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201. Lessons from the INTERVAL study – Authors' reply

Author: John Danesh, Emanuele Di Angelantonio, Simon G. Thompson, David J. Roberts, Stephen Kaptoge, Di Angelantonio, Emanuele [0000-0001-8776-6719], Kaptoge, Stephen [0000-0002-1155-4872], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: 03 medical and health sciences, 0302 clinical medicine, European research, Political science, MEDLINE, Library science, 42 Health Sciences, European commission, 32 Biomedical and Clinical Sciences, 030212 general & internal medicine, General Medicine, 030204 cardiovascular system & hematology, Medical research
Abstract: The INTERVAL study randomly assigned 45 263 whole-blood donors to different intervals between donations to assess the effect of varying the frequency of donation on donor health and blood supply. Reducing the inter-donation intervals used in the UK to those used in blood services in the USA or western Europe led to a substantial increase in the amount of blood collected over the 2-year study period. For instance, reducing the inter-donation interval from 12 weeks to 8 weeks in men led to an increase in blood supply of 33% (an average of 1·7 units per donor). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation related symptoms (eg, tiredness), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin. Katja van den Hurk and colleagues noted that ...
Published: 2018
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202. DNA Sequence Variation in

Author: Connor A, Emdin, Amit V, Khera, Krishna, Aragam, Mary, Haas, Mark, Chaffin, Derek, Klarin, Pradeep, Natarajan, Alexander, Bick, Seyedeh M, Zekavat, Akihiro, Nomura, Diego, Ardissino, James G, Wilson, Heribert, Schunkert, Ruth, McPherson, Hugh, Watkins, Roberto, Elosua, Matthew J, Bown, Nilesh J, Samani, Usman, Baber, Jeanette, Erdmann, Namrata, Gupta, John, Danesh, Danish, Saleheen, Stacey, Gabriel, and Sekar, Kathiresan
Subjects: Diabetes Mellitus, Type 2, Humans, Exome, Genetic Predisposition to Disease, Genetics/Genomes/Proteomics/Metabolomics, Sequence Analysis, DNA, Activin Receptors, Type I, Algorithms, Genome-Wide Association Study
Abstract: A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (−0.09 SD, P = 3.4 × 10(−17)), Ile195Thr (−0.15 SD, P = 1.0 × 10(−9)), Ile482Val (−0.019 SD, P = 1.6 × 10(−5)), and rs72927479 (−0.035 SD, P = 2.6 × 10(−12)). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 × 10(−13)). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes.
Published: 2018

203. Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults: Implications for Primary Prevention

Author: Michael, Inouye, Gad, Abraham, Christopher P, Nelson, Angela M, Wood, Michael J, Sweeting, Frank, Dudbridge, Florence Y, Lai, Stephen, Kaptoge, Marta, Brozynska, Tingting, Wang, Shu, Ye, Thomas R, Webb, Martin K, Rutter, Ioanna, Tzoulaki, Riyaz S, Patel, Ruth J F, Loos, Bernard, Keavney, Harry, Hemingway, John, Thompson, Hugh, Watkins, Panos, Deloukas, Emanuele, Di Angelantonio, Adam S, Butterworth, John, Danesh, and Nilesh J, Samani
Subjects: Male, Multifactorial Inheritance, Coronary Artery Disease, Genomics, Middle Aged, Risk Assessment, United Kingdom, Primary Prevention, Predictive Value of Tests, Research Design, Risk Factors, Humans, Mass Screening, Female, Genome-Wide Association Study
Abstract: Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes.This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention.Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank.The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age.The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction.
Published: 2018

204. New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

Author: Nick Shrine, Anna L Guyatt, A Mesut Erzurumluoglu, Victoria E Jackson, Brian D Hobbs, Carl Melbourne, Chiara Batini, Katherine A Fawcett, Kijoung Song, Phuwanat Sakornsakolpat, Xingnan Li, Ruth Boxall, Nicola F Reeve, Ma’en Obeidat, Jing Hua Zhao, Matthias Wielscher, Understanding Society Scientific Group, Stefan Weiss, Katherine A Kentistou, James P Cook, Benjamin B Sun, Jian Zhou, Jennie Hui, Stefan Karrasch, Medea Imboden, Sarah E Harris, Jonathan Marten, Stefan Enroth, Shona M Kerr, Ida Surakka, Veronique Vitart, Terho Lehtimäki, Richard J Allen, Per S Bakke, Terri H Beaty, Eugene R Bleecker, Yohan Bossé, Corry-Anke Brandsma, Zhengming Chen, James D Crapo, John Danesh, Dawn L DeMeo, Frank Dudbridge, Ralf Ewert, Christian Gieger, Amund Gulsvik, Anna L Hansell, Ke Hao, Josh D Hoffman, John Hokanson, Georg Homuth, Peter K Joshi, Philippe Joubert, Claudia Langenberg, Xuan Li, Liming Li, Kuang Lin, Lars Lind, Nick Locantore, Jian’an Luan, Anubha Mahajan, Joseph C Maranville, Alison Murray, David C Nickle, Richard Packer, Margaret M Parker, Megan L Paynton, David Porteous, Dmitry Prokopenko, Dandi Qiao, Rajesh Rawal, Heiko Runz, Ian Sayers, Don D Sin, Blair H Smith, María Soler Artigas, David Sparrow, Ruth Tal-Singer, Paul RHJ Timmers, Maarten Van den Berge, John C Whittaker, Prescott Woodruff, Laura M Yerges Armstrong, Olga G Troyanskaya, Olli T Raitakari, Mika Kähönen, Ozren Polasek, Ulf Gyllensten, Igor Rudan, Ian J Deary, Nicole M Probst-Hensch, Holger Schulz, Alan L James, James F Wilson, Beate Stubbe, Eleftheria Zeggini, Marjo-Riitta Jarvelin, Nick Wareham, Edwin K Silverman, Caroline Hayward, Andrew P Morris, Adam S Butterworth, Robert A Scott, Robin G Walters, Deborah A Meyers, Michael H Cho, David P Strachan, Ian P Hall, Martin D Tobin, and Louise V Wain
Subjects: 0303 health sciences, COPD, business.industry, Pulmonary disease, Bioinformatics, medicine.disease, 3. Good health, respiratory tract diseases, 03 medical and health sciences, 0302 clinical medicine, Pleiotropy (drugs), Medicine, business, 030217 neurology & neurosurgery, Lung function, 030304 developmental biology, Genetic association
Abstract: Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, one-half of which are new. In combination these variants strongly predict COPD in deeply-phenotyped patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
Published: 2018
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205. Genomic atlas of the human plasma proteome

Author: Mihir A Kamat, Robert M. Plenge, An Chi, Nicholas W. Morrell, Adam S. Butterworth, James E. Peters, Heiko Runz, Joseph C. Maranville, James A. Blackshaw, James R Staley, Caroline S. Fox, Clare Oliver-Williams, Ellie Paige, Benjamin B. Sun, Tao Jiang, Angela M. Wood, John Danesh, John A. Todd, Stephen Burgess, John Bradley, David Stacey, Sheri K. Wilcox, Nebojsa Janjic, Narinder Bansal, Bram P. Prins, Sarah L. Spain, Willem H. Ouwehand, Praveen Surendran, Erik S Zimmerman, Nicole Soranzo, David J. Roberts, Dirk S. Paul, Karsten Suhre, Sun, Ben [0000-0001-6347-2281], Blackshaw, James [0000-0002-0343-0319], Burgess, Stephen [0000-0001-5365-8760], Surendran, Praveen [0000-0002-4911-6077], Oliver-Williams, Clare [0000-0002-3573-2426], Bansal, Narinder [0000-0002-6925-1719], Wood, Angela [0000-0002-7937-304X], Morrell, Nicholas [0000-0001-5700-9792], Bradley, John [0000-0002-7774-8805], Ouwehand, Willem [0000-0002-7744-1790], Soranzo, Nicole [0000-0003-1095-3852], Paul, Dirk [0000-0002-8230-0116], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], Apollo - University of Cambridge Repository, and United Kingdom Research and Innovation
Subjects: 0301 basic medicine, Male, Vasculitis, Proteome, General Science & Technology, Myeloblastin, Quantitative Trait Loci, Mutation, Missense, Genomics, Disease, Computational biology, Quantitative trait locus, Biology, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Proto-Oncogene Proteins, Genetic variation, medicine, Humans, Mutation, Multidisciplinary, Hepatocyte Growth Factor, Mendelian Randomization Analysis, Blood Proteins, Inflammatory Bowel Diseases, Genetic architecture, 030104 developmental biology, alpha 1-Antitrypsin, Female, Positive Regulatory Domain I-Binding Factor 1, 030217 neurology & neurosurgery
Abstract: Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.
Published: 2018

206. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

Author: Danish Saleheen, Krishna G. Aragam, Wendy S. Post, Jerome I. Rotter, Pradeep Natarajan, Jennifer A. Mattera, Roberto Elosua, Usman Baber, Matthew J. Bown, Ruth McPherson, John Danesh, Yii-Der Ida Chen, Stephen S. Rich, Derek Klarin, Paul M. Ridker, Sekar Kathiresan, Kent D. Taylor, James G. Wilson, Seyedeh M. Zekavat, Akihiro Nomura, Diego Ardissino, Amit Khera, Connor A. Emdin, John A. Spertus, Bruce M. Psaty, Daniel I. Chasman, Namrata Gupta, Wayne H-H Sheu, Judith H. Lichtman, Joshua C. Denny, Hugh Watkins, Harlan M. Krumholz, Heribert Schunkert, Gail D'Onofrio, Stacey Gabriel, Mark Chaffin, Alexander G. Bick, Jeanette Erdmann, Mary E. Haas, Lisa Bastarache, Nilesh J. Samani, Emdin, Connor A [0000-0002-2385-8259], Chaffin, Mark [0000-0002-1234-5562], Erdmann, Jeanette [0000-0002-4486-6231], Saleheen, Danish [0000-0001-6193-020X], Kathiresan, Sekar [0000-0002-6724-032X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, General Physics and Astronomy, Disease, 030204 cardiovascular system & hematology, Cardiovascular, 0302 clinical medicine, Gene Frequency, Databases, Genetic, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, 2. Zero hunger, Genetics, Multidisciplinary, Diabetis, medicine.diagnostic_test, Metabolisme, 3. Good health, Fenotip, Heart Disease, Phenotype, Type 2, Biotechnology, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Frameshift mutation, Databases, 03 medical and health sciences, Genetic, Genetic variation, Diabetes Mellitus, medicine, Respiratory Hypersensitivity, Humans, Genetic Testing, Obesity, Allele, Allele frequency, Gene, Heart Disease - Coronary Heart Disease, Metabolic and endocrine, Loss function, Genetic testing, Human Genome, Genetic Variation, Proteins, General Chemistry, Atherosclerosis, United Kingdom, Good Health and Well Being, 030104 developmental biology, Diabetes Mellitus, Type 2, lcsh:Q
Abstract: Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency, Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.
Published: 2018

207. Lipoprotein Signatures of Cholesteryl Ester Transfer Protein and HMG-CoA Reductase Inhibition

Author: Adam S. Butterworth, Marjo-Riitta Jarvinen, Mika Ala-Korpela, Alun D. Hughes, Pauli Ohukainen, Mika Kähönen, Olga Anufrieva, Veikko Salomaa, Markus Perola, George Davey Smith, Johannes Kettunen, Jorma Viikari, Michael V. Holmes, Elias Allara, Clare Oliver-Williams, John Danesh, Therese Tillin, Olli T. Raitakari, Terho Lehtimäki, Emanuele Di Angelantonio, and Nish Chaturvedi
Subjects: 0303 health sciences, medicine.medical_specialty, education.field_of_study, Apolipoprotein B, biology, Triglyceride, Chemistry, Cholesterol, Population, 030204 cardiovascular system & hematology, Lower risk, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Internal medicine, Cholesterylester transfer protein, HMG-CoA reductase, biology.protein, medicine, lipids (amino acids, peptides, and proteins), education, 030304 developmental biology, Lipoprotein
Abstract: BackgroundCETP inhibition reduces vascular event rates but confusion surrounds its low-density lipoprotein (LDL)-cholesterol effects. We sought to clarify associations of genetic inhibition of CETP on detailed lipoproteins.Methods and ResultsWe used variants associated withCETP(rs247617) andHMGCR(rs12916) expression in 62,400 Europeans with detailed lipoprotein profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% lower risk of coronary heart disease (CHD). Associations of lipoprotein measures with risk of incident CHD in three population-based cohorts (770 cases) were examined.CETPandHMGCRhad near-identical associations with LDL-cholesterol concentration estimated by Friedewald-equation.HMGCRhad a relatively consistent effect on cholesterol concentrations across all apolipoprotein B-containing lipoproteins.CETPhad stronger effects on remnant and very-low-density lipoprotein cholesterol but no effect on cholesterol concentrations in LDL defined by particle size (diameter 18–26 nm) (-0.02SD 95%CI: -0.10, 0.05 forCETPversus -0.24SD, 95%CI -0.30, -0.18 forHMGCR).CETPhad profound effects on lipid compositions of lipoproteins, with strong reductions in the triglyceride content of all highdensity lipoprotein (HDL) particles. These alterations in triglyceride composition within HDL subclasses were observationally associated with risk of CHD, independently of total cholesterol and triglycerides (strongest HR per 1-SD higher triglyceride composition in very-large HDL 1.35; 95%CI: 1.18, 1.54).ConclusionCETP inhibition does not affect size-specific LDL cholesterol but may lower CHD risk by lowering cholesterol in other apolipoprotein-B containing lipoproteins and lowering triglyceride content of HDL particles. Conventional composite lipid assays may mask heterogeneous effects of lipid-altering therapies.
Published: 2018

208. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Author: Ching-Ti Liu, Michael Boehnke, George Dedoussis, Sophie V. Eastwood, Ruth J. F. Loos, Keng-Hung Lin, Denis Rybin, Fredrik Karpe, Martina Müller-Nurasyid, Michael A. Province, Alison D. Murray, Bo Isomaa, Eirini Marouli, Konstantin Strauch, Michael Preuss, Paul M. Ridker, Jette Bork-Jensen, Albert V. Smith, Hugoline G. de Haan, Wayne Huey-Herng Sheu, Barbara Thorand, Wolfgang Rathmann, Lawrence F. Bielak, Peter Kovacs, Marit E. Jørgensen, Jennifer Wessel, Danish Saleheen, Jung-Jin Lee, James B. Meigs, Veikko Salomaa, Alena Stančáková, Tibor V. Varga, Hidetoshi Kitajima, Inês Barroso, Kent D. Taylor, Claudia Langenberg, Yoon Shin Cho, Joanna M. M. Howson, Andrew T. Hattersley, Marie-France Hivert, Markku Laakso, Kai-Uwe Eckardt, Bram P. Prins, Matthias B. Schulze, Andrew D. Morris, Susanne Jäger, Francis S. Collins, Kristi Läll, Xu Lin, Anette Varbo, Benjamin Lehne, Girish N. Nadkarni, Jonathan Marchini, Daniel I. Chasman, Michael Stumvoll, Mark O. Goodarzi, Cécile Lecoeur, Philippe M. Frossard, Noël P. Burtt, Frank Kee, Jasmina Kravic, Alain G. Bertoni, Ivan Brandslund, Najaf Amin, Lenore J. Launer, Oluf Pedersen, Johanna Kuusisto, Line Rode, Eleftheria Zeggini, Yingchang Lu, Markus Perola, Helen R. Warren, André G. Uitterlinden, Hanieh Yaghootkar, Torben Hansen, Harald Grallert, Annemari Käräjämäki, Abbas Dehghan, Gina M. Peloso, Yii-Der Ida Chen, Man Li, Shaofeng Huo, Lars Lind, Karen L. Mohlke, Adrienne Tin, Yang Hai, Renée de Mutsert, Gudmar Thorleifsson, Marie Moitry, Sune F. Nielsen, Sara M. Willems, Matthias Wuttke, Weihua Zhang, Young-Jin Kim, Giovanni Malerba, Richard A. Jensen, Loic Yengo, Mickaël Canouil, Kurt Lohman, Robert A. Scott, Tamara B. Harris, Ruifang Li-Gao, Florian Kronenberg, Anke Tönjes, Bok-Ghee Han, Krista Fischer, Thomas Meitinger, James S. Pankow, Jaakko Tuomilehto, Adam S. Butterworth, Jerome I. Rotter, Olov Rolandsson, Xiuqing Guo, Cramer Christensen, Marie Loh, Elizabeth Selvin, Bong-Jo Kim, Audrey Y. Chu, Reedik Mägi, Josée Dupuis, Anna Köttgen, Jean Ferrières, Jin Li, Robert Sladek, Leslie A. Lange, Niels Grarup, Roberta McKean-Cowdin, Cristen J. Willer, Jose C. Florez, Valgerdur Steinthorsdottir, Karina Meidtner, Annette Peters, Børge G. Nordestgaard, Rajiv Chowdhury, Ioanna Ntalla, Emma Ahlqvist, Leif Groop, Nicholas J. Wareham, Kerrin S. Small, Tiinamaija Tuomi, Cecilia M. Lindgren, Katharine R. Owen, Giovanni Gambaro, Cornelia M. van Duijn, Dennis O. Mook-Kanamori, Kenneth Rice, Erik Ingelsson, Colin N. A. Palmer, Sharon L.R. Kardia, Neil R. Robertson, Dajiang J. Liu, Sebastian Schönherr, Daniel Taliun, Sekar Kathiresan, James G. Wilson, Ping An, Patricia A. Peyser, Matthias Blüher, Frits R. Rosendaal, John C. Chambers, Caroline Hayward, Shoaib Afzal, Fernando Rivadineira, Marielisa Graff, Pranav Yajnik, Vasiliki Mamakou, Juan Fernandez Tajes, Stefan Gustafsson, Heather M. Highland, Vilmantas Giedraitis, Andrew R. Wood, Saima Afaq, Jaspal S. Kooner, Megan L. Grove, Jennifer A. Brody, Andrew P. Morris, James P. Cook, Praveen Surendran, Jennifer Kriebel, Heikki A. Koistinen, Kari Stefansson, Anders Rosengren, Rainer Rauramaa, Satu Männistö, Oscar H. Franco, Yongmei Liu, N. William Rayner, Blair H. Smith, Erwin P. Bottinger, Ayse Demirkan, Allan Linneberg, Jonathan Marten, Huaixing Li, Sung Soo Kim, Sophie Hackinger, Cristina Bombieri, Lia B. Bang, Jun Liu, Asif Rasheed, Tim D. Spector, Paul W. Franks, Mark I. McCarthy, Heiner Boeing, Anne E. Justice, Vilmundur Gudnason, Sohee Han, Unnur Thorsteinsdottir, Panos Deloukas, Naveed Sattar, Eric Boerwinkle, Martin Ingelsson, John Danesh, Vassily Trubetskoy, Marco M Ferrario, Marju Orho-Melander, Wei Gan, Philippe Froguel, Symen Ligthart, Susan R. Heckbert, Jie Yao, Anne Tybjærg-Hansen, Robin Young, Daniel R. Witte, Anubha Mahajan, Peter Almgren, Timothy M. Frayling, Tanya M. Teslovich, Matt Neville, Philippe Amouyel, Wei Zhao, Andres Metspalu, Yao Hu, Olle Melander, Kari Kuulasmaa, Jason Flannick, Torben Jørgensen, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Rohit Varma, Epidemiology, and Internal Medicine
Subjects: 0301 basic medicine, Male, Inference, Genome-wide association study, Whole Exome Sequencing, 0302 clinical medicine, type 2 diabetes, coding variant associations signals, mechanistic inference, fine mapping, Coding region, Chromosome Mapping/statistics & numerical data, European Continental Ancestry Group/genetics, CONFERS SUSCEPTIBILITY, Exome sequencing, 11 Medical and Health Sciences, Genetics, Genetics & Heredity, 0303 health sciences, MAGIC Consortium, Chromosome Mapping, Whole Exome Sequencing/statistics & numerical data, Identification (information), RARE VARIANTS, LOW-FREQUENCY, Female, ExomeBP Consortium, Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, Posterior probability, European Continental Ancestry Group, 030209 endocrinology & metabolism, Context (language use), Computational biology, Biology, GENOTYPE IMPUTATION, Article, White People, GENETIC ARCHITECTURE, 03 medical and health sciences, SDG 3 - Good Health and Well-being, QUALITY-CONTROL, Exome Sequencing, Genome-Wide Association Study/statistics & numerical data, Journal Article, GIANT Consortium, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Alleles, Genetic association, 030304 developmental biology, FATTY LIVER-DISEASE, Science & Technology, Genetic Variation, 06 Biological Sciences, Genetic architecture, Minor allele frequency, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Diabetes Mellitus, Type 2/classification, 030217 neurology & neurosurgery, Coding (social sciences), Genome-Wide Association Study, Developmental Biology
Abstract: Identification of coding variant associations for complex diseases offers a direct route to biological insight, but is dependent on appropriate inference concerning the causal impact of those variants on disease risk. We aggregated coding variant data for 81,412 type 2 diabetes (T2D) cases and 370,832 controls of diverse ancestry, identifying 40 distinct coding variant association signals (at 38 loci) reaching significance (p−7). Of these, 16 represent novel associations mapping outside known genome-wide association study (GWAS) signals. We make two important observations. First, despite a threefold increase in sample size over previous efforts, only five of the 40 signals are driven by variants with minor allele frequency 1.29. Second, we used GWAS data from 50,160 T2D cases and 465,272 controls of European ancestry to fine-map these associated coding variants in their regional context, with and without additional weighting to account for the global enrichment of complex trait association signals in coding exons. At the 37 signals for which we attempted fine-mapping, we demonstrate convincing support (posterior probability >80% under the “annotation-weighted” model) that coding variants are causal for the association at 16 (including novel signals involving POC5 p.His36Arg, ANKH p.Arg187Gln, WSCD2 p.Thr113Ile, PLCB3 p.Ser778Leu, and PNPLA3 p.Ile148Met). However, at 13 of the 37 loci, the associated coding variants represent “false leads” and naïve analysis could have led to an erroneous inference regarding the effector transcript mediating the signal. Accurate identification of validated targets is dependent on correct specification of the contribution of coding and non-coding mediated mechanisms at associated loci.
Published: 2018

209. Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Author: Britt Kilian, Arthur Gilly, Ida Moltke, Eleftheria Zeggini, Daniel Suveges, Thea Bjørnland, Kousik Kundu, Ioanna Ntalla, Klaudia Walter, Inês Barroso, Konstantinos Hatzikotoulas, Giorgio E. M. Melloni, Adam S. Butterworth, Elisabetta Casalone, Emil V. R. Appel, Karoline Kuchenbaecker, Aliki-Eleni Farmaki, Lorraine Southam, Ryan K. Waples, Emmanouil Tsafantakis, George Dedoussis, John Danesh, Nigel W. Rayner, Martin O. Pollard, Pollard, Martin [0000-0001-8738-0920], Southam, Lorraine [0000-0002-7546-9650], Hatzikotoulas, Konstantinos [0000-0002-4699-3672], Appel, Emil VR [0000-0001-7704-6611], Melloni, Giorgio [0000-0001-6371-1334], Kundu, Kousik [0000-0002-1019-8351], Walter, Klaudia [0000-0003-4448-0301], Butterworth, Adam [0000-0002-6915-9015], Barroso, Inês [0000-0001-5800-4520], Moltke, Ida [0000-0001-7052-8554], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Science, General Physics and Astronomy, Biology, Article, General Biochemistry, Genetics and Molecular Biology, GeneralLiterature_MISCELLANEOUS, Cohort Studies, Quantitative Trait, 03 medical and health sciences, Quantitative Trait, Heritable, Gene Frequency, Humans, Allele, Author Correction, lcsh:Science, Heritable, Gene, Alleles, 030304 developmental biology, Genetics, Whole genome sequencing, 0303 health sciences, Multidisciplinary, Whole Genome Sequencing, Adiponectin, ComputingMilieux_THECOMPUTINGPROFESSION, 030305 genetics & heredity, Genetic Variation, Lipid metabolism, General Chemistry, 030104 developmental biology, Isolated population, Cohort, lcsh:Q
Abstract: The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10−8; APOC3 and triglyceride levels, P = 1.5 × 10−26), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10−8), indicating a role for this gene in lipid metabolism., Rare genetic variants can contribute to complex traits but this contribution is not well understood. Here, the authors analyse deep whole genome sequencing data across 1457 individuals from an isolated Greek population and find association of rare variant burdens with cardiometabolic traits.
Published: 2018
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210. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center
Subjects: 0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Published: 2018

211. Genomic risk prediction of coronary artery disease in nearly 500,000 adults: implications for early screening and primary prevention

Author: Ruth J. F. Loos, Emanuele Di Angelantonio, Ioanna Tzoulaki, Michael Inouye, Riyaz S. Patel, Florence Lai, Martin K. Rutter, Hugh Watkins, Tingting Wang, Christopher P. Nelson, Adam S. Butterworth, Panos Deloukas, Shu Ye, Stephen Kaptoge, Harry Hemingway, Bernard Keavney, John Danesh, Angela M. Wood, Michael J. Sweeting, Marta Brozynska, Tom R. Webb, John F. Thompson, Frank Dudbridge, Gad Abraham, and Nilesh J. Samani
Subjects: 2. Zero hunger, 0303 health sciences, medicine.medical_specialty, Framingham Risk Score, business.industry, Hazard ratio, 030204 cardiovascular system & hematology, Heritability, medicine.disease, Biobank, 3. Good health, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal medicine, medicine, business, Body mass index, 030304 developmental biology, Genetic association
Abstract: BackgroundCoronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention.MethodsUsing a meta-analytic approach to combine large-scale genome-wide and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS), consisting of 1.7 million genetic variants. We externally tested metaGRS, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank.FindingsIn UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68–1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97–4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615–0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61– 3.07) between the top and bottom 20% of the metaGRS distribution.InterpretationRecent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification.FundingNational Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.
Published: 2018

212. Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment

Author: Kuang Lin, Sylvain Sebert, Robert Clarke, George Davey Smith, Michael V. Holmes, Clare Oliver Williams, Zhengming Chen, Adam S. Butterworth, Liming Li, Iona Y Millwood, Debbie A Lawlor, Johannes Kettunen, Naomi Rankin, Veikko Salomaa, Qin Wang, Marjo-Riitta Järvelin, Mika Ala-Korpela, Ian Ford, Naveed Sattar, Stella Trompet, John Danesh, Christian Delles, Paul Welsh, Peter Würtz, Charles Boachie, Eeva Sliz, Robin G. Walters, Markus Perola, J. Wouter Jukema, Minna Männikkö, Diabetes and Obesity Research Program, University of Helsinki, Research Programs Unit, UNIVERSITY OF OULU, Oliver-Williams, Clare [0000-0002-3573-2426], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, Very low-density lipoprotein, Cardiac & Cardiovascular Systems, Heart disease, Metabolite, Cholesterol, VLDL, Genome-wide association study, 030204 cardiovascular system & hematology, Pharmacology, PCSK9, chemistry.chemical_compound, 0302 clinical medicine, Original Research Articles, EPIDEMIOLOGY, Amino Acids, 1102 Cardiorespiratory Medicine and Haematology, Pravastatin, chemistry.chemical_classification, Aged, 80 and over, RISK, 0303 health sciences, education.field_of_study, PCSK9 Inhibitors, metabolomics, 3. Good health, Cardiovascular Diseases, SAFETY, Low-density lipoprotein, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Kexin, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, REDUCING LIPIDS, medicine.drug, Statin, medicine.drug_class, Population, Mendelian randomization analysis, LOW-DENSITY-LIPOPROTEIN, HEART-DISEASE, 1117 Public Health and Health Services, statins, 03 medical and health sciences, Double-Blind Method, MAGNETIC-RESONANCE METABOLOMICS, Physiology (medical), Mendelian randomization, medicine, Humans, GENOME-WIDE ASSOCIATION, education, 030304 developmental biology, Aged, Science & Technology, lipids and lipoprotein metabolism, business.industry, Subtilisin, Fatty acid, 1103 Clinical Sciences, Cholesterol, LDL, Placebo Effect, Proprotein convertase, medicine.disease, lipoproteins, PHYSICAL-ACTIVITY, 030104 developmental biology, Peripheral Vascular Disease, Cardiovascular System & Hematology, chemistry, statin therapy, 3121 General medicine, internal medicine and other clinical medicine, Cardiovascular System & Cardiology, Hydroxymethylglutaryl-CoA Reductase Inhibitors, LDL CHOLESTEROL, business, Lipoprotein
Abstract: Supplemental Digital Content is available in the text., Background: Both statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower blood low-density lipoprotein cholesterol levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these 2 lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial. Methods: Two hundred twenty-eight circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5359 individuals (2659 on treatment) in the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial at 6 months postrandomization. The corresponding metabolic measures were analyzed in 8 population cohorts (N=72 185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Results: Scaled to an equivalent lowering of low-density lipoprotein cholesterol, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of very-low-density lipoprotein cholesterol compared with statin therapy (54% versus 77% reduction, relative to the lowering effect on low-density lipoprotein cholesterol; P=2×10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA), whereas statin treatment weakly lowered GlycA levels. Conclusions: Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on very-low-density lipoprotein lipids compared with statins for an equivalent lowering of low-density lipoprotein cholesterol, which potentially translate into smaller reductions in cardiovascular disease risk.
Published: 2018

213. Alcohol intake in relation to non-fatal and fatal coronary heart disease and stroke: EPIC-CVD case-cohort study

Author: Eleni Maria Papatesta, Antonia Trichopoulou, Pietro Ferrari, Michael J. Sweeting, Calogero Saieva, Rodolfo Saracci, Fabrice Bonnet, Diana Gavrila, Elisabete Weiderpass, W M Monique Verschuren, Timothy J. Key, Ioanna Tzoulaki, Larraitz Arriola, Cristian Ricci, Jan-Håkan Jansson, Jolanda M. A. Boer, Claudia Agnoli, Rosario Tumino, Paul Brennan, Nicholas J. Wareham, Marc J. Gunter, Ivonne Sluijs, Heinz Freisling, David C. Muller, Rudolf Kaaks, Nita G. Forouhi, Conchi Moreno Iribas, Eleni Peppa, Camille Lassale, Kim Overvad, Stephen J. Sharp, Salvatore Panico, Ann-Sofie Forslund, Angela M. Wood, Domenico Palli, Olle Melander, María José Sánchez, Cecilie Kyrø, John Danesh, Annemieke M.W. Spijkerman, J. Ramón Quirós, Yvonne T. van der Schouw, Claudia Langenberg, Antonio Agudo, Ruth C. Travis, Anne Tjønneland, Tilman Kühn, Adam S. Butterworth, Gunnar Engström, Elio Riboli, Giuseppe Matullo, Samantha Warnakula, Heiner Boeing, University of Helsinki, Clinicum, Ricci, Cristian, Wood, Angela, Muller, David, Gunter, Marc J, Agudo, Antonio, Boeing, Heiner, van der Schouw, Yvonne T, Warnakula, Samantha, Saieva, Calogero, Spijkerman, Annemieke, Sluijs, Ivonne, Tjønneland, Anne, Kyrø, Cecilie, Weiderpass, Elisabete, Kühn, Tilman, Kaaks, Rudolf, Sánchez, Maria-Jose, Panico, Salvatore, Agnoli, Claudia, Palli, Domenico, Tumino, Rosario, Engström, Gunnar, Melander, Olle, Bonnet, Fabrice, Boer, Jolanda M A, Key, Timothy J, Travis, Ruth C, Overvad, Kim, Verschuren, W M Monique, Quirós, J Ramón, Trichopoulou, Antonia, Papatesta, Eleni-Maria, Peppa, Eleni, Iribas, Conchi Moreno, Gavrila, Diana, Forslund, Ann-Sofie, Jansson, Jan-Håkan, Matullo, Giuseppe, Arriola, Larraitz, Freisling, Heinz, Lassale, Camille, Tzoulaki, Ioanna, Sharp, Stephen J, Forouhi, Nita G, Langenberg, Claudia, Saracci, Rodolfo, Sweeting, Michael, Brennan, Paul, Butterworth, Adam S, Riboli, Elio, Wareham, Nick J, Danesh, John, and Ferrari, Pietro
Subjects: Male, Time Factors, Stroke/classification, Coronary Artery Disease, 030204 cardiovascular system & hematology, Body Mass Index, Alcohol Drinking/adverse effects, 0302 clinical medicine, Cause of Death, Smoking/adverse effects, Medicine, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Stroke, Cause of death, Medicine(all), Kardiologi, Medicine (all), Hazard ratio, Smoking, INDIVIDUAL-PARTICIPANT DATA, General Medicine, Middle Aged, CANCER, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, CARDIOVASCULAR-DISEASE, Cohort, LIFE-STYLE, Female, Coronary Artery Disease/classification, Drug, Life Sciences & Biomedicine, Human, Cohort study, medicine.medical_specialty, Alcohol Drinking, Endpoint Determination, 1117 Public Health and Health Services, Dose-Response Relationship, 03 medical and health sciences, Medicine, General & Internal, POLYPHENOLS, Internal medicine, General & Internal Medicine, Humans, cardiovascular diseases, Exercise, METAANALYSIS, Science & Technology, Dose-Response Relationship, Drug, business.industry, Research, 1103 Clinical Sciences, CAUSE-SPECIFIC MORTALITY, CONSUMPTION, SMOKING-CESSATION, medicine.disease, Prospective Studie, 3121 General medicine, internal medicine and other clinical medicine, RISK-FACTORS, Risk Reduction Behavior, business, Body mass index
Abstract: OBJECTIVE:To investigate the association between alcohol consumption (at baseline and over lifetime) and non-fatal and fatal coronary heart disease (CHD) and stroke. DESIGN:Multicentre case-cohort study. SETTING:A study of cardiovascular disease (CVD) determinants within the European Prospective Investigation into Cancer and nutrition cohort (EPIC-CVD) from eight European countries. PARTICIPANTS:32 549 participants without baseline CVD, comprised of incident CVD cases and a subcohort for comparison. MAIN OUTCOME MEASURES:Non-fatal and fatal CHD and stroke (including ischaemic and haemorrhagic stroke). RESULTS:There were 9307 non-fatal CHD events, 1699 fatal CHD, 5855 non-fatal stroke, and 733 fatal stroke. Baseline alcohol intake was inversely associated with non-fatal CHD, with a hazard ratio of 0.94 (95% confidence interval 0.92 to 0.96) per 12 g/day higher intake. There was a J shaped association between baseline alcohol intake and risk of fatal CHD. The hazard ratios were 0.83 (0.70 to 0.98), 0.65 (0.53 to 0.81), and 0.82 (0.65 to 1.03) for categories 5.0-14.9 g/day, 15.0-29.9 g/day, and 30.0-59.9 g/day of total alcohol intake, respectively, compared with 0.1-4.9 g/day. In contrast, hazard ratios for non-fatal and fatal stroke risk were 1.04 (1.02 to 1.07), and 1.05 (0.98 to 1.13) per 12 g/day increase in baseline alcohol intake, respectively, including broadly similar findings for ischaemic and haemorrhagic stroke. Associations with cardiovascular outcomes were broadly similar with average lifetime alcohol consumption as for baseline alcohol intake, and across the eight countries studied. There was no strong evidence for interactions of alcohol consumption with smoking status on the risk of CVD events. CONCLUSIONS:Alcohol intake was inversely associated with non-fatal CHD risk but positively associated with the risk of different stroke subtypes. This highlights the opposing associations of alcohol intake with different CVD types and strengthens the evidence for policies to reduce alcohol consumption.
Published: 2018

214. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)
Published: 2018

215. Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference

Author: John C. Whittaker, Frank Dudbridge, Nicholas J. Timpson, Louise V. Wain, David A. van Heel, Laura J Corbin, Nathalie Kingston, Fredrik Karpe, George Davey Smith, Kaitlin H Wade, David M. Evans, Katherine E. Tansey, Martin D. Tobin, Joanna M. M. Howson, David A. Hughes, Catherine John, Paul W. Franks, John Danesh, Dirk S. Paul, Robert A. Scott, Ewan R. Pearson, Michael John Owen, Mark I. McCarthy, Vanessa Y Tan, Momodou W. Jallow, Colin N. A. Palmer, Stephen O'Rahilly, Timothy M. Frayling, Michael O'Donavan, Frances Butcher, Cecilia M. Lindgren, Corbin, Laura J [0000-0002-4032-9500], Paul, Dirk S [0000-0002-8230-0116], O'Donavan, Michael [0000-0001-7073-2379], O'Rahilly, Stephen [0000-0003-2199-4449], Owen, Michael J [0000-0003-4798-0862], Palmer, Colin NA [0000-0002-6415-6560], van Heel, David A [0000-0002-0637-2265], Tobin, Martin D [0000-0002-3596-7874], Wain, Louise V [0000-0003-4951-1867], McCarthy, Mark I [0000-0002-4393-0510], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Genotype, Computer science, Science, General Physics and Astronomy, Genome-wide association study, Review Article, 030105 genetics & heredity, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Risk Factors, Humans, lcsh:Science, Medicinsk genetik, Molecular Epidemiology, Multidisciplinary, Recall, Genetic Variation, General Chemistry, Causality, Data science, United Kingdom, 030104 developmental biology, Phenotype, Causal inference, lcsh:Q, ICEP, Medical Genetics, Genome-Wide Association Study
Abstract: Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner., Recall-by-Genotype (RbG) is an approach to recall participants from genetic studies based on their specific genotype for further, more extensive phenotyping. Here, the authors discuss examples of RbG as well as practical and ethical considerations and provide an online tool to aid in designing RbG studies.
Published: 2018

216. Statistics, epidemiology, clinical trials, meta-analyses and evidence-based medicine

Author: Christopher Jm Whitty, John Danesh, and William Rosenberg
Subjects: Clinical trial, medicine.medical_specialty, business.industry, Family medicine, Epidemiology, medicine, Evidence-based medicine, business
Published: 2017

217. Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci

Author: Paul, Ds, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Akkerman, Jan Willem N., Albers, Cornelis A., Ale, Algra, Abtehale Al Hussani, Hooman, Allayee, Franco, Anni, Asselbergs, Folkert W., Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Baumeister, Sebastian E., Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Bis, Joshua C., Lorenzo, Bomba, Amélie, Bonnefond, Boomsma, Dorret I., Bradley, John R., François, Cambien, Chambers, John C., Marina, Ciullo, Cookson, William O., Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Das, Gail, Davies, Paul IW de Bakker, de Boer, Rudolf A., Eco JC de Geus, Deary, Ian J., Dedoussis, George V., Panos, Deloukas, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghaus, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, Evans, David M., Eyjolfsson, Gudmundur I., Mario, Falchi, Wei, Feng, Ferreira, Manuel A., Luigi, Ferrucci, Krista, Fischer, Folsom, Aaron R., Paolo, Fortina, Andre, Franke, Lude, Franke, Frazer, Ian H., Philippe, Froguel, Renzo, Galanello, Ganesh, Santhi K., Garner, Stephen F., Gasparini, Paolo, Bernd, Genser, Gibson, Quince D., Christian, Gieger, Girotto, Giorgia, Glazer, Nicole L., Martin, Gögele, Goodall, Alison H., Andreas, Greinacher, Gudbjartsson, Daniel F., Chris, Hammond, Harris, Sarah E., Jaana, Hartiala, Anna Liisa Hartikainen, Hazen, Stanley L., Heckbert, Susan R., Hedblad, Bo, Christian, Hengstenberg, Micha, Hersch, Hicks, Andrew A., Hilma, Holm, Jouke Jan Hottenga, Thomas, Illig, Marjo Riitta Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Kema, Ido P., Kemp, John P., Jyoti, Khadake, Kay Tee Khaw, Kleber, Marcus E., Kooner, Jaspal S., Peter, Kovacs, Brigitte, Kühnel, Marie Christine Kyrtsonis, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort Study, Heather Lloyd Jones, Ruth JF Loos, Lopez, Lorna M., Thomas, Lumley, Leo Pekka Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Martin, Nicholas G., Andrea, Maschio, Irene Mateo Leach, Barbara, Mcknight, Stuart, Meacham, Medland, Sarah E., Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Mitchell, Braxton D., Moffatt, Miriam F., Montgomery, Grant W., Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navis, Nolte, Ilja M., Ute, Nöthlings, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Onundarson, Pall T., O’Reilly, Paul F., Ouwehand, Willem H., Debora, Parracciani, Afshin, Parsa, Paul, Dirk S., Penninger, Josef M., Penninx, Brenda W., Mario, Pirastu, Pirastu, Nicola, Giorgio, Pistis, Eleonora, Porcu, Laura, Portas, David, Porteous, Anneli, Pouta, Pramstaller, Peter P., Inga, Prokopenko, Psaty, Bruce M., Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez Solis, Augusto, Rendon, Ried, Janina S., Ring, Susan M., Robino, Antonietta, Rotter, Jerome I., Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Saluments, Samani, Nilesh J., Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Schmidt, Carsten O., Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic Canic, So Youn Shin, Shuldiner, Alan R., Rob, Sladek, Smit, Johannes H., George Davey Smith, Gustav Smith, J., Smith, Nicholas L., Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Spector, Timothy D., Starr, John M., Kari, Stefansson, Derek, Stemple, Jonathan, Stephens, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönjes, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der Harst, Ellen van der Schoot, C., van Gilst, Wiek H., Joost van Pelt, L., van Veldhuisen, Dirk J., Niek, Verweij, Visscher, Peter M., Uwe, Völker, Peter, Vollenweider, Katrin, Voss, Wareham, Nicholas J., Lorenz, Wernisch, Harm Jan Westra, Whitfield, John B., Herich, Wichmann, Wiggins, Kerri L., Gonneke, Willemsen, Winkelmann, Bernhard R., Gerald, Wirnsberger, Bruce HR Wolffenbuttel, Jian, Yang, Tsun Po Yang, Weihua, Zhang, Jing Hua Zhao, Paavo, Zitting, Jaap Jan Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Paul, D, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Jan Willem N., Akkerman, Cornelis A., Alber, Ale, Algra, Abtehale Al, Hussani, Hooman, Allayee, Franco, Anni, Folkert W., Asselberg, Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Sebastian E., Baumeister, Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Joshua C., Bi, Lorenzo, Bomba, Amélie, Bonnefond, Dorret I., Boomsma, John R., Bradley, François, Cambien, John C., Chamber, Marina, Ciullo, William O., Cookson, Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Da, Gail, Davie, Paul IW de, Bakker, Rudolf A., de Boer, Eco JC de, Geu, Ian J., Deary, George V., Dedoussi, Panos, Delouka, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghau, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, David M., Evan, Gudmundur I., Eyjolfsson, Mario, Falchi, Wei, Feng, Manuel A., Ferreira, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Paolo, Fortina, Andre, Franke, Lude, Franke, Ian H., Frazer, Philippe, Froguel, Renzo, Galanello, Santhi K., Ganesh, Stephen F., Garner, Gasparini, Paolo, Bernd, Genser, Quince D., Gibson, Christian, Gieger, Girotto, Giorgia, Nicole L., Glazer, Martin, Gögele, Alison H., Goodall, Andreas, Greinacher, Daniel F., Gudbjartsson, Chris, Hammond, Sarah E., Harri, Jaana, Hartiala, Anna Liisa, Hartikainen, Stanley L., Hazen, Susan R., Heckbert, Bo, Hedblad, Christian, Hengstenberg, Micha, Hersch, Andrew A., Hick, Hilma, Holm, Jouke Jan, Hottenga, Thomas, Illig, Marjo Riitta, Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Ido P., Kema, John P., Kemp, Jyoti, Khadake, Kay Tee, Khaw, Marcus E., Kleber, Jaspal S., Kooner, Peter, Kovac, Brigitte, Kühnel, Marie Christine, Kyrtsoni, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort, Study, Heather Lloyd, Jone, Ruth JF, Loo, Lorna M., Lopez, Thomas, Lumley, Leo Pekka, Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Nicholas G., Martin, Andrea, Maschio, Irene Mateo, Leach, Barbara, Mcknight, Stuart, Meacham, Sarah E., Medland, Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Braxton D., Mitchell, Miriam F., Moffatt, Grant W., Montgomery, Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navi, Ilja M., Nolte, Ute, Nöthling, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Pall T., Onundarson, Paul F., O’Reilly, Willem H., Ouwehand, Debora, Parracciani, Afshin, Parsa, Dirk S., Paul, Josef M., Penninger, Brenda W., Penninx, Mario, Pirastu, Pirastu, Nicola, Giorgio, Pisti, Eleonora, Porcu, Laura, Porta, David, Porteou, Anneli, Pouta, Peter P., Pramstaller, Inga, Prokopenko, Bruce M., Psaty, Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez, Soli, Augusto, Rendon, Janina S., Ried, Susan M., Ring, Robino, Antonietta, Jerome I., Rotter, Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Salument, Nilesh J., Samani, Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Carsten O., Schmidt, Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic, Canic, So Youn, Shin, Alan R., Shuldiner, Rob, Sladek, Johannes H., Smit, George Davey, Smith, J., Gustav Smith, Nicholas L., Smith, Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Timothy D., Spector, John M., Starr, Kari, Stefansson, Derek, Stemple, Jonathan, Stephen, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung, Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson, Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay, Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönje, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der, Harst, C., Ellen van der Schoot, Wiek H., van Gilst, L., Joost van Pelt, Dirk J., van Veldhuisen, Niek, Verweij, Peter M., Visscher, Uwe, Völker, Peter, Vollenweider, Katrin, Vo, Nicholas J., Wareham, Lorenz, Wernisch, Harm Jan, Westra, John B., Whitfield, Herich, Wichmann, Kerri L., Wiggin, Gonneke, Willemsen, Bernhard R., Winkelmann, Gerald, Wirnsberger, Bruce HR, Wolffenbuttel, Jian, Yang, Tsun Po, Yang, Weihua, Zhang, Jing Hua, Zhao, Paavo, Zitting, Jaap Jan, Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England, UCL, UCL Canc Inst, London WC1E 6BT, England, Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, Natl Hlth Serv NHS Blood & Transplant, Cambridge CB2 0PT, England, Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands, Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England, NIHR Biomed Res Ctr, Cambridge CB2 0PT, England, Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands, Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands, Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1NY, England, Hammersmith Hosp, Imperial Coll Healthcare NHS Trust, London W12 0HS, England, Royal Brompton & Harefield Hosp NHS Trust, London SW3 6NP, England, Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England, Psychiatry, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, and Cardiovascular Centre (CVC)
Subjects: Netherlands Twin Register (NTR), Erythrocytes, Genome-wide association study, UNCERTAINTY, Regulatory Sequences, Nucleic Acid, VARIANTS, ANNOTATION, COLORECTAL-CANCER, Histones, 0302 clinical medicine, BINDING, Cluster Analysis, Myeloid Cells, Genetics (clinical), Genetics, hematological trait, 0303 health sciences, Chromosome Mapping, MRP4 ABCC4, Chromatin, Nucleosomes, Phenotype, Organ Specificity, 030220 oncology & carcinogenesis, Blood Platelets, Quantitative Trait Loci, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, DYNAMIN 3, 03 medical and health sciences, Quantitative Trait, Heritable, MEGAKARYOCYTES, Humans, Cell Lineage, ddc:610, GENOME-WIDE ASSOCIATION, Enhancer, Transcription factor, Gene, ChIA-PET, 030304 developmental biology, Research, Genetic Variation, DNA, Chromatin Assembly and Disassembly, Genetic architecture, Gene Expression Regulation, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510
Published: 2013

218. Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study

Author: Christian Gieger, Timothy J. Aitman, John Danesh, Danish Saleheen, Anuradhani Kasturiratne, Soterios A. Kyrtopoulos, Antti J. Kangas, James Scott, Gianluca Campanella, Sujeet Jha, Jeremy B. M. Jowett, Hannah R Elliott, Paul Elliott, Loic Yengo, Ole Ammerpohl, Marjo-Riitta Järvelin, Pasi Soininen, Marc Chadeau-Hyam, Benjamin Lehne, Janne Pitkäniemi, Simon de Lusignan, Weihua Zhang, Barbara Thorand, Christian Herder, Mark I. McCarthy, Simone Wahl, James Abbott, Mika Ala-Korpela, Thomas Illig, Martyna Adamowicz-Brice, Stéphane Cauchi, Tom R. Gaunt, Alexander W. Drong, Norihiro Kato, Philippe Froguel, Ananda R. Wickremasinghe, Jochen Hampe, Harald Grallert, Sian-Tsung Tan, Jennifer Kriebel, Richie Soong, Paolo Vineis, Holger Prokisch, Navaratnam Kotea, Caroline L Relton, Michelle Ann Rozario, Simon Jones, Letizia Tarantini, John C. Chambers, Prakash P Punjabi, Hong Kiat Ng, Sudhir Kowlessur, Rebecca C Richmond, Valeria Motta, William R. Scott, R. Caiazzo, Benedetta Albetti, Valentina Bollati, Jaakko Tuomilehto, Zuan Yu Mok, Uzma Afzal, Kiymet Bozaoglu, Jaspal S. Kooner, Federica Rota, Clemens Schafmayer, Marie Loh, François Pattou, E-Shyong Tai, Pier Alberto Bertazzi, Christine Blancher, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, and Action on Hearing Loss
Subjects: Male, STRESS, Endocrinology, Diabetes and Metabolism, PROTEIN, Type 2 diabetes, GLUCOSE, Epigenesis, Genetic, MELLITUS, 0302 clinical medicine, Endocrinology, Risk Factors, Prospective Studies, media_common, 2. Zero hunger, INSULIN-RESISTANCE, 0303 health sciences, education.field_of_study, Incidence (epidemiology), Middle Aged, 3. Good health, CARBOHYDRATE RESPONSE ELEMENT, OBESITY, Female, Life Sciences & Biomedicine, EXPRESSION, Asian Continental Ancestry Group, Genetic Markers, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Population, 030209 endocrinology & metabolism, Article, White People, Endocrinology & Metabolism, 03 medical and health sciences, INFLAMMATION, Asian People, Diabetes mellitus, Internal Medicine, medicine, Humans, media_common.cataloged_instance, European union, education, 030304 developmental biology, Science & Technology, business.industry, Case-control study, DNA Methylation, medicine.disease, Obesity, Diabetes Mellitus, Type 2, Case-Control Studies, Nested case-control study, business, Genome-Wide Association Study, Demography
Abstract: Background Indian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes. Methods We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p
Published: 2015

219. The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery

Author: Sergio Abrignani, David Adams, Melanie de Almeida, ALTUCCI, Lucia, Viren Amin, Ido Amit, Stylianos E, Antonarakis, Samuel Aparicio, Takahiro Arima, Laura Arrigoni, Rob Arts, Vahid Asnafi, Manel Esteller, Jae Bum Bae, Kevin Bassler, Stephan Beck, Benjamin Berkman, Bradley E, Bernstein, Mikhail Bilenky, Adrian Bird, Christoph Bock, Bernhard Boehm, Guillaume Bourque, Charles E, Breeze, Benedikt Brors, David Bujold, Oliver Burren, Marion J, Bussemakers, Adam Butterworth, Elias Campo, Enrique Carrillo de Santa Pau, Lisa Chadwick, Kui Ming Chan, Wei Chen, Tom H, Cheung, Luca Chiapperino, Nak Hyen Choi, Ho Ryun Chung, Laura Clarke, Joseph M, Connors, Philippe Cronet, John Danesh, Manolis Dermitzakis, Gerard Drewes, Pawel Durek, Stephanie Dyke, Tomasz Dylag, Connie J, Eaves, Peter Ebert, Roland Eils, Jürgen Eils, Catherine A, Ennis, Tariq Enver, Elise A, Feingold, Bärbel Felder, Anne Ferguson Smith, Jude Fitzgibbon, Paul Flicek, Roger S, Y, Foo, Peter Fraser, Mattia Frontini, Eileen Furlong, Sitanshu Gakkhar, Nina Gasparoni, Gilles Gasparoni, Daniel H, Geschwind, Petar Glažar, Thomas Graf, Frank Grosveld, Xin Yuan Guan, Roderic Guigo, Ivo G, Gut, Alf Hamann, Bok Ghee Han, R, Alan Harris, Simon Heath, Kristian Helin, Jan G, Hengstler, Alireza Heravi Moussavi, Karl Herrup, Steven Hill, Jason A, Hilton, Benjamin C, Hitz, Bernhard Horsthemke, Ming Hu, Joo Yeon Hwang, Nancy Y, Takashi Ito, Biola Maria Javierre, Sasa Jenko, Thomas Jenuwein, Yann Joly, Steven J, M, Jones, Yae Kanai, Hee Gyung Kang, Aly Karsan, Alexandra K, Kiemer, Song Cheol Kim, Bong Jo Kim, Hyeon Hoe Kim, Hiroshi Kimura, Sarah Kinkley, Filippos Klironomos, In Uk Koh, Myrto Kostadima, Christopher Kressler, Roman Kreuzhuber, Anshul Kundaje, Ralf Küppers, Carolyn Larabell, Paul Lasko, Mark Lathrop, S, Lee, Suman Lee, Hans Lehrach, Elsa Leitão, Thomas Lengauer, Åke Lernmark, David Leslie, Gilberto K, K, Leung, Danny Leung, Markus Loeffler, Yussanne Ma, Antonello Mai, Thomas Manke, Eric R, Marcotte, Marco A, Marra, Joost H, A, Martens, Jose Ignacio Martin Subero, Karen Maschke, Christoph Merten, Aleksandar Milosavljevic, Saverio Minucci, Totai Mitsuyama, Richard A, Moore, Fabian Müller, Andrew J, Mungall, Mihai G, Netea, Karl Nordström, Irene Norstedt, Hiroaki Okae, Vitor Onuchic, Francis Ouellette, Willem Ouwehand, Massimiliano Pagani, Vera Pancaldi, Thomas Pap, Tomi Pastinen, Ronak Patel, Dirk S, Paul, Michael J, Pazin, Pier Giuseppe Pelicci, Anthony G, Phillips, Julia Polansky, Bo Porse, J, Andrew Pospisilik, Shyam Prabhakar, Dena C, Procaccini, Andreas Radbruch, Nikolaus Rajewsky, Vardham Rakyan, Wolf Reik, Bing Ren, David Richardson, Andreas Richter, Daniel Rico, David J, Roberts, Philip Rosenstiel, Mark Rothstein, Abdulrahman Salhab, Hiroyuki Sasaki, John S, Satterlee, Sascha Sauer, Claudia Schacht, Florian Schmidt, Gerd Schmitz, Stefan Schreiber, Christopher Schröder, Dirk Schübeler, Joachim L, Schultze, Ronald P, Schulyer, Marcel Schulz, Martin Seifert, Katsuhiko Shirahige, Reiner Siebert, Thomas Sierocinski, Laura Siminoff, Anupam Sinha, Nicole Soranzo, Salvatore Spicuglia, Mikhail Spivakov, Christian Steidl, Seth Strattan, Michael Stratton, Peter Südbeck, Hao Sun, Narumi Suzuki, Yutaka Suzuki, Amos Tanay, David Torrents, Frederick L, Tyson, Thomas Ulas, Sebastian Ullrich, Toshikazu Ushijima, Alfonso Valencia, Edo Vellenga, Martin Vingron, Chris Wallace, Stefan Wallner, Jörn Walter, Huating Wang, Stephanie Weber, Nina Weiler, Andreas Weller, Andrew Weng, Steven Wilder, Sam M, Wiseman, Angela R, Zhenguo Wu, Jieyi Xiong, Yasuhiro Yamashita, Xinyi Yang, Desmond Y, Yap, Kevin Y, Yip, Stephen Yip, Jae Il Yoo, Daniel Zerbino, Gideon Zipprich, Antonarakis, Stylianos, International Human Epigenome Consortium, [0000-0002-8682-6748], Apollo - University of Cambridge Repository, Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Radboud University Medical Center [Nijmegen], Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Hematology, University of Groningen and University Medical Center Groningen, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universitat de Barcelona, Sergio, Abrignani, David, Adam, Melanie de, Almeida, Altucci, Lucia, Viren, Amin, Ido, Amit, Stylianos, E, Antonarakis, Samuel, Aparicio, Takahiro, Arima, Laura, Arrigoni, Rob, Art, Vahid, Asnafi, Manel, Esteller, Jae Bum, Bae, Kevin, Bassler, Stephan, Beck, Benjamin, Berkman, Bradley, E, Bernstein, Mikhail, Bilenky, Adrian, Bird, Christoph, Bock, Bernhard, Boehm, Guillaume, Bourque, Charles, E, Breeze, Benedikt, Bror, David, Bujold, Oliver, Burren, Marion, J, Bussemakers, Adam, Butterworth, Elias, Campo, Enrique Carrillo de Santa, Pau, Lisa, Chadwick, Kui Ming, Chan, Wei, Chen, Tom, H, Cheung, Luca, Chiapperino, Nak Hyen, Choi, Ho Ryun, Chung, Laura, Clarke, Joseph, M, Connors, Philippe, Cronet, John, Danesh, Manolis, Dermitzaki, Gerard, Drewe, Pawel, Durek, Stephanie, Dyke, Tomasz, Dylag, Connie, J, Eaves, Peter, Ebert, Roland, Eil, Jürgen, Eil, Catherine, A, Ennis, Tariq, Enver, Elise, A, Feingold, Bärbel, Felder, Anne Ferguson, Smith, Jude, Fitzgibbon, Paul, Flicek, Roger, S, Y, Foo, Peter, Fraser, Mattia, Frontini, Eileen, Furlong, Sitanshu, Gakkhar, Nina, Gasparoni, Gilles, Gasparoni, Daniel, H, Geschwind, Petar, Glažar, Thomas, Graf, Frank, Grosveld, Xin Yuan, Guan, Roderic, Guigo, Ivo, G, Gut, Alf, Hamann, Bok Ghee, Han, R, Alan, Harri, Simon, Heath, Kristian, Helin, Jan, G, Hengstler, Alireza Heravi, Moussavi, Karl, Herrup, Steven, Hill, Jason, A, Hilton, Benjamin, C, Hitz, Bernhard, Horsthemke, Ming, Hu, Joo Yeon, Hwang, Nancy, Y, Ip, Takashi, Ito, Biola Maria, Javierre, Sasa, Jenko, Thomas, Jenuwein, Yann, Joly, Steven, J, M, Jone, Yae, Kanai, Hee Gyung, Kang, Aly, Karsan, Alexandra, K, Kiemer, Song Cheol, Kim, Bong Jo, Kim, Hyeon Hoe, Kim, Hiroshi, Kimura, Sarah, Kinkley, Filippos, Klironomo, In Uk, Koh, Myrto, Kostadima, Christopher, Kressler, Roman, Kreuzhuber, Anshul, Kundaje, Ralf, Küpper, Carolyn, Larabell, Paul, Lasko, Mark, Lathrop, S, Lee, Suman, Lee, Hans, Lehrach, Elsa, Leitão, Thomas, Lengauer, Åke, Lernmark, David, Leslie, Gilberto, K, K, Leung, Danny, Leung, Markus, Loeffler, Yussanne, Ma, Antonello, Mai, Thomas, Manke, Eric, R, Marcotte, Marco, A, Marra, Joost, H, A, Marten, Jose Ignacio Martin, Subero, Karen, Maschke, Christoph, Merten, Aleksandar, Milosavljevic, Saverio, Minucci, Totai, Mitsuyama, Richard, A, Moore, Fabian, Müller, Andrew, J, Mungall, Mihai, G, Netea, Karl, Nordström, Irene, Norstedt, Hiroaki, Okae, Vitor, Onuchic, Francis, Ouellette, Willem, Ouwehand, Massimiliano, Pagani, Vera, Pancaldi, Thomas, Pap, Tomi, Pastinen, Ronak, Patel, Dirk, S, Paul, Michael, J, Pazin, Pier Giuseppe, Pelicci, Anthony, G, Phillips, Julia, Polansky, Bo, Porse, J, Andrew, Pospisilik, Shyam, Prabhakar, Dena, C, Procaccini, Andreas, Radbruch, Nikolaus, Rajewsky, Vardham, Rakyan, Wolf, Reik, Bing, Ren, David, Richardson, Andreas, Richter, Daniel, Rico, David, J, Roberts, Philip, Rosenstiel, Mark, Rothstein, Abdulrahman, Salhab, Hiroyuki, Sasaki, John, S, Satterlee, Sascha, Sauer, Claudia, Schacht, Florian, Schmidt, Gerd, Schmitz, Stefan, Schreiber, Christopher, Schröder, Dirk, Schübeler, Joachim, L, Schultze, Ronald, P, Schulyer, Marcel, Schulz, Martin, Seifert, Katsuhiko, Shirahige, Reiner, Siebert, Thomas, Sierocinski, Laura, Siminoff, Anupam, Sinha, Nicole, Soranzo, Salvatore, Spicuglia, Mikhail, Spivakov, Christian, Steidl, Seth, Strattan, Michael, Stratton, Peter, Südbeck, Hao, Sun, Narumi, Suzuki, Yutaka, Suzuki, Amos, Tanay, David, Torrent, Frederick, L, Tyson, Thomas, Ula, Sebastian, Ullrich, Toshikazu, Ushijima, Alfonso, Valencia, Edo, Vellenga, Martin, Vingron, Chris, Wallace, Stefan, Wallner, Jörn, Walter, Huating, Wang, Stephanie, Weber, Nina, Weiler, Andreas, Weller, Andrew, Weng, Steven, Wilder, Sam, M, Wiseman, Angela, R, Wu, Zhenguo, Wu, Jieyi, Xiong, Yasuhiro, Yamashita, Xinyi, Yang, Desmond, Y, Yap, Kevin, Y, Yip, Stephen, Yip, Jae Il, Yoo, Daniel, Zerbino, and Gideon, Zipprich
Subjects: Epigenomics, 0301 basic medicine, [SDV]Life Sciences [q-bio], ADN, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Medizin, Biology, Genoma humà, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, World Wide Web, 03 medical and health sciences, Human health, 0302 clinical medicine, Blueprint, Databases, Genetic, Humans, Disease, ddc:576.5, DNA methylation, databases, genetic, disease, histone code, humans, epigenesis, genetic, epigenomics, genome, human, biochemistry, genetics and molecular biology (all), Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Human genome, Genome, Human, DNA, Epigenome, DNA Methylation, Human cell, Epigenètica, Histone Code, 030104 developmental biology, 030220 oncology & carcinogenesis, Epigenetics
Abstract: Item does not contain fulltext The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalog of high-resolution reference epigenomes of major primary human cell types. The studies now presented (see the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC) highlight the coordinated achievements of IHEC teams to gather and interpret comprehensive epigenomic datasets to gain insights in the epigenetic control of cell states relevant for human health and disease. PAPERCLIP.
Published: 2016

220. Genetic analysis of over one million people identifies 535 novel loci for blood pressure

Author: Lorenz Risch, Anne-Claire Vergnaud, Nguyen Quang Tri, Rona J. Strawbridge, Alan F. Wright, Francesco Cucca, Evan Tzanis, Caterina Barbieri, Jaakko Tuomilehto, Louise V. Wain, Jonathan Marten, James F. Wilson, Christopher Newton-Cheh, Reedik Mägi, Olli T. Raitakari, Peter W.F. Wilson, Joris Deelen, Morris Brown, Anna Morgan, Nabi Shah, Weihua Zhang, Ganesh Chauhan, Gail Davies, Peter S. Braund, Bram P. Prins, Alison Pattie, Marcus Dörr, Zoltán Kutalik, Marco Brumat, Franco Giulianini, Rainer Rettig, Uwe Völker, Georgios Ntritsos, Teresa Nutile, Todd L. Edwards, Albertine J. Oldehinkel, Christopher J. O'Donnell, Jaume Marrugat, Evangelos Evangelou, Nilesh J. Samani, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Francis S. Collins, Tim D. Spector, Simon Thom, Sarah E. Harris, Heather J. Cordell, Helen R. Warren, Cinzia Sala, Peter P. Pramstaller, Seppo Koskinen, Paul F. O'Reilly, Aravinda Chakravarti, Joshua C. Bis, Archie Campbell, Bernard Keavney, Sébastien Thériault, Gonneke Willemsen, Lynda M. Rose, Massimiliano Cocca, Jennifer E. Huffman, Meixia Ren, Massimo Mangino, Markus Perola, Joanna M. M. Howson, David Mosen-Ansorena, Harriëtte Riese, Martin Farrall, Albert V. Smith, Lenore J. Launer, Marina Ciullo, Antti-Pekka Sarin, Veikko Salomaa, Ilaria Gandin, Kent D. Taylor, Peter S. Sever, Markku Laakso, André G. Uitterlinden, Yan V. Sun, Raymond Noordam, Renée de Mutsert, Alan L. James, Jing Hua Zhao, Stefan Enroth, Andrew D. Morris, David S. Siscovick, Andrew D. Johnson, Igor Rudan, Tõnu Esko, Jun Ding, David P. Strachan, Martin D. Tobin, Christopher P. Nelson, Daniela Toniolo, J. Wouter Jukema, Vilmundur Gudnason, Borbala Mifsud, Marty Larson, Andrew A. Hicks, Adriana M. Hung, Antonietta Robino, Ruifang Li-Gao, Paul Elliott, Anne U. Jackson, Michela Traglia, Martin H. de Borst, Germaine C. Verwoert, Rheinhold Schmidt, Fabiola M Del Greco, Åsa Johansson, Anders Hamsten, Csaba P. Kovesdy, Mark J. Caulfield, Cumhur Y Demirkale, John M. C. Connell, Jian'an Luan, K. Witkowska, Georg Ehret, Cecilia M. Lindgren, Oscar H. Franco, Yongmei Liu, Ioanna Tzoulaki, Eric Boerwinkle, Catharina A. Hartman, Muralidharan Sargurupremraj, Claudia Langenberg, J. Michael Gaziano, Peter K. Joshi, Cornelia M. van Duijn, Maris Laan, Nick Shrine, Peter J. van der Most, Michael Boehnke, Leo-Pekka Lyytikäinen, Samuli Ripatti, Ben A. Oostra, Robert A. Scott, Lingchan Lu, Edward G. Lakatta, Yasaman Saba, Daniel Levy, Li Lin, Harold Schneider, Alex S. F. Doney, Michael R. Barnes, Najaf Amin, Hugh Watkins, Paul M. Ridker, Janina S Reid, Ayush Giri, Sekar Kathiresan, Lorna M. Lopez, Mike A. Nalls, Marina Evangelou, Erik Ingelsson, Lili Milani, Alice Stanton, Ozren Polasek, Sara M. Willems, Colin N. A. Palmer, Stéphanie Debette, Dan E. Arking, Helena Schmidt, Paul Knekt, John M. Starr, Yong Qian, Cristina Menni, Yuri Milaneschi, Christophe Tzourio, Tamara B. Harris, Kristin L. Ayers, Peter Vollenweider, Paolo Gasparini, Dennis O. Mook-Kanamori, Rodney J. Scott, Sandosh Padmanabhan, Anubha Mahajan, Peter Almgren, Jacklyn N. Hellwege, Teemu J. Niiranen, Mika Kähönen, Shih-Jen Hwang, Elizabeth G. Holliday, Edith Hofer, Priyanka Nandakumar, Peter J. Munson, Rick Jansen, Andrew P. Morris, Walter Palmas, Ilja M. Nolte, Siim Sõber, Thibaud Boutin, Ahmad Vaez, Albert Hofman, He Gao, Brenda W.J.H. Penninx, Neil Poulter, Alan J. Gow, Caroline Hayward, Nicholas J. Wareham, Elin Org, Philip S. Tsao, Claudia P. Cabrera, Aki S. Havulinna, Dragana Vuckovic, Kelly Cho, Jie Yao, Lars Lind, Jerome I. Rotter, David J. Stott, Ivana Kolcic, Wei-Yu Lin, Tatijana Zemunik, Tineka Blake, Kenneth Rice, Veronique Vitart, Alanna C. Morrison, Kay-Tee Khaw, Marjo-Riitta Järvelin, Guillaume Paré, Jouke-Jan Hottenga, Giorgia Girotto, Chiara Batini, Niki Dimou, Stella Trompet, John Danesh, Annette Peters, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Morris A. Swertz, Jaspal S. Kooner, Niek Verweij, Ibrahim Karaman, Murielle Bochud, Christian Gieger, Ruth J. F. Loos, Daniella Ruggiero, Arno Palotie, David Conen, Raha Pazoki, Denis C. Shields, Rossella Sorice, Philippe Amouyel, Gonçalo R. Abecasis, Andres Metspalu, John Attia, Bruce M. Psaty, Sarah H. Wild, Patricia B. Munroe, Daniel I. Chasman, Ollie Melander, John C. Chambers, Roby Joehanes, Eleftheria Zeggini, Johan Sundström, Chrysovalanto Mamasoula, Benjamin Lehne, Kati Kristiansson, Christopher Oldmeadow, Eco J. C. de Geus, A. Mesut Erzurumluoglu, Anuj Goel, Adam S. Butterworth, Digna R. Velez Edwards, Xiuqing Guo, Antti Jula, Praveen Surendran, Terho Lehtimäki, Mattias Frånberg, Teresa Ferreira, Ian J. Deary, David C. Liewald, Pim van der Harst, Erwin P. Bottinger, Roberto Elosua, and Fu Liang Ng
Subjects: Genetics, 0303 health sciences, Diastole, Disease, 030204 cardiovascular system & hematology, Biology, Precision medicine, Genetic analysis, 3. Good health, Pulse pressure, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Disease prevention, 030304 developmental biology, Genetic association
Abstract: High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.
Published: 2017

221. Efficiency and safety of varying the frequency of whole blood donation: randomised trial of 45,000 donors

Author: Emanuele Di Angelantonio, Simon G Thompson, Stephen Kaptoge, Carmel Moore, Matthew Walker, Jane Armitage, Willem H Ouwehand, David J Roberts, John Danesh, Jenny Donovan, Ian Ford, Rachel Henry, Beverley J Hunt, Bridget Le Huray, Susan Mehenny, Gail Miflin, Jane Green, Mike Stredder, Nicholas A Watkins, Alan McDermott, Clive Ronaldson, Claire Thomson, Zoe Tolkien, Lorna Williamson, David Allen, Jennifer Sambrook, Tracey Hammerton, David Bruce, Fizzah Choudry, Cedric Ghevaert, Kirstie Johnston, Anne Kelly, Andrew King, Alfred Mo, Lizanne Page, Penny Richardson, Peter Senior, Yagnesh Umrania, Henna Wong, Gavin Murphy, Adrian C Newland, Keith Wheatley, Michael Greaves, Marc Turner, Tahir Aziz, Richard Brain, Christine Davies, Ruth Turner, Paula Wakeman, Alison Dent, Alan Wakeman, Ben Anthony, Desmond Bland, Will Parrondo, Helen Vincent, Candy Weatherill, Andrea Forsyth, Carol Butterfield, Tracey Wright, Karen Ellis, Pat Poynton, Carolyn Brooks, Emma Martin, Lara Littler, Lindsay Williams, Donna Blair, Karen Ackerley, Lynn Woods, Sophie Stanley, Gemma Walsh, Gayle Franklin, Cheryl Howath, Sarah Sharpe, Deborah Smith, Lauren Botham, Caroline Williams, Claire Alexander, Gareth Sowerbutts, Diane Furnival, Michael Thake, Shilpa Patel, Carolyn Roost, Sandra Sowerby, Mary Joy Appleton, Eileen Bays, Geoff Bowyer, Steven Clarkson, Stuart Halson, Kate Holmes, Gareth Humphries, Lee Parvin-Cooper, Jason Towler, Joanne Addy, Patricia Barrass, Louise Stennett, Susan Burton, Hannah Dingwall, Victoria Clarke, Maria Potton, Thomas Bolton, Michael Daynes, Sarah Spackman, Abudu Momodu, James Fenton, Adam King, Omer Muhammed, Nicholas Oates, Tim Peakman, Christine Ryan, Kristian Spreckley, Craig Stubbins, Joanna Williams, James Brennan, Cedric Mochon, Samantha Taylor, Kimberley Warren, and Jonathan Mant
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Time Factors, Anemia, Blood Donors, Efficiency, 030204 cardiovascular system & hematology, Risk Assessment, Article, law.invention, 03 medical and health sciences, Patient safety, Young Adult, 0302 clinical medicine, Sex Factors, Randomized controlled trial, Quality of life, law, Medicine, Humans, 030212 general & internal medicine, Young adult, Whole blood, Anemia, Iron-Deficiency, business.industry, Age Factors, General Medicine, Middle Aged, medicine.disease, United Kingdom, 3. Good health, Donation, Ferritins, Female, Patient Safety, business, Risk assessment
Abstract: Summary Background Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p
Published: 2017

222. Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk

Author: John J.P. Kastelein, Stephen J. Nicholls, Brian A. Ference, Marc S. Sabatine, Ulrich Laufs, Robert D. Brook, Henry N. Ginsberg, Adam S. Butterworth, Clare Oliver-Williams, George Davey Smith, M. John Chapman, John Danesh, Alberico L. Catapano, Chris J. Packard, Kausik K. Ray, Oliver-Williams, Clare [0000-0002-3573-2426], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], Apollo - University of Cambridge Repository, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes
Subjects: Cardiovascular event, Gerontology, Male, medicine.medical_specialty, Hypercholesterolemia, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Epidemiology, medicine, Humans, 030212 general & internal medicine, Biology, Apolipoproteins B, Original Investigation, business.industry, European research, Anticholesteremic Agents, Research, Cholesterol, HDL, Genetic variants, Genetic Variation, General Medicine, Apolipoproteins b, Cholesterol, LDL, Mendelian Randomization Analysis, Middle Aged, Medical research, Lipids, Cholesterol Ester Transfer Proteins, Cardiovascular Diseases, LDL Cholesterol Lipoproteins, Female, Hydroxymethylglutaryl CoA Reductases, lipids (amino acids, peptides, and proteins), Hydroxymethylglutaryl-CoA Reductase Inhibitors, business
Abstract: Importance: Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered. Objective: To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. Design, Setting, and Participants: Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015. Exposures: Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median. Main Outcomes and Measures: Odds ratio (OR) for major cardiovascular events. Results: The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Conclusions and Relevance: Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.
Published: 2017

223. Association analyses based on false discovery rate implicate new loci for coronary artery disease

Author: Martin Farrall, Themistocles L. Assimes, Florence Lai, Theodosios Kyriakou, Evangelos Evangelou, Winfried März, Emanuele Di Angelantonio, Aroon D. Hingorani, Ruth J. F. Loos, Erik Ingelsson, Colin N. A. Palmer, Tao Jiang, George Dedoussis, Panos Deloukas, Stavroula Kanoni, Pierre Zalloua, Ruth McPherson, Patrick T. Ellinor, Tom R. Webb, Heribert Schunkert, Mar Pujades-Rodriguez, Adnan Kastrati, Eleftheria Zeggini, Riyaz S. Patel, CARDIoGRAMplusC D, Eric E. Schadt, Christopher P. Nelson, Michael J. Sweeting, John Danesh, Bernard Keavney, Paul W. Franks, Jaspal S. Kooner, Robert Clarke, Richard M Cubbon, Yingchang Lu, Raili Ermel, Nilesh J. Samani, Adam S. Butterworth, Anuj Goel, Martin K. Rutter, Dongfeng Gu, Lingyao Zeng, Christopher Grace, Xiangfeng Lu, Ioanna Tzoulaki, Andres Metspalu, John C. Chambers, Amand F. Schmidt, Johan L.M. Björkegren, Hugh Watkins, Erwin P. Bottinger, Olga Giannakopoulou, Maciej Tomaszewski, Arno Ruusalepp, Stephen E. Hamby, Jemma C. Hopewell, Ioanna Ntalla, Kamal Alghalayini, Joanna M. M. Howson, Eirini Marouli, Thorsten Kessler, Terho Lehtimäki, Jeanette Erdmann, Butterworth, Adam [0000-0002-6915-9015], Di Angelantonio, Emanuele [0000-0001-8776-6719], Howson, Joanna [0000-0001-7618-0050], Sweeting, Michael [0000-0003-0980-8965], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, False discovery rate, UK Biobank CardioMetabolic Consortium CHD working group, Genome-wide association study, Blood vessel morphogenesis, Coronary Artery Disease, 030204 cardiovascular system & hematology, ANNOTATION, Angina, Coronary artery disease, Health Information Systems, 0302 clinical medicine, RARE, Risk Factors, Polymorphism (computer science), GENETIC-VARIANTS, genetics, Genetics & Heredity, Genetics, sequence annotation, 11 Medical And Health Sciences, Phenotype, Medical genetics, LOW-FREQUENCY, Life Sciences & Biomedicine, medicine.medical_specialty, Genotype, DATABASE, Biology, Polymorphism, Single Nucleotide, EPIC-CVD Consortium, 03 medical and health sciences, Meta-Analysis as Topic, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Genetic Association Studies, Genetic association, Science & Technology, Reproducibility of Results, PROFILES, 06 Biological Sciences, medicine.disease, RISK LOCI, United Kingdom, cardiovascular diseases, 030104 developmental biology, ATHEROSCLEROSIS, Genetic Loci, genome-wide association studies, CARDIoGRAMplusC4D, Developmental Biology, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10(-8)) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.
Published: 2017

224. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis

Author: Joseph L. Witztum, Zia Yaqoob, Santica M. Marcovina, Manjinder S. Sandhu, Asif Rasheed, Danish Saleheen, Sotirios Tsimikas, Faisal Majeed, Atif Imran, Fazal-ur-Rehman Memon, Khan Shah Zaman, Philippe M. Frossard, Anis Memon, Daniel J. Rader, Syed Zahed Rasheed, Naveeduddin Ahmed, Saba Akhtar, John Danesh, M. Ishaq, Tahir Saghir, Syed Nadeem Hasan Rizvi, Adam Taleb, Nadeem Qamar, Philip C Haycock, Wei Zhao, Nadeem Hayyat Mallick, Shahid Abbas, Khalid Mahmood, Sandhu, Manjinder [0000-0002-2725-142X], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Apolipoprotein B, Genotype, Endocrinology, Diabetes and Metabolism, Myocardial Infarction, Coronary Disease, 030204 cardiovascular system & hematology, Apoprotein(a), Polymorphism, Single Nucleotide, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Polymorphism (computer science), Risk Factors, Internal medicine, Internal Medicine, medicine, Humans, Protein Isoforms, Genetic Predisposition to Disease, Pakistan, Myocardial infarction, biology, business.industry, Incidence, Case-control study, Articles, Odds ratio, Lipoprotein(a), Mendelian Randomization Analysis, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Phenotype, Case-Control Studies, biology.protein, lipids (amino acids, peptides, and proteins), Female, business, Biomarkers, Lipoprotein
Abstract: Background The lipoprotein(a) pathway is a causal factor in coronary heart disease. We used a genetic approach to distinguish the relevance of two distinct components of this pathway, apolipoprotein(a) isoform size and circulating lipoprotein(a) concentration, to coronary heart disease. Methods In this mendelian randomisation study, we measured lipoprotein(a) concentration and determined apolipoprotein(a) isoform size with a genetic method (kringle IV type 2 [KIV2] repeats in the LPA gene) and a serum-based electrophoretic assay in patients and controls (frequency matched for age and sex) from the Pakistan Risk of Myocardial Infarction Study (PROMIS). We calculated odds ratios (ORs) for myocardial infarction per 1-SD difference in either LPA KIV2 repeats or lipoprotein(a) concentration. In a genome-wide analysis of up to 17 503 participants in PROMIS, we identified genetic variants associated with either apolipoprotein(a) isoform size or lipoprotein(a) concentration. Using a mendelian randomisation study design and genetic data on 60 801 patients with coronary heart disease and 123 504 controls from the CARDIoGRAMplusC4D consortium, we calculated ORs for myocardial infarction with variants that produced similar differences in either apolipoprotein(a) isoform size in serum or lipoprotein(a) concentration. Finally, we compared phenotypic versus genotypic ORs to estimate whether apolipoprotein(a) isoform size, lipoprotein(a) concentration, or both were causally associated with coronary heart disease. Findings The PROMIS cohort included 9015 patients with acute myocardial infarction and 8629 matched controls. In participants for whom KIV2 repeat and lipoprotein(a) data were available, the OR for myocardial infarction was 0·93 (95% CI 0·90–0·97; p
Published: 2017

225. Clonal hematopoiesis and risk for atherosclerotic cardiovascular disease

Author: Christopher J. Gibson, Eugenia Shvartz, Alexander J. Silver, Diego Ardissino, Peter Libby, Namrata Gupta, Galina K. Sukhova, Roxana Mehran, Donna Neuberg, Olle Melander, Siddhartha Jaiswal, Danish Saleheen, Benjamin L. Ebert, John Danesh, Marie McConkey, Usman Baber, Pradeep Natarajan, Valentin Fuster, Stacey Gabriel, Philippe M. Frossard, Alexander G. Bick, and Sekar Kathiresan
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Somatic cell, Clone (cell biology), 030204 cardiovascular system & hematology, Bioinformatics, Somatic evolution in cancer, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Exome, business.industry, Case-control study, Hematopoietic Stem Cell Transplantation, General Medicine, medicine.disease, Atherosclerosis, Hematopoiesis, Haematopoiesis, 030104 developmental biology, Cardiovascular Diseases, Mutation, Medical genetics, business
Abstract: BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the presence of an expanded somatic blood cell clone in those without other hematologic abnormalities, is common in older individuals and associates with an increased risk of developing hematologic cancer. We previously found preliminary evidence for an association of CHIP with human atherosclerotic cardiovascular disease, but the nature of this association was unclear. METHODS: We used whole exome sequencing to detect the presence of CHIP in peripheral blood cells and associated this with coronary heart disease in four case-control studies together comprising 4,794 cases and 3,537 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. RESULTS: In nested case-control analyses from two prospective cohorts, carriers of CHIP had a 1.9-fold (95% confidence interval 1.4–2.7) increased risk of coronary heart disease compared to non-carriers. In two retrospective case-control cohorts for early-onset myocardial infarction, those with CHIP had a 4.0-fold greater risk (95% confidence interval 2.4–6.7) of having myocardial infarction. Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. Those with clonal hematopoiesis also had increased coronary artery calcification, a marker of coronary atherosclerosis burden. Hyperlipidemic mice engrafted with Tet2−/− or Tet2+/− bone marrow developed larger atherosclerotic lesions in the aortic root and aorta than mice receiving control marrow. Analyses of Tet2−/− macrophages demonstrated elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. CONCLUSIONS: Clonal hematopoiesis robustly associates with coronary heart disease in humans and causes accelerated atherosclerosis in mice.
Published: 2017

226. Protein Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease

Author: Jaume Marrugat, Fumihiko Takeuchi, Tanya M. Teslovich, Norihiro Kato, Masa-aki Kawashiri, Jun-Sing Wang, H. Lester Kirchner, Peter S. Braund, Masahiro Nakatochi, Heribert Schunkert, Rosanna Asselta, Danish Saleheen, Daniel R. Lavage, Dustin N. Hartze, Roberto Elosua, Stacey Gabriel, Ingrid B. Borecki, Nilesh J. Samani, Frederick E. Dewey, David J. Carey, Yukihide Momozawa, Chao A. Hsiung, Jerome I. Rotter, Michael F. Murray, Matthew J. Bown, John Danesh, Shane McCarthy, Piera Angelica Merlini, Joseph B. Leader, Namrata Gupta, Tomohiro Katsuya, Gina M. Peloso, Cristen J. Willer, Eitaro Nakashima, Hayato Tada, Gonçalo R. Abecasis, Amit Khera, Pradeep Natarajan, Ken Yamamoto, Derek Klarin, Alistair S. Hall, Connor A. Emdin, Thorsten Kessler, Seyedeh M. Zekavat, Mitsuhiro Yokota, Yii-Der Ida Chen, Akihiro Nomura, Martin Farrall, Hong-Hee Won, Michiaki Kubo, Hugh Watkins, Eric S. Lander, Sekar Kathiresan, James G. Wilson, Ruth McPherson, Masakazu Yamagishi, Kaoru Ito, Adolfo Correa, Jyh-Ming Jimmy Juang, J. Neil Manus, Shih-Yi Lin, Diego Ardissino, Stefano Duga, Daniel J. Rader, Akihiro Inazu, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Adult, Male, Human dna, Physiology, Clinical Sciences, cholesteryl ester transfer protein, Coronary Disease, Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Cardiovascular, Article, Truncate, lipids, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Cholesterylester transfer protein, Genetics, Humans, Gene, Heart Disease - Coronary Heart Disease, Aged, biology, Chemistry, case-control studies, Genetic Variation, Middle Aged, Atherosclerosis, Coronary heart disease, Cholesterol Ester Transfer Proteins, Heart Disease, 030104 developmental biology, Cardiovascular System & Hematology, Case-Control Studies, Cancer research, biology.protein, lipids (amino acids, peptides, and proteins), Female, Cardiology and Cardiovascular Medicine
Abstract: Rationale : Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. Objective: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We sequenced the exons of the CETP gene in 58 469 participants from 12 case–control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case–control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18–27; P −4 ), lower low-density lipoprotein cholesterol (−12.2 mg/dL; 95% confidence interval, −23 to −0.98; P =0.033), and lower triglycerides (−6.3%; 95% confidence interval, −12 to −0.22; P =0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54–0.90; P =5.1×10 −3 ). Conclusions: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.
Published: 2017

227. Consequences of natural perturbations in the human plasma proteome

Author: Dirk S. Paul, Joseph C. Maranville, Sarah L. Spain, Ellie Paige, Karsten Suhre, Caroline S. Fox, Bradley, Benjamin B. Sun, Praveen Surendran, David J. Roberts, James E. Peters, Clare Oliver-Williams, John Danesh, David Stacey, Mihir A Kamat, Nebojsa Janjic, Robert M. Plenge, An Chi, Narinder Bansal, Tao Jiang, Angela M. Wood, Erik S Zimmerman, Bram P. Prins, Willem H. Ouwehand, Stephen Burgess, James A. Blackshaw, Heiko Runz, John A. Todd, Sheri K. Wilcox, Adam S. Butterworth, Staley, Nicole Soranzo, and Nicholas W. Morrell
Subjects: Genetics, Drug, 0303 health sciences, media_common.quotation_subject, Mendelian Randomization Analysis, Genomics, Disease, Biology, Genetic architecture, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Human plasma, Genetic variation, Proteome, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract: Proteins are the primary functional units of biology and the direct targets of most drugs, yet there is limited knowledge of the genetic factors determining inter-individual variation in protein levels. Here we reveal the genetic architecture of the human plasma proteome, testing 10.6 million DNA variants against levels of 2,994 proteins in 3,301 individuals. We identify 1,927 genetic associations with 1,478 proteins, a 4-fold increase on existing knowledge, including trans associations for 1,104 proteins. To understand consequences of perturbations in plasma protein levels, we introduce an approach that links naturally occurring genetic variation with biological, disease, and drug databases. We provide insights into pathogenesis by uncovering the molecular effects of disease-associated variants. We identify causal roles for protein biomarkers in disease through Mendelian randomization analysis. Our results reveal new drug targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.
Published: 2017
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228. New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals

Author: Anne-Claire Vergnaud, Tibor V. Varga, Melissa A. Richard, Jaakko Tuomilehto, Louise V. Wain, Leif Groop, Reedik Mägi, Danish Saleheen, Olle Melander, Marcus Dörr, He Zhang, Alena Stančáková, Michael Boehnke, Claudia Langenberg, Paul Elliott, Adam S. Butterworth, Andrianos M. Yiorkas, Yingchang Lu, Tea Skaaby, George Dedoussis, Xiuqing Guo, Robin Young, Cristiano Fava, Timo A. Lakka, Igor Rudan, Riccardo E. Marioni, Helen R. Warren, Ioanna Tzoulaki, Myriam Fornage, Bruce M. Psaty, Tõnu Esko, Najaf Amin, Vilmundur Gudnason, Ozren Polasek, Yongmei Liu, Panos Deloukas, Paul M. Ridker, Vinicius Tragante, John M. C. Connell, Mark J. Caulfield, Jette Bork-Jensen, Giovanni Malerba, Eric Boerwinkle, Alanna C. Morrison, Todd L. Edwards, Teresa Ferreira, Torben Hansen, Aldi T. Kraja, He Gao, Alaitz Poveda, Praveen Surendran, Christopher Newton-Cheh, Christian Theil Have, Cramer Christensen, Daniel I. Chasman, Paul W. Franks, Ian J. Deary, Xueling Sim, Evangelos Evangelou, Roby Joehanes, Daniel R. Witte, Cristina Menni, Niels Grarup, Weihua Zhang, Eleftheria Zeggini, Anubha Mahajan, Nora Franceschini, Fredrik Karpe, Lars Lind, Rainer Rauramaa, Oluf Pedersen, Pim van der Harst, Jeanette M. Stafford, Alisa K. Manning, Lori L. Bonnycastle, Rudolf A. de Boer, Kenneth Rice, Nicholas J. Wareham, Tiinamaija Tuomi, Charles Kooperberg, Alexandra I. F. Blakemore, Kathleen Stirrups, Marjo-Riitta Järvelin, Michael A. Province, Marit E. Jørgensen, Allan Linneberg, Veikko Salomaa, Albert V. Smith, Cornelia M. van Duijn, Hao Mei, Mark I. McCarthy, Nilesh J. Samani, Anna F. Dominiczak, Joanna M. M. Howson, Erik Ingelsson, Colin N. A. Palmer, Markku Laakso, Karen L. Mohlke, Folkert W. Asselbergs, Sarah E. Harris, Ayush Giri, Daniel Levy, Anne Mari Käräjämäki, Michael R. Barnes, Aliki-Eleni Farmaki, Muhammad Riaz, Lorraine Southam, Karl-Heinz Herzig, Caroline Hayward, Nigel W. Rayner, John Danesh, Ruth J. F. Loos, Jennifer A. Smith, Ivan Brandslund, Neil Poulter, Jerome I. Rotter, Peter S. Sever, Chunyu Liu, John M. Starr, Stefan Weiss, Georg Ehret, Cecilia M. Lindgren, Walter Palmas, Fotios Drenos, Jaspal S. Kooner, Göran Hallmans, Megan L. Grove, Patricia B. Munroe, Andrew P. Morris, Aki S. Havulinna, James P. Cook, John C. Chambers, Cristen J. Willer, Claudia P. Cabrera, Sharon L.R. Kardia, Peter van der Meer, James G. Wilson, Louis Little, Sandosh Padmanabhan, Oksa Heikki, Franco Giulianini, Giovanni Gambaro, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Ehret, Georg Benedikt, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, British Heart Foundation, Imperial College Healthcare NHS Trust- BRC Funding, Epidemiology, Medical Informatics, Medical Oncology, Internal Medicine, and Gastroenterology & Hepatology
Subjects: 0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, Databases, Factual, Neuronal, Association Studies, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, VARIANTS, Lymphocyte Homing, DISEASE, Antiporters, Cell Adhesion Molecules, Neuronal/genetics, 0302 clinical medicine, Genotype, Receptors, Missense mutation, Settore MED/14 - NEFROLOGIA, FUNCTIONAL VARIATION, CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group†, genetics, Exome, Genetics (clinical), Genetics, Genetics & Heredity, ddc:616, Antiporters/genetics, Microfilament Proteins, blood pressure, Single Nucleotide, sample size, Phenotype, COMPARATIVE RISK-ASSESSMENT, exome, genotype, Cell Adhesion Molecules, Neuronal, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Receptors, Lymphocyte Homing, Genetic Loci, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, SCAVENGER RECEPTOR, Understanding Society Scientific Group, Blood Pressure/genetics, Neuronal/genetics, Locus (genetics), Biology, Gene Expression and Regulation, 1102 Cardiovascular Medicine And Haematology, 03 medical and health sciences, Databases, Microfilament Proteins/genetics, SYSTEMATIC ANALYSIS, Journal Article, GENOME-WIDE ASSOCIATION, Polymorphism, COMMON, Receptors, Lymphocyte Homing/genetics, Factual, Genetic association, 0604 Genetics, Science & Technology, FAT DISTRIBUTION, GLOBAL BURDEN, Minor allele frequency, 030104 developmental biology, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, Cell Adhesion Molecules, Lymphocyte Homing/genetics
Abstract: Background— Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results— Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant ( P − 8 ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP ), rs7437940 ( AFAP1 ), rs13303 (missense, STAB1 ), and rs1055144 ( 7p15.2 ). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L ) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency DBH ) was genome-wide significant. Conclusions— We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
Published: 2017

229. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity

Author: Sumeet A. Khetarpal, Maria Samuel, Khan Shah Zaman, Khalid Mahmood, Saba Akhtar, Daniel J. Rader, Kevin Trindade, Shahid Abbas, Syed Nadeem Hasan Rizvi, Zia Yaqoob, Pradeep Natarajan, Faisal Majeed, Syed Zahed Rasheed, Asif Rasheed, Benjamin Weisburd, Atif Imran, Nadeem Hayat Mallick, Namrata Gupta, Daniel G. MacArthur, John Danesh, Kaitlin E. Samocha, Hong-Hee Won, Madiha Ishaq, Wei Zhao, Mozzam Zaidi, Mohammad Ishaq, Anis Memon, Anne H. O’Donnell-Luria, Nadeem Qamar, Eric S. Lander, Fazal-ur-Rehman Memon, Irina M. Armean, Konrad J. Karczewski, Tahir Saghir, Ronald M. Krauss, Megan L. Mucksavage, Philippe M. Frossard, Naveeduddin Ahmed, Stacey Gabriel, Danish Saleheen, Sekar Kathiresan, Ron Do, Mark J. Daly, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, DNA Mutational Analysis, Myocardial Infarction, Coronary Disease, medicine.disease_cause, Cohort Studies, Consanguinity, Gene Frequency, Pakistan, Exome, Neuregulins, Genetics, Mutation, Multidisciplinary, Homozygote, Fasting, Middle Aged, Postprandial Period, Circadian Rhythm, 3. Good health, Pedigree, Phenotype, Female, Sodium-Hydrogen Exchangers, Offspring, General Science & Technology, Sodium-Hydrogen Antiporter, Biology, Article, 03 medical and health sciences, medicine, Humans, Cytochrome P450 Family 2, Gene, Allele frequency, Gene knockout, Triglycerides, Genetic Association Studies, Apolipoprotein C-III, Interleukin-8, Phosphoproteins, Dietary Fats, Reverse Genetics, Minor allele frequency, 030104 developmental biology, Genes, 1-Alkyl-2-acetylglycerophosphocholine Esterase, RNA Splice Sites, Gene Deletion
Abstract: A major goal of biomedicine is to understand the function of every gene in the human genome.1 Loss-of-function (LoF) mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such ‘human knockouts’ can provide insight into gene function. Consanguineous unions are more likely to result in offspring who carry LoF mutations in a homozygous state. In Pakistan, consanguinity rates are notably high.2 Here, we sequenced the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS) designed to understand the determinants of cardiometabolic diseases in South Asians.3 We identified individuals carrying predicted LoF (pLoF) mutations in the homozygous state, and performed phenotypic analysis involving >200 biochemical and disease traits. We enumerated 49,138 rare (
Published: 2017

230. Commentary on 'A meta-analysis but not a systematic review: an evaluation of the Global BMI Mortality Collaboration'

Author: Emanuele Di Angelantonio, Shilpa N Bhupathiraju, John Danesh, Frank B. Hu, Di Angelantonio, Emanuele [0000-0001-8776-6719], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: Gerontology, medicine.medical_specialty, Epidemiology, Extramural, business.industry, Alternative medicine, MEDLINE, 42 Health Sciences, 3 Good Health and Well Being, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Meta-analysis, medicine, 4206 Public Health, 030212 general & internal medicine, business
Published: 2017

231. Exome-wide association study of plasma lipids in >300,000 individuals

Author: Asif Rasheed, Mary F. Feitosa, Ian J. Deary, Melissa E. Garcia, Danish Saleheen, Christian Gieger, Andrea Maschio, Lia E. Bang, Cliona Molony, Ivan Brandslund, Dan M. Roden, Ian Ford, Paul M. Ridker, Alisa K. Manning, Giorgio Pistis, Anette Varbo, Alexander P. Reiner, Kathleen Stirrups, David C. Liewald, Tim D. Spector, Paul W. Franks, Cristen J. Willer, Daniel I. Chasman, Jean Ferrières, Vilmundur Gudnason, Tapani Ebeling, Neil Poulter, Magdalena Zoledziewska, Elizabeth K. Speliotes, Eleftheria Zeggini, Megan L. Grove, Hua Tang, Stavroula Kanoni, Peter Weeke, Panos Deloukas, Daniel J. Rader, Amit Khera, Serena Sanna, Dorota Pasko, Gina M. Peloso, Charles Kooperberg, Suthesh Sivapalaratnam, Natalie R. van Zuydam, Christian M. Shaffer, Fredrik Karpe, Naveed Sattar, Pieter Muntendam, Ruth J. F. Loos, Eric Boerwinkle, Wei Gao, Mark J. Caulfield, Matt Neville, Sangeetha Somayajula, Olle Melander, Hayato Tada, Jose M. Ordovas, He Zhang, John D. Rioux, Michael Boehnke, Erwin P. Bottinger, Franco Giulianini, Martina Müller-Nurasyid, Stella Trompet, Connor A. Emdin, Andrew P. Morris, Johanne Marie Justesen, Alan R. Tall, Kari Kuulasmaa, Adam S. Butterworth, Marie-Pierre Dubé, Dajiang J. Liu, Paul L. Auer, Jennifer E. Huffman, Usman Baber, John Danesh, Xiao Wang, Anna F. Dominiczak, Jarmo Virtamo, John M. Starr, Ozren Polasek, Gonçalo R. Abecasis, Timo A. Lakka, Stephen S. Rich, Marco M Ferrario, Marju Orho-Melander, Xueling Sim, Dominique Arveiler, Dermot F. Reilly, Torsten Lauritzen, Gudny Eiriksdottir, Marit E. Jørgensen, Anubha Mahajan, Colin N. A. Palmer, Veikko Salomaa, Nicholas J. Wareham, Dewan S. Alam, Anne Tybjærg-Hansen, Ellen M. Schmidt, Y. Eugene Chen, Heather M. Stringham, Bruce M. Psaty, Christie M. Ballantyne, Nan Wang, Joshua C. Bis, Myriam Fornage, Neil S Zheng, Kristian Hveem, Praveen Surendran, Yingchang Lu, Peter S. Sever, James B. Meigs, Heikki A. Koistinen, Charlotta Pisinger, Tibor V. Varga, Yii-Der Ida Chen, Konstantin Strauch, Timothy M. Frayling, Patricia B. Munroe, Albert V. Smith, Ruth Frikke-Schmidt, Lorraine Southam, Frida Renström, Philippe Amouyel, Nicholas G. D. Masca, Alexessander Couto Alves, Xiangfeng Lu, Andres Metspalu, Anne Langsted, Joanna M. M. Howson, Tamara B. Harris, Leif Groop, Chad A. Cowan, Cramer Christensen, Audrey Y. Chu, Markku Laakso, Torben Hansen, Li-An Lin, John C. Chambers, Jonas B. Nielsen, Niels Grarup, Neil R. Robertson, Kiran Musunuru, Joshua S. Weinstock, Morris J. Brown, Jean-Claude Tardif, Gorm B. Jensen, Jerome I. Rotter, Harald Grallert, Yan Zhang, Kerrin S. Small, Nathan O. Stitziel, Fabio Busonero, Jennifer Wessel, Themistocles L. Assimes, Lenore J. Launer, Lars G. Fritsche, Mark O. Goodarzi, Peter W.F. Wilson, Sekar Kathiresan, Philippe M. Frossard, Emanuele Di Angelantonio, Yanhua Zhou, James G. Wilson, Frank Kee, Scott M. Damrauer, Weihua Zhang, Gail Davies, Oluf Pedersen, Sune F. Nielsen, Alanna C. Morrison, Raquel S. Sevilla, Helen R. Warren, Johanna Kuusisto, Hanieh Yaghootkar, Sandosh Padmanabhan, Philip S. Tsao, Caroline Hayward, Tõnu Esko, Ming Xu, Anders Mälarstig, Anne U. Jackson, Eirini Marouli, Jette Bork-Jensen, Robin Young, C.J. O'Donnell, Yong Huo, Melanie Waldenberger, Jaspal S. Kooner, Pekka Mäntyselkä, Marjo-Riitta Järvelin, Santhi K. Ganesh, Annette Peters, L. Adrienne Cupples, Wei Zhou, Derek Klarin, Markus Perola, Francesco Cucca, Allan Linneberg, Mark I. McCarthy, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, J. Wouter Jukema, Valentin Fuster, Claudia Langenberg, Roxana Mehran, Børge G. Nordestgaard, Jaakko Tuomilehto, Reedik Mägi, Blair H. Smith, Johanna Jakobsdottir, Marianne Benn, Kent D. Taylor, Ani Manichaikul, Igor Rudan, Aniruddh P. Patel, Joshua C. Denny, Oddgeir L. Holmen, John M. C. Connell, Robert A. Scott, Haojie Yu, Rajiv Chowdhury, Sehrish Jabeen, Antonella Mulas, Aliki-Eleni Farmaki, Rainer Rauramaa, George Dedoussis, Vascular Medicine, Nielsen, Jonas B [0000-0002-6654-2852], Kathiresan, Sekar [0000-0002-6724-032X], Apollo - University of Cambridge Repository, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: 0301 basic medicine, Exome/genetics, Genome-wide association study, Type 2 diabetes, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, Charge Diabetes Working Group, Macular Degeneration, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Exome, Macular Degeneration/blood, Genetics & Heredity, Genetic Predisposition to Disease/genetics, CLONAL HEMATOPOIESIS, 11 Medical And Health Sciences, CODING-SEQUENCE VARIANTS, Lipids, Phenotype, CARDIOVASCULAR-DISEASE, VA Million Veteran Program, lipids (amino acids, peptides, and proteins), GOLD Consortium, LOW-FREQUENCY, EPIC-InterAct Consortium, Diabetes Mellitus, Type 2/blood, Life Sciences & Biomedicine, Type 2, medicine.medical_specialty, Genotype, APOBEC-1 COMPLEMENTATION FACTOR, Biology, Lower risk, Article, EPIC-CVD Consortium, GENETIC ARCHITECTURE, 03 medical and health sciences, Coronary Artery Disease/blood, Diabetes mellitus, Internal medicine, Genetics, medicine, Diabetes Mellitus, Journal Article, Lipolysis, Humans, Genetic Predisposition to Disease, Allele, TYROSINE KINASE JAK2, Genetic Association Studies, B MESSENGER-RNA, Science & Technology, MACULAR DEGENERATION, MYELOPROLIFERATIVE DISORDERS, Cholesterol, Lipids/blood, Genetic Variation, 06 Biological Sciences, medicine.disease, cardiovascular diseases, genome wide association studies, Genetic Association Studies/methods, 030104 developmental biology, Endocrinology, chemistry, Diabetes Mellitus, Type 2, TM6SF2, Developmental Biology
Abstract: We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.
Published: 2017

232. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Author: Pia R. Kamstrup, Nilesh J. Samani, Daniel F. Freitag, Nora Franceschini, Børge G. Nordestgaard, Chao A. Hsiung, Charles Kooperberg, Elias Salfati, Rajiv Chowdhury, Kristin L. Young, Wayne Huey-Herng Sheu, Asif Rasheed, Cara L. Carty, I-Te Lee, Jemma B. Wilk, Ying-Hsiang Chen, Lucia A. Hindorff, Praveen Surendran, Alexander P. Reiner, Ren-Hua Chung, Dewan S. Alam, Andrew D. Johnson, Jeanette Erdmann, Sune F. Nielsen, Adam S. Butterworth, Heribert Schunkert, Thomas Quertermous, Abdulla Al Shafi Majumder, Julie A. Johnson, Sekar Kathiresan, Robin Young, Themistocles L. Assimes, CARDIoGRAMplusC D, Xiuqing Guo, Katrine L. Rasmussen, John A. Spertus, Daniel J. Rader, Joanna M. M. Howson, John D. Eicher, Anne E. Justice, Stanley L. Hazen, Panos Deloukas, Eric B. Fauman, Devin Absher, Eric Boerwinkle, Danish Saleheen, John Danesh, Daniel R. Barnes, Epic-Cvd, Weang Kee Ho, Philippe M. Frossard, Hugh Watkins, Yi-Jen Hung, Anne Tybjærg-Hansen, Anders Mälarstig, Jyh-Ming Jimmy Juang, Ulrike Peters, Jerome I. Rotter, Emanuele Di Angelantonio, Tzung-Dau Wang, Ron Do, Carl J. Pepine, Wei-Yu Lin, Wen-Jane Lee, Benjamin B. Sun, Kari E. North, Lindsay L. Waite, Mariaelisa Graff, Steven Buyske, Yii-Der Ida Chen, Wei Zhao, Arshed A. Quyyumi, Kent D. Taylor, and Dirk S. Paul
Subjects: 0301 basic medicine, Male, Leukocyte migration, Genotype, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Quantitative trait locus, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, Muscle, Smooth, Vascular, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Genetics, medicine, Cell Adhesion, Humans, Genetic Predisposition to Disease, Genetic association, Arteries, medicine.disease, Atherosclerosis, 3. Good health, Histone Code, Chemotaxis, Leukocyte, 030104 developmental biology, Vascular smooth muscle cell differentiation, Female, Energy Metabolism, Genome-Wide Association Study
Abstract: Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide1,2. Although 58 genomic regions have been associated with CAD thus far3-9, most of the heritability is unexplained9, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed metaanalysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 x 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p. Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with celltype- specific gene expression and plasma protein levels sheds light on potential disease mechanisms.
Published: 2017

233. Big data from electronic health records for early and late translational cardiovascular research: challenges and potential

Author: Harry Hemingway, Folkert W Asselbergs, John Danesh, Richard Dobson, Nikolaos Maniadakis, Aldo Maggioni, Ghislaine JM van Thiel, Maureen Cronin, Gunnar Brobert, Panos Vardas, Stefan D Anker, Diederick E Grobbee, Spiros Denaxas, Folkert Asselbergs, Arno Hoes, Ghislaine van Thiel, Hans van Delden, René Eijkemans, Rolf Groenwold, Pieter Stolk, Olaf Klungel, and Gerd P
Published: 2017
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234. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Author: Tazeen H. Jafar, Lars Lind, Peter Almgren, Wendy Winckler, Eitaro Nakashima, Young Min Cho, Annette Peters, Rona J. Strawbridge, Ananda R. Wickremasinghe, Katharine R. Owen, Lee-Ming Chuang, Tien-Jyun Chang, Graeme I. Bell, James B. Meigs, Bill Musk, Timo A. Lakka, Elin Grundberg, Wei Lu, Sarah Edkins, George Dedoussis, Weiping Jia, Danish Saleheen, Suthesh Sivapalaratnam, Maria Samuel, Tien Yin Wong, Lu Qi, Pierre Fontanillas, Momoko Horikoshi, Jirong Long, Abdul Basit, Anubha Mahajan, Andrew T. Hattersley, Markus M. Nöthen, Denis Rybin, Inger Njølstad, S. Krithika, Miguel Cruz, Delilah Zabaneh, Leena Peltonen, Jasmina Kravic, Sangsoo Kim, David Couper, Lori L. Bonnycastle, Heather M. Stringham, Yi-Cheng Chang, Paul Elliott, Eric J.G. Sijbrands, Nita G. Forouhi, Alena Stančáková, Ghazala Mirza, Robert W. Lawrence, Ruth J. F. Loos, Norman Klopp, Shiro Maeda, Martina Müller-Nurasyid, Jer-Yuarn Wu, Jianjun Liu, Kee Seng Chia, Elodie Eury, Loukianos S. Rallidis, Timothy M. Frayling, Ken Yamamoto, David Altshuler, Gunnar Sigurosson, Harald Grallert, Jackie F. Price, Barbara Thorand, Jouko Saramies, Malene M. Kristensen, Sonali Pechlivanis, Inês Barroso, Jong-Young Lee, Melissa Parkin, Josée Dupuis, Stéphane Lobbens, Jesús Kumate, Elena Tremoli, Sudhir Kowlessur, Xueling Sim, Norihiro Kato, Philippe Froguel, Kathleen Stirrups, Eero Lindholm, Alex S. F. Doney, Andres Metspalu, Yu-Tang Gao, Roman Wennauer, Xiao-Ou Shu, Marilyn C. Cornelis, Veikko Salomaa, Nanette R. Lee, Johanna Kuusisto, Caroline S. Fox, Man Li, James Scott, Wing-Yee So, Andrew R. Wood, Inga Prokopenko, Oddgeir L. Holmen, Tin Aung, Ryoichi Takayanagi, Chen Suo, Hara Kazuo, Carl G. P. Platou, Ann M. Kelly, Teresa Ferreira, Karl-Heinz Jöckel, Wei-Yen Lim, James F. Wilson, Tom Forsén, Qi Sun, Valur Emilsson, Gonçalo R. Abecasis, Fan Zhang, Timo Saaristo, Harry Campbell, Ying Wu, Mark Seielstad, Wei Zheng, Han Chen, Stavroula Kanoni, Yuqian Bao, Jose C. Florez, Wan Ting Tay, Ronald C. WMa, Gerald Steinbach, Min Jin Go, Rong Zhang, Junbin Liang, Vasiliki Lagou, Leif Groop, Emil Rehnberg, Nabi Shah, Weihua Zhang, Yun Li, Bengt Sennblad, Olle Melander, Nancy L. Pedersen, Muhammed Islam, Jaakko Tuomilehto, Young Jin Kim, Richard N. Bergman, Juliana C.N. Chan, Eleftheria Zeggini, Andrew D. Johnson, Kees Hovingh, Joban Sehmi, Rainer Rauramaa, Satu Männistö, Reedik Mägi, Samuel Liju, Mingyu Yang, Ayellet V. Segrè, Noël P. Burtt, Mozhgan Dorkhan, Beverley Balkau, Neelam Hassanali, Hyun Min Kang, Fabrizio Veglia, Eeva Korpi-Hyövälti, Loic Yengo, Elizabeth J. Rossin, Angela Silveira, Maggie C.Y. Ng, Yuan-Tsong Chen, Anders Hamsten, David R. Matthews, Mark J. Caulfield, Emmi Tikkanen, Tanya M. Teslovich, John R. B. Perry, Karen L. Mohlke, Sarah E. Hunt, Soo Heon Kwak, Jorge Escobedo, Christopher J. Groves, Ulf de Faire, Jeremy B M Jowett, Gudmar Thorleifsson, Michael Roden, Evelin Mihailov, Viswanathan Mohan, Craig L. Hanis, Thomas WMühleisen, Congrong Wang, Sonia Shah, Kyle J. Gaulton, Jaspal S. Kooner, Jiro Nakamura, Mustafa Atalay, Linda S. Adair, S Wiltshire, Tõnu Esko, Anna Jonsson, Antigone S. Dimas, Karin Leander, Li Ching Chang, George B. Grant, Bo Isomaa, Anne U. Jackson, Claudia Langenberg, Kristian Hveem, Yoon Shin Cho, Astradur B. Hreidarsson, Xu Wang, Keizo Ohnaka, Alexandra C. Nica, Simon D. Rees, Pau Navarro, Sekar Kathiresan, Rob M. van Dam, Zafar I. Hydrie, Bok Ghee Han, Francis S. Collins, Fuu Jen Tsai, Unnur Thorsteinsdottir, Ross M. Fraser, Caroline Hayward, Cornelia M. van Duijn, Samuli Ripatti, Mieke D. Trip, Hyung Lae Kim, Rafn Benediktsson, Candace Guiducci, Bruna Gigante, Kyong Soo Park, Wen Hong L. Kao, Tom Wilsgaard, Leena Kinnunen, John Danesh, Alan James, Alan R. Shuldiner, Mitsuhiro Yokota, Jen Mai Lee, Kari Stefansson, Erik Ingelsson, Colin N. A. Palmer, David J. Hunter, Paul Zimmet, Manickam Chidambaram, Sirkka Keinänen-Kiukaanniemi, Laura J. Scott, Susanne Moebus, Benjamin F. Voight, Wolfgang Rathmann, Hassan Khan, Thomas Illig, Prasad Katulanda, Christian Gieger, Andrew D. Morris, Yik Ying Teo, Andrew P. Morris, Venkatesan Radha, N. William Rayner, Johan G. Eriksson, Christian Dina, Igor Rudan, Sailaja Vedantam, Cheng Hu, James S. Pankow, Ann-Christine Syvänen, Karl Gertow, Valeriya Lyssenko, Guillaume Charpentier, Albert Hofman, Chiea Chuen Khor, Joseph Trakalo, Peter Kraft, Takashi Kadowaki, Qiuyin Cai, John C. Chambers, André G. Uitterlinden, Simon C. Potter, Nicholas J. Wareham, Soumya Raychaudhuri, Jian'an Luan, Tiinamaija Tuomi, Anthony H. Barnett, Juha Saltevo, Robert A. Scott, Valgerdur Steinthorsdottir, Peng Keat Ng, Mark I. McCarthy, Åsa K. Hedman, Kerrin S. Small, Julia Meyer, Frank B. Hu, Cecilia M. Lindgren, Jennifer E. Below, Nancy J. Cox, Jennie Hui, Andrew Crenshaw, Latonya F. Been, Nam H. Cho, Janani Pinidiyapathirage, A. Samad Shera, Bernhard OBoehm, Jason Carey, Augustine Kong, Twee Hee Ong, Philippe M. Frossard, Donald W. Bowden, Toshimasa Yamauchi, Steve E. Humphries, Cordelia Langford, Xinzhong Li, Hiroshi Ikegami, Stéphane Cauchi, Ching-Ti Liu, Michael Boehnke, Peter M. Nilsson, Debashish Das, John Beilby, Robin Young, Christian Herder, Asif Rasheed, Neil Robertson, Raimund Erbel, Fumihiko Takeuchi, Markku Laakso, Esteban J. Parra, Panos Deloukas, Eric Boerwinkle, Adan Valladares-Salgado, Chien-Hsiun Chen, Kay-Tee Khaw, Damiano Baldassarre, Ashok Kumar, E. Shyong Tai, Peter S. Chines, Dharambir KSanghera, Peter Donnelly, [ 1 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 2 ] Natl Inst Hlth, Ctr Genome Sci, Gangoe Myeon, Yeonje Ri, South Korea [ 3 ] Univ London Imperial Coll Sci Technol & Med, London, England [ 4 ] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA [ 5 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England [ 6 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 7 ] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA [ 8 ] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA [ 9 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England [ 10 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England [ 11 ] Ctr Noncommunicable Dis Pakistan, Karachi, Pakistan [ 12 ] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117548, Singapore [ 13 ] Wellcome Trust Sanger Inst, Cambridge, England [ 14 ] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA [ 15 ] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA [ 16 ] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden [ 17 ] Univ Eastern Finland, Inst Biomed, Kuopio, Finland [ 18 ] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore [ 19 ] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore [ 20 ] IRCCS, Ctr Cardiol Monzino, Milan, Italy [ 21 ] Univ Milan, Dept Pharmacol Sci, Milan, Italy [ 22 ] INSERM, Ctr Rech Epidemiol & Sante Populat CESP, U1018, Villejuif, France [ 23 ] Univ Paris 11, UMRS 1018, Villejuif, France [ 24 ] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Endocrinol & Metab, Shanghai Key Lab Diabet Mellitus,Shanghai Diabet, Shanghai 200030, Peoples R China [ 25 ] Univ Birmingham, Coll Med & Dent Sci, Birmingham, W Midlands, England [ 26 ] Heart England Natl Hlth Serv NHS Fdn Trust, Ctr Biomed Res, Birmingham, W Midlands, England [ 27 ] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England [ 28 ] Addenbrookes Hosp, Inst Metab Sci, Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England [ 29 ] Baqai Inst Diabetol & Endocrinol, Karachi, Pakistan [ 30 ] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat,Sect Genet, Oklahoma City, OK 73190 USA [ 31 ] Sir Charles Gairdner Hosp, Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia [ 32 ] Queen Elizabeth II Med Ctr, PathWest Lab Med Western Australia, Nedlands, WA, Australia [ 33 ] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia [ 34 ] Univ Chicago, Dept Med, Chicago, IL 60637 USA [ 35 ] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA [ 36 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 37 ] Landspitali Univ Hosp, Reykjavik, Iceland [ 38 ] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA [ 39 ] Univ Med Ctr Ulm, Div Endocrinol & Diabet, Dept Internal Med, Ulm, Germany [ 40 ] Nanyang Technol Univ, Lee Kong Chian LKC Sch Med, Singapore 639798, Singapore [ 41 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 42 ] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA [ 43 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 44 ] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA [ 45 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Dept Med, Nashville, TN 37212 USA [ 46 ] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland [ 47 ] Univ Edinburgh, Western Gen Hosp, MRC, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland [ 48 ] CNRS, Unite Mixte Rech UMR 8199, Inst Biol, Lille, France [ 49 ] Univ Lille 2, Inst Pasteur, Lille, France [ 50 ] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, London, England [ 51 ] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Barts & London Genome Ctr, London, England [ 52 ] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China [ 53 ] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan [ 54 ] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan [ 55 ] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France [ 56 ] China Med Univ, Sch Chinese Med, Taichung, Taiwan [ 57 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 58 ] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore [ 59 ] Indian Council Med Res, Adv Ctr Genom Diabet, Madras Diabet Res Fdn, Dept Mol Genet, Madras, Tamil Nadu, India [ 60 ] Ajou Univ, Sch Med, Dept Prevent Med, Suwon 441749, South Korea [ 61 ] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea [ 62 ] Natl Taiwan Univ, Sch Med, Grad Inst Clin Med, Taipei 10764, Taiwan [ 63 ] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA [ 64 ] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA [ 65 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 66 ] Ealing Hosp NHS Trust, Southall, Middx, England [ 67 ] Karolinska Inst, Inst Environm Med, Divis Cardiovasc Epidemiol, S-10401 Stockholm, Sweden [ 68 ] Harokopio Univ, Dept Dietet Nutr, Athens, Greece [ 69 ] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland [ 70 ] Biomed Sci Res Ctr Alexander Fleming, Vari, Greece [ 71 ] INSERM, UMR 1087, Nantes, France [ 72 ] CNRS, UMR 6291, Nantes, France [ 73 ] Univ Nantes, Nantes, France [ 74 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Diabet Res Ctr, Dundee, Scotland [ 75 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland [ 76 ] Univ Oxford, Dept Stat, Oxford OX1 3TG, England [ 77 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 78 ] Netherlands Consortium Healthy Ageing, Netherland Genom Initiat, Rotterdam, Netherlands [ 79 ] Ctr Med Syst Biol, Rotterdam, Netherlands [ 80 ] Univ London Imperial Coll Sci Technol & Med, MRC, Hlth Protect Agcy, Ctr Environm & Hlth, London, England [ 81 ] Iceland Heart Assoc, Kopavogur, Iceland [ 82 ] Univ Duisburg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany [ 83 ] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland [ 84 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 85 ] Univ Helsinki, Gen Hosp, Unit Gen Practice, Helsinki, Finland [ 86 ] Folkhalsan Res Ctr, Helsinki, Finland [ 87 ] Inst Mexicano Seguro Social, Hosp Gen Reg 1, Unidad Invest Epidemiol Clin, Mexico City, DF, Mexico [ 88 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 89 ] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia [ 90 ] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA [ 91 ] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA [ 92 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 93 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 94 ] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA [ 95 ] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England [ 96 ] Vaasa Hlth Care Ctr, Vaasa, Finland [ 97 ] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA [ 98 ] Harvard Univ, Sch Med, Boston, MA USA [ 99 ] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England [ 100 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 101 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 102 ] Karolinska Univ, Hosp Solna, Ctr Mol Med, Stockholm, Sweden [ 103 ] Helmholtz Zentrum Muenchen, Inst Genet Epidemiol, Neuherberg, Germany [ 104 ] Helmholtz Zentrum Muenchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 105 ] Univ Munich, Clin Cooperat Grp Diabet, Munich, Germany [ 106 ] Helmholtz Zentrum Muenchen, Munich, Germany [ 107 ] Tech Univ Munich, Clin Cooperat Grp Nutrigen & Type Diabet 2, Munich, Germany [ 108 ] German Ctr Diabet Res DZD, Neuherberg, Germany [ 109 ] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England [ 110 ] Univ Tokyo, Grad Sch Med, Dept Diabet & Metab Dis, Tokyo, Japan [ 111 ] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England [ 112 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany [ 113 ] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway [ 114 ] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands [ 115 ] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA [ 116 ] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia [ 117 ] UCL, Inst Cardiovasc Sci, London, England [ 118 ] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA [ 119 ] Kinki Univ, Sch Med, Dept Diabet Endocrinol & Metab, Osaka 589, Japan [ 120 ] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany [ 121 ] Univ Uppsala Hosp, Dept Mol Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 122 ] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan [ 123 ] Dept Social Serv & Hlth Care, Pietarsaari, Finland [ 124 ] Aga Khan Univ, Dept Med, Karachi, Pakistan [ 125 ] Queen Elizabeth II Med Ctr, West Australian Sleep Disorders Res Inst, Dept Pulm Physiol & Sleep Med, Nedlands, WA, Australia [ 126 ] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia [ 127 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 128 ] Heart & Diabet Inst, Baker Int Diabet Inst IDI, Melbourne, Australia [ 129 ] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA [ 130 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA [ 131 ] Natl Ctr Global Hlth & Med, Res Inst, Shinjuku Ku, Tokyo, Japan [ 132 ] Univ Colombo, Dept Clin Med, Diabet Res Unit, Colombo, Sri Lanka [ 133 ] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland [ 134 ] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland [ 135 ] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore [ 136 ] Ewha Womans Univ, Sch Med, Dept Biochem, Seoul, South Korea [ 137 ] Soongsil Univ, Sch Syst Biomed Sci, Seoul, South Korea [ 138 ] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland [ 139 ] deCODE Genet, Reykjavik, Iceland [ 140 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 141 ] Minist Hlth, Port Louis, Mauritius [ 142 ] Univ Toronto, Dept Anthropol, Mississauga, ON L5L 1C6, Canada [ 143 ] Fdn IMSS, Mexico City, DF, Mexico [ 144 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 145 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 146 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 147 ] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Nedlands, WA 6009, Australia [ 148 ] Univ San Carlos, Off Populat Studies Fdn Inc, Cebu, Philippines [ 149 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England [ 150 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 151 ] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA [ 152 ] Beijing Genom Inst, Shenzhen, Peoples R China [ 153 ] Uppsala Univ, Akad Sjukhuset, Dept Med Sci, Uppsala, Sweden [ 154 ] Mt Sinai Sch Med, Charles R Bronfman Inst Personalized Med, New York, NY USA [ 155 ] Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA [ 156 ] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA [ 157 ] Shanghai Inst Prevent Med, Shanghai, Peoples R China [ 158 ] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA [ 159 ] Dr Mohans Diabet Specialties Ctr, Madras, Tamil Nadu, India [ 160 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 161 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 162 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany [ 163 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 164 ] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia [ 165 ] Nagoya Univ, Grad Sch Med, Div Endocrinol & Diabet, Dept Internal Med, Nagoya, Aichi 4648601, Japan [ 166 ] Chubu Rosai Hosp, Dept Endocrinol & Diabet, Nagoya, Aichi, Japan [ 167 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 168 ] Kyushu Univ, Grad Sch Med Sci, Dept Geriatr Med, Higashi Ku, Fukuoka 812, Japan [ 169 ] Churchill Hosp, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Oxford OX3 7LJ, England [ 170 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 171 ] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, World Class Univ Program, Seoul, South Korea [ 172 ] Seoul Natl Univ, Coll Med, Seoul, South Korea [ 173 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 174 ] Inst Mol Med Finland FIMM, Helsinki, Finland [ 175 ] Helmholtz Zentrum Muenchen, Inst Epidemiol 2, Neuherberg, Germany [ 176 ] Univ Kelaniya, Fac Med, Dept Publ Hlth, Ragama, Sri Lanka [ 177 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 178 ] Univ Gen Hosp Attikon, Athens, Greece [ 179 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany [ 180 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 181 ] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA [ 182 ] Partners Ctr Personalized Genom Med, Boston, MA USA [ 183 ] Univ Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 184 ] Univ Dusseldorf, Dept Metab Dis, Dusseldorf, Germany [ 185 ] Harvard Univ, Hlth Sci & Technol MD Program, Boston, MA 02115 USA [ 186 ] MIT, Boston, MA USA [ 187 ] Harvard Univ, Harvard Biol & Biomed Sci Program, Boston, MA 02115 USA [ 188 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 189 ] Finnish Diabet Assoc, Tampere, Finland [ 190 ] Pirkanmaa Hosp Dist, Tampere, Finland [ 191 ] Cent Finland Cent Hosp, Dept Med, Jyvaskyla, Finland [ 192 ] South Karelia Cent Hosp, Lappeenranta, Finland [ 193 ] UCL, Dept Genet Evolut & Environm, Genet Inst, London, England [ 194 ] Diabet Assoc Pakistan, Karachi, Pakistan [ 195 ] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA [ 196 ] Baltimore Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA [ 197 ] Univ Maryland, Sch Med, Program Personalised & Genom Med, Baltimore, MD 21201 USA [ 198 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 199 ] Univ Ulm, Dept Clin Chem, D-89069 Ulm, Germany [ 200 ] Univ Ulm, Cent Lab, D-89069 Ulm, Germany [ 201 ] Uppsala Univ, Dept Med Sci, Uppsala, Sweden [ 202 ] Kyushu Univ, Grad Sch Med Sci, Dept Internal Med & Bioregulatory Sci, Higashi Ku, Fukuoka 812, Japan [ 203 ] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland [ 204 ] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain [ 205 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 206 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 207 ] IMSS, Ctr Med Nacl Siglo 21, Hosp Especialidades, Unidad Invest Med Bioquim, Mexico City, DF, Mexico [ 208 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 209 ] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic, Australia [ 210 ] Kyushu Univ, Med Inst Bioregulat, Res Ctr Genet Informat, Div Genome Anal,Higashi Ku, Fukuoka 812, Japan [ 211 ] Univ Lille 1, Math Lab, CNRS UMR 8524, MODAL Team,INRIA Lille Nord Europe, F-59655 Villeneuve Dascq, France [ 212 ] Aichi Gakuin Univ, Sch Dent, Dept Genome Sci, Nagoya, Aichi 464, Japan [ 213 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 214 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 215 ] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA [ 216 ] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA [ 217 ] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA [ 218 ] Hallym Univ, Dept Biomed Sci, Chunchon, Gangwon Do, South Korea [ 219 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 220 ] Imperial Coll Healthcare NHS Trust, London, England [ 221 ] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA [ 222 ] Blood Syst Res Inst, San Francisco, CA USA [ 223 ] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore [ 224 ] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore [ 225 ] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore [ 226 ] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore [ 227 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England, Obstetrics & Gynecology, Radiology & Nuclear Medicine, Surgery, Epidemiology, Dermatology, Internal Medicine, Medical Microbiology & Infectious Diseases, Medical Research Council (MRC), National Institute for Health Research, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Cardiology
Subjects: CHROMATIN, endocrine system diseases, South Asian Type 2 Diabetes (SAT2D) Consortium, SCALE ASSOCIATION ANALYSIS, Medizin, LOCI, Genome-wide association study, VARIANTS, 0302 clinical medicine, Risk Factors, IMPUTATION, Glucose homeostasis, 11 Medical and Health Sciences, Genetics & Heredity, Genetics, 0303 health sciences, IDENTIFY, Hispanic or Latino, 3. Good health, MAP, POPULATIONS, Medical genetics, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Hispanic Americans, Life Sciences & Biomedicine, Asian Continental Ancestry Group, medicine.medical_specialty, European Continental Ancestry Group, TRANSETHNIC METAANALYSIS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Sykursýki, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Allele, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, Alleles, 030304 developmental biology, Genetic association, Science & Technology, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, 06 Biological Sciences, Arfgengi, Genetic architecture, INDIVIDUALS, Diabetes Mellitus, Type 2, Case-Control Studies, GLUCOSE-HOMEOSTASIS, ASSOCIATION ANALYSES, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413
Published: 2014

235. ANGPTL3 Deficiency and Protection Against Coronary Artery Disease

Author: Sekar Kathiresan, Svati H. Shah, Derek Klarin, Stacey Gabriel, A. Christina Vourakis, Akihiro Nomura, Heribert Schunkert, Bing Yu, Daniel J. Rader, John Danesh, Eric S. Lander, Nathan O. Stitziel, Asif Rasheed, Amit Khera, Philippe M. Frossard, Connor A. Emdin, Pradeep Natarajan, Kiran Musunuru, Namrata Gupta, Nilesh J. Samani, William E. Kraus, Seyedeh M. Zekavat, Jeanette Erdmann, Xiao Wang, Danish Saleheen, Alexandra E Sperry, Promis, Eric Boerwinkle, Andrew J. Bierhals, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Evinacumab, Population, Mutation, Missense, Myocardial Infarction, human genetics, Coronary Artery Disease, 030204 cardiovascular system & hematology, Lower risk, Compound heterozygosity, Gastroenterology, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Medicine, Animals, Humans, Myocardial infarction, education, Angiopoietin-Like Protein 3, Genes, vif, Mice, Knockout, education.field_of_study, business.industry, Case-control study, Odds ratio, Middle Aged, loss-of-function mutations, medicine.disease, Atherosclerosis, Lipids, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Angiopoietin-like Proteins, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, business, Angiopoietins
Abstract: Background Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. Objectives The study goal was to leverage 3 distinct lines of evidence—a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)—to test whether ANGPTL3 deficiency is associated with lower risk for CAD. Methods We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in
Published: 2016

236. Genetic invalidation of Lp-PLA

Author: John M, Gregson, Daniel F, Freitag, Praveen, Surendran, Nathan O, Stitziel, Rajiv, Chowdhury, Stephen, Burgess, Stephen, Kaptoge, Pei, Gao, James R, Staley, Peter, Willeit, Sune F, Nielsen, Muriel, Caslake, Stella, Trompet, Linda M, Polfus, Kari, Kuulasmaa, Jukka, Kontto, Markus, Perola, Stefan, Blankenberg, Giovanni, Veronesi, Francesco, Gianfagna, Satu, Männistö, Akinori, Kimura, Honghuang, Lin, Dermot F, Reilly, Mathias, Gorski, Vladan, Mijatovic, Patricia B, Munroe, Georg B, Ehret, Alex, Thompson, Maria, Uria-Nickelsen, Anders, Malarstig, Abbas, Dehghan, Thomas F, Vogt, Taishi, Sasaoka, Fumihiko, Takeuchi, Norihiro, Kato, Yoshiji, Yamada, Frank, Kee, Martina, Müller-Nurasyid, Jean, Ferrières, Dominique, Arveiler, Philippe, Amouyel, Veikko, Salomaa, Eric, Boerwinkle, Simon G, Thompson, Ian, Ford, J, Wouter Jukema, Naveed, Sattar, Chris J, Packard, Abdulla Al, Shafi Majumder, Dewan S, Alam, Panos, Deloukas, Heribert, Schunkert, Nilesh J, Samani, Sekar, Kathiresan, Børge G, Nordestgaard, Danish, Saleheen, Joanna Mm, Howson, Emanuele, Di Angelantonio, Adam S, Butterworth, and John, Danesh
Subjects: Adult, Male, Genotype, Phospholipase A2 Inhibitors, Reproducibility of Results, Coronary Disease, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Treatment Outcome, Gene Expression Regulation, Reference Values, Benzaldehydes, Case-Control Studies, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Oximes, Humans, Female, Molecular Targeted Therapy, Alleles, Aged, Randomized Controlled Trials as Topic
Abstract: Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A
Published: 2016

237. Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma

Author: Neda, Farahi, Ellie, Paige, Jozef, Balla, Emily, Prudence, Ricardo C, Ferreira, Mark, Southwood, Sarah L, Appleby, Per, Bakke, Amund, Gulsvik, Augusto A, Litonjua, David, Sparrow, Edwin K, Silverman, Michael H, Cho, John, Danesh, Dirk S, Paul, Daniel F, Freitag, and Edwin R, Chilvers
Subjects: Male, Pulmonary Disease, Chronic Obstructive, Neutrophils, Association Studies Articles, Humans, Female, Lung, Receptors, Interleukin-6, Asthma, Genetic Association Studies, respiratory tract diseases
Abstract: The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.
Published: 2016

238. Analysis of protein-coding genetic variation in 60,706 humans

Author: Jack A. Kosmicki, Mark A. DePristo, Mark I. McCarthy, Patrick F. Sullivan, Laramie E. Duncan, Ryan Poplin, David Neil Cooper, Mitja I. Kurki, Aarno Palotie, Hong-Hee Won, Dermot P.B. McGovern, John Danesh, Jose C. Florez, Grace Tiao, Anne H. O’Donnell-Luria, Timothy Fennell, Gad Getz, Douglas M. Ruderfer, Joanne Berghout, Mark J. Daly, Monkol Lek, Daniel P. Howrigan, Stacey Gabriel, Daniel P. Birnbaum, Ami Levy Moonshine, Michael Boehnke, Ben Weisburd, Ruth McPherson, Christine Stevens, Dongmei Yu, Sekar Kathiresan, Andrew J. Hill, James G. Wilson, James S. Ware, Hugh Watkins, Benjamin M. Neale, Khalid Shakir, David Altshuler, María Teresa Tusié-Luna, Lorena Orozco, James Zou, Samuel A. Rose, Menachem Fromer, Jeremiah M. Scharf, Daniel G. MacArthur, Namrata Gupta, Pamela Sklar, Eric Vallabh Minikel, Steven A. McCarroll, Jaakko Tuomilehto, Jackie Goldstein, Ming T. Tsuang, Stacey Donnelly, Konrad J. Karczewski, Fengmei Zhao, Stephen J. Glatt, Ron Do, Nicole A. Deflaux, Adam Kiezun, Emma Pierce-Hoffman, Markku Laakso, Beryl B. Cummings, Pradeep Natarajan, Danish Saleheen, Karol Estrada, Peter D. Stenson, Manuel A. Rivas, Diego Ardissino, Kaitlin E. Samocha, Gina M. Peloso, Laura D. Gauthier, Eric Banks, Brett Thomas, Shaun Purcell, Taru Tukiainen, Valentin Ruano-Rubio, Christina M. Hultman, Jason Flannick, Roberto Elosua, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Jaakko Tuomilehto Research Group, Department of Public Health, Clinicum, Genomics of Neurological and Neuropsychiatric Disorders, Danesh, John [0000-0003-1158-6791], Apollo - University of Cambridge Repository, Wellcome Trust, and The Academy of Medical Sciences
Subjects: 0301 basic medicine, Proteome, DNA Mutational Analysis, Datasets as Topic, Human genetic variation, GUIDELINES, 0302 clinical medicine, Exome Aggregation Consortium, SEQUENCE VARIANTS, Coding region, 2.1 Biological and endogenous factors, Exome, Aetiology, MUTATION, Genetics, 0303 health sciences, Multidisciplinary, HUMAN-DISEASE, NETWORKS, Multidisciplinary Sciences, Phenotype, Mutation (genetic algorithm), Science & Technology - Other Topics, Biotechnology, General Science & Technology, Genomics, Computational biology, Biology, DNA sequencing, 03 medical and health sciences, Rare Diseases, Clinical Research, Genetic variation, Humans, Genetic Testing, Gene, 030304 developmental biology, Science & Technology, Human Genome, HUMAN-POPULATION HISTORY, Genetic Variation, FRAMEWORK, R1, EVOLUTION, 030104 developmental biology, DISCOVERY, Sample Size, Generic health relevance, 3111 Biomedicine, Genètica humana -- Variació, 030217 neurology & neurosurgery
Abstract: SummaryLarge-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). The resulting catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We show that this catalogue can be used to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; we identify 3,230 genes with near-complete depletion of truncating variants, 72% of which have no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes.
Published: 2016

239. Common variants associated with plasma triglycerides and risk for coronary artery disease

Author: Richard S. Cooper, Angela Döring, Cisca Wijmenga, Jerome I. Rotter, Linda S. Adair, Tõnu Esko, Jennifer L. Bragg-Gresham, Danish Saleheen, Narisu Narisu, Xiaohui Li, Kathleen Stirrups, Ulf de Faire, Nicholas G. Martin, Dmitry Shungin, Peter Vollenweider, Yii-Der Ida Chen, Dharambir K. Sanghera, George Dedoussis, Toshiko Tanaka, Manjinder S. Sandhu, Anne U. Jackson, Nancy L. Pedersen, Maria Dimitriou, Shih-Yi Lin, David P. Strachan, Isleifur Olafsson, Ruth J. F. Loos, Kay-Tee Khaw, Antero Kesäniemi, Rainer Rauramaa, Wendy L. McArdle, Gonneke Willemsen, Dena G. Hernandez, May E. Montasser, Amy J. Swift, Colin A. McKenzie, Aaron Isaacs, Latonya F. Been, Leif Groop, Massimo Mangino, Martina Müller-Nurasyid, Karen L. Mohlke, Ci Song, Sailaja Vedantam, Anna-Liisa Hartikainen, Lori L. Bonnycastle, Ilja M. Nolte, Jaakko Kaprio, Anneli Pouta, Unnur Thorsteinsdottir, Paul Elliott, Muredach P. Reilly, Jean Ferrières, Daniel J. Rader, Elizabeth H. Young, Jaspal S. Kooner, Leena Moilanen, Markku Laakso, Albert Hofman, Kelly A. Volcik, Sekar Kathiresan, Tamara B. Harris, Eric Kim, Aimo Ruokonen, Andrea Ganna, Serena Sanna, John J.P. Kastelein, Martha L. Gravito, Ronald M. Krauss, Ken K. Ong, Paul M. Ridker, Kristian Hveem, Ayse Demirkan, Alena Stančáková, Pierre Meneton, Thomas Quertermous, John Danesh, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Christopher J. Groves, Jaakko Tuomilehto, Michael Boehnke, Jose M. Ordovas, Alan B. Feranil, Chao A. Hsiung, Wayne Huey-Herng Sheu, Igor Rudan, Christa Meisinger, Rebecca N. Nsubuga, Bruna Gigante, Inger Njølstad, Göran Hallmans, Aroon D. Hingorani, Jouko Saramies, Deepti Gurdasani, Fernando Rivadeneira, Andres Metspalu, Stephen E. Epstein, Gonçalo R. Abecasis, Braxton D. Mitchell, Devin Absher, Marcus E. Kleber, Sonia Shah, Pierre Fontanillas, Jeffrey R. O'Connell, Louise A. Donnelly, Jing Hua Zhao, Martin L. Buchkovich, Francis S. Collins, Gabrielle Müller, Matti Uusitupa, Evelin Mihailov, Nicholas J. Wareham, Andrew A. Hicks, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Jaana Lindström, Mark I. McCarthy, Evita G. Van Den Herik, Kirsten Ohm Kyvik, Vilmundur Gudnason, Jackie F. Price, Joel N. Hirschhorn, Winfried März, Aravinda Chakravarti, Pontiano Kaleebu, James F. Wilson, Lindsay L. Waite, Leo-Pekka Lyytikäinen, Sebanti Sengupta, Mika Kivimäki, David Altshuler, Hilma Holm, Rona J. Strawbridge, Harald Grallert, Ramaiah Nagaraja, Laurence Tiret, G. Kees Hovingh, Meena Kumari, Nilesh J. Samani, Daniel F. Freitag, Nelson B. Freimer, Thomas Illig, Panos Deloukas, Bernhard O. Boehm, Nicholas W.J. Wainwright, Mark J. Daly, Mika Kähönen, Michel Burnier, Norman Klopp, L. Adrienne Cupples, Aarno Palotie, Markus Perola, Bamidele O. Tayo, Timo A. Lakka, Matthew Jones, Sarah H. Wild, Patricia B. Munroe, Antti Jula, François Mach, Peter J. Koudstaal, Pirjo Komulainen, Eric Boerwinkle, L. Joost van Pelt, Veikko Salomaa, Ann-Kristin Petersen, Ida Surakka, Andrew Wong, Caroline Hayward, Chi Gao, Cristen J. Willer, Stephen S. Rich, Yi Jen Hung, Peter P. Pramstaller, Diana Kuh, Ron Do, Dominique Arveiler, Mark O. Goodarzi, Ross M. Fraser, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Mary Susan Burnett, Patrik K. E. Magnusson, John C. Chambers, Benjamin M. Neale, Peter Schwarz, Jennifer L. Bolton, Murielle Bochud, Heleen M. den Hertog, Christian Gieger, Cristina Pomilla, Teresa Ferreira, Lars Wallentin, Richa Saxena, André G. Uitterlinden, Kaisa Silander, Ying Wu, Bruce M. Psaty, Jian'an Luan, Hsing-Yi Chang, Jin Chen, Daniel I. Chasman, Ulf Gyllensten, Kari Stefansson, Kauko Heikkilä, Tom Wilsgaard, Alan R. Shuldiner, Carlos Iribarren, Stavroula Kanoni, John Whitfield, Gershim Asiki, Marika Kaakinen, Georg Ehret, Elina Hyppönen, Claudia Langenberg, Gina M. Peloso, Cecilia M. Lindgren, Carlo Sidore, Gudmundur I. Eyjolfsson, Cameron D. Palmer, Jacques S. Beckmann, Hubert Scharnagl, Tanya M. Teslovich, Mary F. Feitosa, Terho Lehtimäki, Steve E. Humphries, Chris Power, Benjamin F. Voight, Stefania Bandinelli, Andrew D. Morris, Gudmar Thorleifsson, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Themistocles L. Assimes, Pascal Bovet, Luigi Ferrucci, Johannes Kettunen, Inês Barroso, Franklyn I. Bennett, Stefan Gustafsson, Paolo Brambilla, Theodore Papamarkou, Elena Tremoli, Janet Seeley, Alex S. F. Doney, Johanna Kuusisto, Giancarlo Cesana, Bruce H. R. Wolffenbuttel, Lars Lind, Stefan R. Bornstein, Åsa Johansson, Anders Hamsten, Marjo-Riitta Järvelin, Krista Fischer, Agneta Siegbahn, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, Do, Ron, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Hyppönen, Elina, Kathiresan, Sekar, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Do, R, Willer, C, Schmidt, E, Sengupta, S, Gao, C, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stančáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Altshuler, D, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Mohlke, K, Ingelsson, E, Abecasis, G, Daly, M, Neale, B, and Kathiresan, S
Subjects: Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Heart disease, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, ISCHEMIC-HEART-DISEASE, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Polymorphism (computer science), Risk Factors, High-density-lipoprotein, Genetic epidemiology, 11 Medical and Health Sciences, Genetics & Heredity, 0303 health sciences, Cholesterol, HDL/blood, Cholesterol levels, Loci, Contribute, Single Nucleotide, LDL/blood, Triglycerides/blood, Cholesterol, Cholesterol, LDL/blood, HDL/blood, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Human, medicine.medical_specialty, TYPE-2 DIABETES-MELLITUS, Biology, Polymorphism, Single Nucleotide, Article, HIGH-DENSITY-LIPOPROTEIN ISCHEMIC-HEART-DISEASE TYPE-2 DIABETES-MELLITUS MENDELIAN RANDOMIZATION CARDIOVASCULAR-DISEASE GENETIC EPIDEMIOLOGY CHOLESTEROL LEVELS LOCI CONTRIBUTE THERAPY, 03 medical and health sciences, Coronary Artery Disease/blood, SDG 3 - Good Health and Well-being, Cardiovascular-disease, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Polymorphism, plasma, Triglycerides, 030304 developmental biology, Science & Technology, Risk Factor, Cholesterol, HDL, Biological Transport, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, Heart-disease, lipoproteins, Endocrinology, chemistry, Therapy, Developmental Biology
Abstract: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10 -8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. © 2013 Nature America, Inc. All rights reserved.
Published: 2013

240. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Aravinda Chakravarti, Jennifer E. Huffman, Meixia Ren, Veikko Salomaa, Christopher Newton-Cheh, Johan Sundström, Alan L. James, Joris Deelen, Raha Pazoki, Michela Traglia, Tõnu Esko, Seppo Koskinen, Christopher J. O'Donnell, Csaba P. Kovesdy, Daniel I. Chasman, Paul F. O'Reilly, Roby Joehanes, Paul M. Ridker, G. Abecasis, Lars Lind, Dragana Vuckovic, Yingchang Lu, Antonietta Robino, Anders Hamsten, Muralidharan Sargurupremraj, Caterina Barbieri, Anne U. Jackson, Anna Morgan, Claudia Langenberg, Peter S. Braund, Rainer Rettig, Murielle Bochud, Vilmundur Gudnason, Eleftheria Zeggini, David J. Stott, Joop Jukema, Nick Shrine, Jun Ding, Olle Melander, Massimo Mangino, Borbala Mifsud, Frank H. Collins, Liewald Dcm., Tineka Blake, Peter K. Joshi, Yan V. Sun, Aarno Palotie, Maciej Tomaszewski, Jarvelin M-R., Kati Kristiansson, L. J. Launer, Sara M. Willems, Ian J. Deary, Christophe Tzourio, Alan J. Gow, Caroline Hayward, Guillaume Paré, Christopher Oldmeadow, John M. Starr, Paul Elliott, Morris A. Swertz, C M van Duijn, Sekar Kathiresan, Lorna M. Lopez, Neil R Poulter, Mike A. Nalls, Erik Ingelsson, Eric Boerwinkle, Catharina A. Hartman, Giorgia Girotto, Ben A. Oostra, Markus Perola, Paul Knekt, Lyytikäinen L-P., T.B. Harris, J. C. Bis, Harriëtte Riese, J. Marrugat, Samuli Ripatti, Howson Jmm., Archie Campbell, C M Lindgren, Adam S. Butterworth, Xiuqing Guo, Lin W-Y., Priyanka Nandakumar, David Mosen-Ansorena, Alison Pattie, Marco Brumat, Annette Peters, Georgios Ntritsos, Ivana Kolcic, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Stella Trompet, K. Witkowska, Hottenga J-J., Tim D. Spector, Maris Laan, Vilmantas Giedraitis, Bram P. Prins, Loos Rjf., M. H. de Borst, Antti Jula, Lynda M. Rose, Massimiliano Cocca, Daniela Toniolo, Igor Rudan, P. J. van der Most, Fu Liang Ng, Heather J. Cordell, Walter Palmas, John Danesh, John Attia, Dan E. Arking, Ganesh Chauhan, C Gieger, P. van der Harst, Penninx Bwjh., Kristin L. Ayers, Germaine C. Verwoert, Bruce M. Psaty, Jaspal S. Kooner, Ruifang Li-Gao, Benjamin Lehne, Khaw K-T., Sandosh Padmanabhan, Franco Giulianini, Erwin P. Bottinger, Roberto Elosua, Christopher P. Nelson, Ozren Polasek, D.R. Velez Edwards, Martin Farrall, Ioanna Tzoulaki, Peter Vollenweider, Uwe Völker, Albertine J. Oldehinkel, Åsa Johansson, Helen R. Warren, Evan Tzanis, Albert V. Smith, Hwang S-J., Teresa Ferreira, E.J.C. de Geus, Evangelos Evangelou, Niek Verweij, R. J. Scott, Pekka Jousilahti, Elin Org, Stefan Enroth, Dorret I. Boomsma, Harry Campbell, Andrew D. Johnson, David Conen, James F. Wilson, Edward G. Lakatta, Anuj Goel, Raymond Noordam, Najaf Amin, David P. Strachan, Martin D. Tobin, Francesco Cucca, Doney Asf., Todd L. Edwards, Jerome I. Rotter, Mika Kähönen, Hugh Watkins, Rossella Sorice, John M. C. Connell, David S. Siscovick, Sébastien Thériault, Jian'an Luan, Marty Larson, Philippe Amouyel, A C Morrison, Louise V. Wain, Reedik Mägi, Jonathan Marten, Thibaud Boutin, Nabi Shah, Weihua Zhang, Palmer Cna., Daniela Ruggiero, Zhao J-H., Olli T. Raitakari, Bernard Keavney, Peter S. Sever, Philip S. Tsao, Jie Yao, André G. Uitterlinden, Marina Evangelou, Zoltán Kutalik, Robert A. Scott, Helena Schmidt, J. Tuomilehto, Nilesh J. Samani, Quang Tri Nguyen, John Michael Gaziano, Georg Ehret, Praveen Surendran, Terho Lehtimäki, Mark J. Caulfield, Denis C. Shields, Rick Jansen, Sarin A-P., Alice Stanton, Mattias Frånberg, Cumhur Y Demirkale, Stéphanie Debette, Paolo Gasparini, Ilaria Gandin, Simon Thom, Kent D. Taylor, Andrew D. Morris, Claudia P. Cabrera, Teemu J. Niiranen, Nicholas J. Wareham, Andrew P. Morris, Yasaman Saba, Daniel Levy, Aki S. Havulinna, Kelly Cho, Sarah E. Harris, Li Lin, Janina S. Ried, Michael R. Barnes, Sarah H. Wild, Patricia B. Munroe, Vergnaud A-C., Lorenz Risch, Rona J. Strawbridge, Y. Milaneschi, John C. Chambers, Yong Qian, Cristina Menni, Anubha Mahajan, Peter Almgren, Gary Davies, Jacklyn N. Hellwege, Elizabeth G. Holliday, A. Metspalu, Ilja M. Nolte, Peter J. Munson, He Gao, Marcus Dörr, Cinzia Sala, Peter P. Pramstaller, Teresa Nutile, Wilson Pwf., Gonneke Willemsen, Markku Laakso, Chiara Batini, Harold Snieder, Ibrahim Karaman, Adriana M. Hung, Reinhold Schmidt, R. de Mutsert, Michael Boehnke, Lili Milani, Alan F. Wright, Edith Hofer, Siim Sõber, Ahmad Vaez, Albert Hofman, Oscar H. Franco, Yongmei Liu, Tatijana Zemunik, Kenneth Rice, Veronique Vitart, Marina Ciullo, Niki Dimou, Morris J. Brown, Crysovalanto Mamasoula, A.M. Erzurumluoglu, Andrew A. Hicks, Ayush Giri, Dennis O. Mook-Kanamori, Home Office, UNIVERSITY OF OULU, Commission of the European Communities, Medical Research Council (MRC), Action on Hearing Loss, British Heart Foundation, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, and UK DRI Ltd
Subjects: Genetics & Heredity, 0301 basic medicine, Netherlands Twin Register (NTR), Science & Technology, computer.internet_protocol, Million Veteran Program, Genome-wide association study, Computational biology, 06 Biological Sciences, Biology, Genetic analysis, 03 medical and health sciences, 030104 developmental biology, Genetics, Genome informatics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, computer, 11 Medical and Health Sciences, XML, Developmental Biology
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Published: 2018

241. Author Correction: Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Author: Klaudia Walter, Giorgio E. M. Melloni, Arthur Gilly, George Dedoussis, Martin O. Pollard, Nigel W. Rayner, Karoline Kuchenbaecker, Emil V. R. Appel, Thea Bjørnland, Emmanouil Tsafantakis, Kousik Kundu, Britt Kilian, Aliki-Eleni Farmaki, Lorraine Southam, Ryan K. Waples, Ida Moltke, Ioanna Ntalla, Elisabetta Casalone, Eleftheria Zeggini, Daniel Suveges, Adam S. Butterworth, Inês Barroso, John Danesh, and Konstantinos Hatzikotoulas
Subjects: 0301 basic medicine, Whole genome sequencing, Multidisciplinary, Science, General Physics and Astronomy, General Chemistry, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, GeneralLiterature_MISCELLANEOUS, 03 medical and health sciences, 030104 developmental biology, Cohort, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, lcsh:Q, Allele, Architecture, lcsh:Science
Abstract: The original version of this Article contained an error in Fig. 2. In panel a, the two legend items “rare” and “common” were inadvertently swapped. This has been corrected in both the PDF and HTML versions of the Article.
Published: 2018

242. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis

Author: Stephen Kaptoge, Torben Jørgensen, Gordon D.O. Lowe, Adam S. Butterworth, Vilmundur Gudnason, Pei Gao, Ann Rumley, Anders Borglykke, John Danesh, Sreenivasa Rao Kondapally Seshasai, Emanuele Di Angelantonio, Daniel F. Freitag, Kaptoge, Stephen [0000-0002-1155-4872], Butterworth, Adam [0000-0002-6915-9015], Di Angelantonio, Emanuele [0000-0001-8776-6719], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, medicine.medical_specialty, Population, Myocardial Infarction, Coronary Disease, Proinflammatory cytokine, Clinical Research, Internal medicine, Humans, Medicine, Prospective Studies, Myocardial infarction, education, Prospective cohort study, Aged, Inflammation, education.field_of_study, business.industry, Vascular disease, Hazard ratio, Editorials, Middle Aged, medicine.disease, Meta-analysis, CHD, Risk factors, Relative risk, Immunology, Cytokines, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract: AIMS: Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta-analysis of prospective studies. METHODS AND RESULTS: Interleukin-6 (IL-6), IL-18, matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and tumour necrosis factor-α (TNF-α) were measured at baseline in a case-cohort study of 1514 participants and 833 incident CHD events within population-based prospective cohorts at the Danish Research Centre for Prevention and Health. Age- and sex-adjusted hazard ratios (HRs) for CHD per 1-SD higher log-transformed baseline levels were: 1.37 (95% CI: 1.21-1.54) for IL-6, 1.26 (1.11-1.44) for IL-18, 1.30 (1.16-1.46) for MMP-9, 1.01 (0.89-1.15) for sCD40L, and 1.13 (1.01-1.27) for TNF-α. Multivariable adjustment for conventional vascular risk factors attenuated the HRs to: 1.26 (1.08-1.46) for IL-6, 1.12 (0.95-1.31) for IL-18, 1.21 (1.05-1.39) for MMP-9, 0.93 (0.78-1.11) for sCD40L, and 1.14 (1.00-1.31) for TNF-α. In meta-analysis of up to 29 population-based prospective studies, adjusted relative risks for non-fatal MI or CHD death per 1-SD higher levels were: 1.25 (1.19-1.32) for IL-6; 1.13 (1.05-1.20) for IL-18; 1.07 (0.97-1.19) for MMP-9; 1.07 (0.95-1.21) for sCD40L; and 1.17 (1.09-1.25) for TNF-α. CONCLUSIONS: Several different pro-inflammatory cytokines are each associated with CHD risk independent of conventional risk factors and in an approximately log-linear manner. The findings lend support to the inflammation hypothesis in vascular disease, but further studies are needed to assess causality.
Published: 2013

243. Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease

Author: Mingyao Li, Weang Kee Ho, Daniel J. Rader, Alan R. Shuldiner, Danish Saleheen, Harold I. Feldman, Crystal A. Gadegbeku, Stephen R. Master, Andrea S. Foulkes, Braxton D. Mitchell, Radhika Kanthety, Sylvia E. Rosas, Michael J. Fischer, Akinlolu O. Ojo, Muredach P. Reilly, John Danesh, Peter A. Kanetsky, Asif Rasheed, Alan S. Go, Jane F. Ferguson, Gregory J. Matthews, Mahboob Rahman, Nehal N. Mehta, Raymond R. Townsend, Robin Young, John M. Flack, Jeffrey R. O'Connell, Jiang He, Atif Qasim, Jackson T. Wright, Haiqing Shen, Dominic S. Raj, John W. Kusek, and Matthew J. Budoff
Subjects: 0303 health sciences, medicine.medical_specialty, Pathology, Linkage disequilibrium, Candidate gene, business.industry, nutritional and metabolic diseases, Single-nucleotide polymorphism, Genome-wide association study, Odds ratio, 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, cardiovascular diseases, Myocardial infarction, business, Cardiology and Cardiovascular Medicine, 030304 developmental biology, Kidney disease
Abstract: Objectives This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). Background CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. Methods We performed a candidate gene study (∼2,100 genes; ∼50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885). Results Of 268 SNPs reaching p −4 for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p chr9p21 and COL4A1 , known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1 ). In PROMIS, 4 of the 23 suggestive CAC loci ( chr9p21 , COL4A1 , ATP2B1 , and ABCA4 ) had significant associations with MI, consistent with their direction of effect on CAC. Conclusions We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
Published: 2013
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244. Discovery and refinement of loci associated with lipid levels

Author: Benjamin F. Voight, Stefania Bandinelli, Pascal Bovet, Latonya F. Been, Ci Song, Luigi Ferrucci, Johannes Kettunen, Andrew D. Morris, Mary Susan Burnett, Ronald M. Krauss, Igor Rudan, Heleen M. den Hertog, Stavroula Kanoni, G. Kees Hovingh, Elina Hyppönen, Kauko Heikkilä, Richard S. Cooper, Daniel I. Chasman, Bruna Gigante, Stefan Gustafsson, Jian'an Luan, Sarah H. Wild, Patricia B. Munroe, Göran Hallmans, Jeffrey R. O'Connell, Danish Saleheen, Aarno Palotie, Leena Moilanen, Jerome I. Rotter, Caroline Hayward, Jennifer L. Bragg-Gresham, Nicholas G. Martin, Claudia Langenberg, George Dedoussis, Carlo Sidore, Ulf Gyllensten, Marika Kaakinen, Jing Hua Zhao, Aimo Ruokonen, Diana Kuh, Maria Dimitriou, Shih-Yi Lin, Gina M. Peloso, Marcus E. Kleber, Christopher J. Groves, Alena Stančáková, Michel Burnier, Patrik K. E. Magnusson, John C. Chambers, Giancarlo Cesana, Francis S. Collins, Gabrielle Müller, Angela Döring, Colin A. McKenzie, Paul Elliott, Lars Lind, Vilmundur Gudnason, Dharambir K. Sanghera, Jean Ferrières, Toshiko Tanaka, Stefan R. Bornstein, Gershim Asiki, Jacques S. Beckmann, Anneli Pouta, Timo A. Lakka, Daniel J. Rader, Elizabeth H. Young, Kelly A. Volcik, Dena G. Hernandez, Ann-Kristin Petersen, Kristian Hveem, Amy J. Swift, Murielle Bochud, Pierre Meneton, Paul M. Ridker, Kathleen Stirrups, Stephen S. Rich, Isleifur Olafsson, Ruth J. F. Loos, Serena Sanna, Markus Perola, Meena Kumari, Cameron D. Palmer, Carlos Iribarren, Nancy L. Pedersen, Mark O. Goodarzi, Panos Deloukas, Norman Klopp, Cristina Pomilla, Stephen E. Epstein, Antti Jula, Themistocles L. Assimes, Martina Müller-Nurasyid, Marjo-Riitta Järvelin, Chao A. Hsiung, Sonia Shah, Christian Gieger, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Nicholas J. Wareham, Krista Fischer, Wendy L. McArdle, Linda S. Adair, Kay-Tee Khaw, Bruce M. Psaty, André G. Uitterlinden, Aaron Isaacs, Tõnu Esko, Jennifer L. Bolton, Rebecca N. Nsubuga, Eric Boerwinkle, L. Joost van Pelt, Jouko Saramies, François Mach, Pierre Fontanillas, Teresa Ferreira, Lars Wallentin, Michael Boehnke, Christa Meisinger, Wayne Huey-Herng Sheu, Gonçalo R. Abecasis, Inês Barroso, Franklyn I. Bennett, Dmitry Shungin, Jaakko Kaprio, Kirsten Ohm Kyvik, Deepti Gurdasani, Anne U. Jackson, Paolo Brambilla, Georg Ehret, Cecilia M. Lindgren, Fernando Rivadeneira, Theodore Papamarkou, Jaakko Tuomilehto, Cristen J. Willer, Martin L. Buchkovich, Antero Kesäniemi, Hubert Scharnagl, Xiaohui Li, Elena Tremoli, Nelson B. Freimer, Mika Kähönen, Ron Do, Karen L. Mohlke, Thomas Illig, Gudmar Thorleifsson, Peter J. Koudstaal, Andres Metspalu, Ulf de Faire, Dominique Arveiler, Harald Grallert, Jaana Lindström, Laurence Tiret, Jaspal S. Kooner, Braxton D. Mitchell, Sebanti Sengupta, Gonneke Willemsen, Anna-Liisa Hartikainen, Terho Lehtimäki, Steve E. Humphries, Peter Schwarz, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Tom Wilsgaard, Janet Seeley, Alex S. F. Doney, Alan R. Shuldiner, John Whitfield, Markku Laakso, Peter Vollenweider, Gudmundur I. Eyjolfsson, Winfried März, Mika Kivimäki, Ying Wu, Johanna Kuusisto, Andrew A. Hicks, Bruce H. R. Wolffenbuttel, May E. Montasser, Bamidele O. Tayo, Unnur Thorsteinsdottir, Muredach P. Reilly, Leo-Pekka Lyytikäinen, Eric Kim, John Danesh, Ida Surakka, Åsa Johansson, Anders Hamsten, Thomas Quertermous, Hsing-Yi Chang, Jin Chen, Agneta Siegbahn, Narisu Narisu, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, Sekar Kathiresan, Manjinder S. Sandhu, Leif Groop, Jose M. Ordovas, Alan B. Feranil, Evelin Mihailov, Hilma Holm, Pontiano Kaleebu, Lindsay L. Waite, Ramaiah Nagaraja, Andrew Wong, Rona J. Strawbridge, David P. Strachan, Yii-Der Ida Chen, Tamara B. Harris, Jackie F. Price, Aravinda Chakravarti, Veikko Salomaa, Sailaja Vedantam, Albert Hofman, Devin Absher, Ross M. Fraser, Kaisa Silander, Pirjo Komulainen, Yi Jen Hung, Peter P. Pramstaller, Kari Stefansson, Aroon D. Hingorani, Tanya M. Teslovich, Matti Uusitupa, L. Adrienne Cupples, Cisca Wijmenga, Lori L. Bonnycastle, Ilja M. Nolte, Andrea Ganna, Ken K. Ong, Inger Njølstad, Bernhard O. Boehm, Nicholas W.J. Wainwright, Richa Saxena, Rainer Rauramaa, Louise A. Donnelly, James F. Wilson, Matthew Jones, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Massimo Mangino, John J.P. Kastelein, Martha L. Gravito, Mark I. McCarthy, Evita G. Van Den Herik, Joel N. Hirschhorn, Nilesh J. Samani, Daniel F. Freitag, Ayse Demirkan, Mary F. Feitosa, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Chris Power, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Willer, C, Schmidt, E, Sengupta, S, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Do, R, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stancáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Kathiresan, S, Mohlke, K, Ingelsson, E, Abecasis, G, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Ehret, Georg Benedikt, Mach, François, Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, National Institute for Health Research, Global Lipids Genetics Consortium, Willer, Cristen, Sengupta, Sebanti, Peloso, Gina, Hypponen, Elina Tuulikki, and Abecasis, Gonçalo R
Subjects: Netherlands Twin Register (NTR), HOMEOSTASIS, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Blood lipids, Genome-wide association study, Type 2 diabetes, Coronary Artery Disease, 030204 cardiovascular system & hematology, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, European Continental Ancestry Group/genetics, triglycerides, IDENTIFIES 13, 11 Medical and Health Sciences, African Continental Ancestry Group, 2. Zero hunger, Genetics, Genetics & Heredity, ddc:616, RISK, 0303 health sciences, Cholesterol, HDL/blood, PLASMA, Global Lipids Genetics Consortium, Cholesterol, HDL/blood/genetics, Lipid, Lipids, 3. Good health, LDL/blood, Triglycerides/blood, Lipids/blood/genetics, Cholesterol, Cholesterol, LDL/blood, DENSITY-LIPOPROTEIN CHOLESTEROL, CARDIOVASCULAR-DISEASE, HDL/blood, CORONARY-ARTERY-DISEASE, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, coronary artery disease, TRAITS, Human, Coronary Artery Disease/blood/genetics, Asian Continental Ancestry Group, Genotype, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Black People, HEART-DISEASE, Biology, Article, White People, lipids, 03 medical and health sciences, Coronary Artery Disease/blood, CORONARY-ARTERY-DISEASE DENSITY-LIPOPROTEIN CHOLESTEROL GENOME-WIDE ASSOCIATION HEART-DISEASE CARDIOVASCULAR-DISEASE SUSCEPTIBILITY LOCI IDENTIFIES 13 RISK GENE METAANALYSIS, Triglycerides/blood/genetics, Asian People, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Humans, Asian Continental Ancestry Group/genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Genotyping, Triglycerides, METAANALYSIS, 030304 developmental biology, Science & Technology, Lipids/blood, Cholesterol, HDL, cholesterol, African Continental Ancestry Group/genetics, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, GENE, chemistry, Cholesterol, LDL/blood/genetics, Lipoprotein, Developmental Biology, Genome-Wide Association Study
Abstract: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10 -8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research. © 2013 Nature America, Inc. All rights reserved.
Published: 2013
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245. Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles

Author: Dewan S. Alam, Martina Müller-Nurasyid, Pei Gao, Akinori Kimura, Danish Saleheen, Emanuele Di Angelantonio, Stefan Blankenberg, Taishi Sasaoka, Jean Ferrières, Børge G. Nordestgaard, Panos Deloukas, Abbas Dehghan, Eric Boerwinkle, Maria Uria-Nickelsen, Simon G. Thompson, Markus Perola, Chris J. Packard, Giovanni Veronesi, Dominique Arveiler, Dermot F. Reilly, Patricia B. Munroe, Stephen Burgess, Rajiv Chowdhury, Philippe Amouyel, J. Wouter Jukema, Alex Thompson, Francesco Gianfagna, Satu Männistö, Honghuang Lin, Nathan O. Stitziel, Heribert Schunkert, Naveed Sattar, Vladan Mijatovic, Abdulla Al Shafi Majumder, Nilesh J. Samani, Daniel F. Freitag, Stephen Kaptoge, Sekar Kathiresan, Stella Trompet, Peter Willeit, Jukka Kontto, John Danesh, Georg Ehret, Veikko Salomaa, Adam S. Butterworth, Joanna M. M. Howson, Ian Ford, Mathias Gorski, Kari Kuulasmaa, Yoshiji Yamada, Norihiro Kato, John M. Gregson, Frank Kee, Fumihiko Takeuchi, Praveen Surendran, James R Staley, Linda M. Polfus, Sune F. Nielsen, Anders Mälarstig, Thomas F. Vogt, Muriel J. Caslake, CKDGen consortium, International Consortium for Blood Pressure, CHARGE inflammation working group, MICAD Exome consortium, EPIC-CVD consortium and the CHD Exome+ consortium, Epidemiology, Surendran, Praveen [0000-0002-4911-6077], Chowdhury, Rajiv [0000-0003-4881-5690], Burgess, Stephen [0000-0001-5365-8760], Kaptoge, Stephen [0000-0002-1155-4872], Thompson, Simon [0000-0002-5274-7814], Howson, Joanna [0000-0001-7618-0050], Di Angelantonio, Emanuele [0000-0001-8776-6719], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], Apollo - University of Cambridge Repository, Institute for Molecular Medicine Finland, University of Helsinki, and Quantitative Genetics
Subjects: 0301 basic medicine, Pathology, Epidemiology, 030204 cardiovascular system & hematology, VARIANTS, Gastroenterology, law.invention, CHARGE inflammation working group, 0302 clinical medicine, Randomized controlled trial, Human genetics, law, Medicine, ARTERY-DISEASE, RISK, 1184 Genetics, developmental biology, physiology, 3. Good health, CARDIOVASCULAR-DISEASE, International Consortium for Blood Pressure, MICAD Exome consortium, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, medicine.medical_specialty, coronary heart disease, darapladib, lipoprotein-associated phospholipase A2, target validation, ACTIVATING-FACTOR ACETYLHYDROLASE, EVENTS, 03 medical and health sciences, Internal medicine, Darapladib, health services administration, lipoprotein-associated phospholipase A(2), CORONARY-HEART-DISEASE, Allele, Risk factor, GENOME-WIDE ASSOCIATION, Genotyping, PHOSPHOLIPASE A(2) ACTIVITY, business.industry, Lipoprotein-associated phospholipase A2, EPIC-CVD consortium and the CHD Exome+ consortium, R1, 030104 developmental biology, CKDGen consortium, Relative risk, 3121 General medicine, internal medicine and other clinical medicine, 1-Alkyl-2-acetylglycerophosphocholine Esterase/drug effects, 1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics, Adult, Aged, Alleles, Benzaldehydes/therapeutic use, Case-Control Studies, Coronary Disease/diagnosis, Coronary Disease/drug therapy, Coronary Disease/genetics, Female, Gene Expression Regulation, Genotype, Humans, Male, Middle Aged, Molecular Targeted Therapy, Oximes/therapeutic use, Phospholipase A2 Inhibitors/therapeutic use, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Reference Values, Reproducibility of Results, Risk Assessment, Treatment Outcome, 3111 Biomedicine, business
Abstract: Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A javax.xml.bind.JAXBElement@3ed2b341 (Lp-PLA javax.xml.bind.JAXBElement@3d94c871 ), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA javax.xml.bind.JAXBElement@ab2bb75 enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA javax.xml.bind.JAXBElement@77eb0872 . We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA javax.xml.bind.JAXBElement@5c08e575 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA javax.xml.bind.JAXBElement@474479c5 -lowering alleles. Results Lp-PLA javax.xml.bind.JAXBElement@58b21b4b activity was decreased by 64% ( p = 2.4 × 10 javax.xml.bind.JAXBElement@77b520b7 ) with carriage of any of the four loss-of-function variants, by 45% ( p < 10 javax.xml.bind.JAXBElement@6c8d5079 ) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 × 10 javax.xml.bind.JAXBElement@8e3967c ) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA javax.xml.bind.JAXBElement@4043bc68 activity by 65% ( p < 10 javax.xml.bind.JAXBElement@1ead8c4f ). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA javax.xml.bind.JAXBElement@1825097b activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA javax.xml.bind.JAXBElement@c612c75 -lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA javax.xml.bind.JAXBElement@511c716d is unlikely to be a causal risk factor.
Published: 2016

246. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Author: Elena Prigmore, Christopher Thornborough, Judith A. Goodship, Koenraad Devriendt, Matthew E. Hurles, Siddharth Banka, Hashim Abdul-Khaliq, Carmel Moore, Denise Williams, Seham Osman Omer, Soo-Mi Park, Diana Rajan, Okan Toka, Ganesh J. Swaminathan, Jeffrey C. Barrett, Martin O. Pollard, Frances A. Bu'Lock, Allan Daly, Anne-Karin Kahlert, Tessa Homfray, Shoumo Bhattacharya, Catherine Cosgrove, Irina-Gabriela Colgiu, Tarjinder Singh, Ingo Daehnert, Karen P. McCarthy, Michael Parker, Brigitte Stiller, Jeroen Breckpot, U.M.M. Bauer, Anna Wilsdon, Kay Metcalfe, Dorin Manase, Ami Ketley, David R. FitzPatrick, Bernard Thienpont, Katherine Lachlan, Jeremy F. McRae, Kirstin Hoff, Helen V. Firth, Marc Gewillig, Sabine Klaassen, Seema Mital, Alan Fryer, Jennifer G. Sambrook, Kerry Setchfield, Willem H. Ouwehand, Hans-Heiner Kramer, Michael Wright, Saeed Al Turki, Jacoba Louw, Bernard Keavney, AK Lampe, Hugh Watkins, Natalie Canham, Jamie Bentham, Riyadh M. Abu-Sulaiman, Ashok Kumar Manickara, Thomas Pickardt, Alejandro Sifrim, David J. Roberts, J. David Brook, Ruth Newbury-Ecob, John Danesh, Caroline F. Wright, Leema Robert, Marc-Phillip Hitz, Felix Berger, Piers E.F. Daubeney, Emma Hobson, Tomas W Fitzgerald, and Helen Cox
Subjects: 0301 basic medicine, Proband, Male, Protein Conformation, Disease, Bioinformatics, Autoantigens, DISEASE, FAMILIES, 0302 clinical medicine, Genotype, Exome, Exome sequencing, Protein Kinase C, Sequence Deletion, Genetics & Heredity, Genetics, 11 Medical And Health Sciences, Syndrome, Deciphering Developmental Disorders Study, Penetrance, GENOTYPE, Medical genetics, Female, Life Sciences & Biomedicine, Mi-2 Nucleosome Remodeling and Deacetylase Complex, INTERVAL Study, Heart Defects, Congenital, medicine.medical_specialty, Biology, Article, 03 medical and health sciences, CDC2 Protein Kinase, Journal Article, medicine, UK10K Consortium, Humans, cardiovascular diseases, Sibling, RECURRENCE, Science & Technology, 06 Biological Sciences, FRAMEWORK, Clinical Genetics, Congenital Heart Defects, Genetics Research, 030104 developmental biology, DE-NOVO MUTATIONS, DISCOVERY, Mutation, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%)3, suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance4, 5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations6, 7. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings8. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.
Published: 2016

247. A prospective study of Helicobacter pylori seropositivity and the risk for future myocardial infarction among socioeconomically similar U.S. men

Author: Meir J. Stampfer, Rory Collins, Linda Youngman, Richard Peto, Paul M. Ridker, Charles H. Hennekens, and John Danesh
Subjects: Male, medicine.medical_specialty, Time Factors, Population, Myocardial Infarction, Helicobacter Infections, Risk Factors, Internal medicine, Epidemiology, Internal Medicine, Humans, Medicine, Prospective Studies, cardiovascular diseases, Myocardial infarction, Risk factor, Prospective cohort study, education, Stroke, education.field_of_study, Helicobacter pylori, biology, business.industry, Confounding Factors, Epidemiologic, Retrospective cohort study, General Medicine, medicine.disease, biology.organism_classification, Surgery, Socioeconomic Factors, Case-Control Studies, Immunoglobulin G, business, Biomarkers
Abstract: BACKGROUND: The role of Helicobacter pylori as a determinant of cardiovascular disease is controversial. OBJECTIVE: To determine whether previous exposure to H. pylori is associated with an increased risk for myocardial infarction. DESIGN: Prospective case-control study. SETTING: Physicians' Health Study. PARTICIPANTS: Initially healthy U.S. men. MEASUREMENTS: Titers of IgG antibody against H. pylori and several inflammatory markers were measured in baseline blood samples obtained from 445 men who subsequently had a myocardial infarction (case-patients) and 445 men matched for age and smoking status who remained free of vascular disease (controls) during a mean follow-up of 8.9 years. RESULTS: Baseline seropositivity was similar among case-patients and controls (43.4% vs. 44.3%; rate ratio, 0.96 [95% CI, 0.7 to 1.3]). Minimal evidence of association was found between magnitude of seropositivity and subsequent risk and between seropositivity and levels of the inflammatory biomarkers. CONCLUSION: In a socioeconomically homogeneous population, we found limited evidence of association between H. pylori exposure and risk for future myocardial infarction.
Published: 2016

248. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies

Author: Rory Collins, Richard Peto, and John Danesh
Subjects: Male, medicine.medical_specialty, Population, Coronary Disease, Risk Factors, Physiology (medical), Internal medicine, medicine, Humans, Prospective Studies, Risk factor, Prospective cohort study, education, Aged, education.field_of_study, biology, business.industry, Case-control study, Lipoprotein(a), Middle Aged, Surgery, Case-Control Studies, Relative risk, Meta-analysis, Cohort, biology.protein, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Background —Studies of the association between the plasma concentration of lipoprotein(a) [Lp(a)] and coronary heart disease (CHD) have reported apparently conflicting findings. We report a meta-analysis of the prospective studies with at least 1 year of follow-up published before 2000. Methods and Results —The following information was abstracted for each study: geographical location of study, size, type of cohort (population-based or selected because of previous disease), mean age, follow-up duration, blood storage temperature and duration, assay methods, degree of adjustment for potential confounders, and relationship of baseline Lp(a) measurement with subsequent CHD risk. There were 5436 deaths from CHD or nonfatal myocardial infarctions during a weighted mean follow-up of 10 years in the 27 eligible studies. Comparison of individuals in the top third of baseline plasma Lp(a) measurements with those in the bottom third in each study yielded a combined risk ratio of 1.6 (95% CI 1.4 to 1.8, 2 P P Conclusions —These prospective studies demonstrate a clear association between Lp(a) and CHD, but further studies are needed to determine the extent to which this is causal.
Published: 2016

249. Postcodes as useful markers of income in 26,000 British households

Author: Paul N. Appleby, S Gault, Richard Peto, John Danesh, and J Semmence
Subjects: Reino unido, Grande bretagne, Wales, Epidemiology, business.industry, Public Health, Environmental and Occupational Health, Articles, United Kingdom, Bias, Scotland, Residence Characteristics, Income, Postal service, Humans, Medicine, Socioeconomics, business, Socioeconomic status, Bias (Epidemiology), Royaume uni
Published: 2016

250. Plasma homocysteine and coronary heart disease: systematic review of published epidemiological studies

Author: Sarah Lewington and John Danesh
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Hyperhomocysteinemia, MEDLINE, Coronary Disease, Coronary heart disease, Risk Factors, Internal medicine, Meta-analysis, medicine, Cardiology, Plasma homocysteine, Humans, business, Cardiology and Cardiovascular Medicine, Homocysteine
Published: 2016

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