cardiovascular disease. The relative effects of poor lifestyle were comparable between genetic risk groups. Behavioral lifestyle changes should be encouraged for all through comprehensive, multifactorial approaches, although high-risk individuals may be selected based on the genetic risk.
Published: 2018
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40. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

Author: Mary F Feitosa, Aldi T Kraja, Daniel I Chasman, Yun J Sung, Thomas W Winkler, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon K Musani, Changwei Li, Amy R Bentley, Michael R Brown, Karen Schwander, Melissa A Richard, Raymond Noordam, Hugues Aschard, Traci M Bartz, Lawrence F Bielak, Rajkumar Dorajoo, Virginia Fisher, Fernando P Hartwig, Andrea R V R Horimoto, Kurt K Lohman, Alisa K Manning, Tuomo Rankinen, Albert V Smith, Salman M Tajuddin, Mary K Wojczynski, Maris Alver, Mathilde Boissel, Qiuyin Cai, Archie Campbell, Jin Fang Chai, Xu Chen, Jasmin Divers, Chuan Gao, Anuj Goel, Yanick Hagemeijer, Sarah E Harris, Meian He, Fang-Chi Hsu, Anne U Jackson, Mika Kähönen, Anuradhani Kasturiratne, Pirjo Komulainen, Brigitte Kühnel, Federica Laguzzi, Jian'an Luan, Nana Matoba, Ilja M Nolte, Sandosh Padmanabhan, Muhammad Riaz, Rico Rueedi, Antonietta Robino, M Abdullah Said, Robert A Scott, Tamar Sofer, Alena Stančáková, Fumihiko Takeuchi, Bamidele O Tayo, Peter J van der Most, Tibor V Varga, Veronique Vitart, Yajuan Wang, Erin B Ware, Helen R Warren, Stefan Weiss, Wanqing Wen, Lisa R Yanek, Weihua Zhang, Jing Hua Zhao, Saima Afaq, Najaf Amin, Marzyeh Amini, Dan E Arking, Tin Aung, Eric Boerwinkle, Ingrid Borecki, Ulrich Broeckel, Morris Brown, Marco Brumat, Gregory L Burke, Mickaël Canouil, Aravinda Chakravarti, Sabanayagam Charumathi, Yii-Der Ida Chen, John M Connell, Adolfo Correa, Lisa de Las Fuentes, Renée de Mutsert, H Janaka de Silva, Xuan Deng, Jingzhong Ding, Qing Duan, Charles B Eaton, Georg Ehret, Ruben N Eppinga, Evangelos Evangelou, Jessica D Faul, Stephan B Felix, Nita G Forouhi, Terrence Forrester, Oscar H Franco, Yechiel Friedlander, Ilaria Gandin, He Gao, Mohsen Ghanbari, Bruna Gigante, C Charles Gu, Dongfeng Gu, Saskia P Hagenaars, Göran Hallmans, Tamara B Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Makoto Hirata, Barbara V Howard, M Arfan Ikram, InterAct Consortium, Ulrich John, Tomohiro Katsuya, Chiea Chuen Khor, Tuomas O Kilpeläinen, Woon-Puay Koh, José E Krieger, Stephen B Kritchevsky, Michiaki Kubo, Johanna Kuusisto, Timo A Lakka, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Benjamin Lehne, Cora E Lewis, Yize Li, Shiow Lin, Jianjun Liu, Jingmin Liu, Marie Loh, Tin Louie, Reedik Mägi, Colin A McKenzie, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Lili Milani, Karen L Mohlke, Yukihide Momozawa, Mike A Nalls, Christopher P Nelson, Nona Sotoodehnia, Jill M Norris, Jeff R O'Connell, Nicholette D Palmer, Thomas Perls, Nancy L Pedersen, Annette Peters, Patricia A Peyser, Neil Poulter, Leslie J Raffel, Olli T Raitakari, Kathryn Roll, Lynda M Rose, Frits R Rosendaal, Jerome I Rotter, Carsten O Schmidt, Pamela J Schreiner, Nicole Schupf, William R Scott, Peter S Sever, Yuan Shi, Stephen Sidney, Mario Sims, Colleen M Sitlani, Jennifer A Smith, Harold Snieder, John M Starr, Konstantin Strauch, Heather M Stringham, Nicholas Y Q Tan, Hua Tang, Kent D Taylor, Yik Ying Teo, Yih Chung Tham, Stephen T Turner, André G Uitterlinden, Peter Vollenweider, Melanie Waldenberger, Lihua Wang, Ya Xing Wang, Wen Bin Wei, Christine Williams, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B Zonderman, Diane M Becker, Michael Boehnke, Donald W Bowden, John C Chambers, Ian J Deary, Tõnu Esko, Martin Farrall, Paul W Franks, Barry I Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Jost Bruno Jonas, Yoichiro Kamatani, Norihiro Kato, Jaspal S Kooner, Zoltán Kutalik, Markku Laakso, Cathy C Laurie, Karin Leander, Terho Lehtimäki, Lifelines Cohort Study, Patrik K E Magnusson, Albertine J Oldehinkel, Brenda W J H Penninx, Ozren Polasek, David J Porteous, Rainer Rauramaa, Nilesh J Samani, James Scott, Xiao-Ou Shu, Pim van der Harst, Lynne E Wagenknecht, Nicholas J Wareham, Hugh Watkins, David R Weir, Ananda R Wickremasinghe, Tangchun Wu, Wei Zheng, Claude Bouchard, Kaare Christensen, Michele K Evans, Vilmundur Gudnason, Bernardo L Horta, Sharon L R Kardia, Yongmei Liu, Alexandre C Pereira, Bruce M Psaty, Paul M Ridker, Rob M van Dam, W James Gauderman, Xiaofeng Zhu, Dennis O Mook-Kanamori, Myriam Fornage, Charles N Rotimi, L Adrienne Cupples, Tanika N Kelly, Ervin R Fox, Caroline Hayward, Cornelia M van Duijn, E Shyong Tai, Tien Yin Wong, Charles Kooperberg, Walter Palmas, Kenneth Rice, Alanna C Morrison, Paul Elliott, Mark J Caulfield, Patricia B Munroe, Dabeeru C Rao, Michael A Province, and Daniel Levy
Subjects: Medicine, Science
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
Published: 2018
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41. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Author: Ntalla I, Weng LC, Cartwright JH, Hall AW, Sveinbjornsson G, Tucker NR, Choi SH, Chaffin MD, Roselli C, Barnes MR, Mifsud B, Warren HR, Hayward C, Marten J, Cranley JJ, Concas MP, Gasparini P, Boutin T, Kolcic I, Polasek O, Rudan I, Araujo NM, Lima-Costa MF, Ribeiro ALP, Souza RP, Tarazona-Santos E, Giedraitis V, Ingelsson E, Mahajan A, Morris AP, Del Greco M F, Foco L, Gögele M, Hicks AA, Cook JP, Lind L, Lindgren CM, Sundström J, Nelson CP, Riaz MB, Samani NJ, Sinagra G, Ulivi S, Kähönen M, Mishra PP, Mononen N, Nikus K, Caulfield MJ, Dominiczak A, Padmanabhan S, Montasser ME, O'Connell JR, Ryan K, Shuldiner AR, Aeschbacher S, Conen D, Risch L, Thériault S, Hutri-Kähönen N, Lehtimäki T, Lyytikäinen LP, Raitakari OT, Barnes CLK, Campbell H, Joshi PK, Wilson JF, Isaacs A, Kors JA, van Duijn CM, Huang PL, Gudnason V, Harris TB, Launer LJ, Smith AV, Bottinger EP, Loos RJF, Nadkarni GN, Preuss MH, Correa A, Mei H, Wilson J, Meitinger T, Müller-Nurasyid M, Peters A, Waldenberger M, Mangino M, Spector TD, Rienstra M, van de Vegte YJ, van der Harst P, Verweij N, Kääb S, Schramm K, Sinner MF, Strauch K, Cutler MJ, Fatkin D, London B, Olesen M, Roden DM, Benjamin Shoemaker M, Gustav Smith J, Biggs ML, Bis JC, Brody JA, Psaty BM, Rice K, Sotoodehnia N, De Grandi A, Fuchsberger C, Pattaro C, Pramstaller PP, Ford I, Wouter Jukema J, Macfarlane PW, Trompet S, Dörr M, Felix SB, Völker U, Weiss S, Havulinna AS, Jula A, Sääksjärvi K, Salomaa V, Guo X, Heckbert SR, Lin HJ, Rotter JI, Taylor KD, Yao J, de Mutsert R, Maan AC, Mook-Kanamori DO, Noordam R, Cucca F, Ding J, Lakatta EG, Qian Y, Tarasov KV, Levy D, Lin H, Newton-Cheh CH, Lunetta KL, Murray AD, Porteous DJ, Smith BH, Stricker BH, Uitterlinden A, van den Berg ME, Haessler J, Jackson RD, Kooperberg C, Peters U, Reiner AP, Whitsel EA, Alonso A, Arking DE, Boerwinkle E, Ehret GB, Soliman EZ, Avery CL, Gogarten SM, Kerr KF, Laurie CC, Seyerle AA, Stilp A, Assa S, Abdullah Said M, Yldau van der Ende M, Lambiase PD, Orini M, Ramirez J, Van Duijvenboden S, Arnar DO, Gudbjartsson DF, Holm H, Sulem P, Thorleifsson G, Thorolfsdottir RB, Thorsteinsdottir U, Benjamin EJ, Tinker A, Stefansson K, Ellinor PT, Jamshidi Y, Lubitz SA, and Munroe PB
Subjects: Arrhythmias, Cardiac physiopathology, Cardiovascular Diseases genetics, Cardiovascular Diseases physiopathology, Endophenotypes, Female, Gene Expression, Genetic Variation, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Quantitative Trait Loci genetics, Arrhythmias, Cardiac genetics, Electrocardiography, Genetic Loci genetics, Genetic Predisposition to Disease genetics
Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
Published: 2020
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