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Nilesh J. Samani

Bio: Nilesh J. Samani is an academic researcher from University of Leicester. The author has contributed to research in topics: Genome-wide association study & Population. The author has an hindex of 149, co-authored 779 publications receiving 113545 citations. Previous affiliations of Nilesh J. Samani include University Hospitals of Leicester NHS Trust & Glenfield Hospital.


Papers
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Journal ArticleDOI
Vinicius Tragante1, Michael R. Barnes2, Santhi K. Ganesh3, Matthew B. Lanktree4, Wei Guo5, Nora Franceschini6, Erin N. Smith7, Toby Johnson2, Michael V. Holmes8, Sandosh Padmanabhan9, Konrad J. Karczewski10, Berta Almoguera8, John Barnard11, Jens Baumert, Yen Pei C. Chang12, Clara C. Elbers1, Martin Farrall13, Mary E. Fischer14, Tom R. Gaunt15, Johannes M.I.H. Gho1, Christian Gieger, Anuj Goel13, Yan Gong16, Aaron Isaacs17, Marcus E. Kleber18, Irene Mateo Leach19, Caitrin W. McDonough16, Matthijs F.L. Meijs1, Olle Melander20, Christopher P. Nelson21, Christopher P. Nelson22, Ilja M. Nolte19, Nathan Pankratz23, Thomas S. Price, Jonathan A. Shaffer24, Sonia Shah25, Maciej Tomaszewski21, Peter J. van der Most19, Erik P A Van Iperen, Judith M. Vonk19, Kate Witkowska2, Caroline O. L. Wong2, Li Zhang11, Amber L. Beitelshees12, Gerald S. Berenson26, Deepak L. Bhatt27, Morris Brown28, Amber A. Burt29, Rhonda M. Cooper-DeHoff16, John M. C. Connell30, Karen J. Cruickshanks14, Sean P. Curtis31, George Davey-Smith15, Christian Delles9, Ron T. Gansevoort19, Xiuqing Guo32, Shen Haiqing12, Claire E. Hastie9, Marten H. Hofker1, Marten H. Hofker19, G. Kees Hovingh, Daniel Seung Kim29, Susan Kirkland33, Barbara E.K. Klein14, Ronald Klein14, Yun Li8, Steffi Maiwald, Christopher Newton-Cheh27, Eoin O'Brien34, N. Charlotte Onland-Moret1, Walter Palmas24, Afshin Parsa12, Brenda W.J.H. Penninx35, Mary Pettinger36, Ramachandran S. Vasan37, Jane E. Ranchalis29, Paul M. Ridker27, Lynda M. Rose27, Peter S. Sever38, Daichi Shimbo24, Laura Steele8, Ronald P. Stolk19, Barbara Thorand, Mieke D. Trip, Cornelia M. van Duijn17, W M Monique Verschuren1, Cisca Wijmenga19, Sharon B. Wyatt39, J. Hunter Young40, Aeilko H. Zwinderman, Connie R. Bezzina41, Eric Boerwinkle42, Juan P. Casas43, Mark J. Caulfield2, Aravinda Chakravarti40, Daniel I. Chasman27, Karina W. Davidson24, Pieter A. Doevendans1, Anna F. Dominiczak9, Garret A. FitzGerald8, John G. Gums16, Myriam Fornage42, Hakon Hakonarson8, Indrani Halder44, Hans L. Hillege19, Thomas Illig45, Gail P. Jarvik38, Julie A. Johnson16, John J.P. Kastelein, Wolfgang Koenig46, Meena Kumari25, Winfried März47, Sarah S. Murray7, Jeffrey R. O'Connell12, Albertine J. Oldehinkel19, James S. Pankow23, Daniel J. Rader8, Susan Redline27, Muredach P. Reilly8, Eric E. Schadt48, Kandice Kottke-Marchant11, Harold Snieder19, Michael Snyder10, Alice Stanton49, Martin D. Tobin21, André G. Uitterlinden17, Pim van der Harst19, Yvonne T. van der Schouw1, Nilesh J. Samani21, Nilesh J. Samani22, Hugh Watkins13, Andrew D. Johnson, Alexander P. Reiner36, Xiaofeng Zhu5, Paul I.W. de Bakker50, Daniel Levy, Folkert W. Asselbergs25, Folkert W. Asselbergs1, Patricia B. Munroe2, Brendan J. Keating8 
TL;DR: The findings extend the understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification and provide support for a putative role in hypertension of several genes.
Abstract: Blood pressure (BP) is a heritable risk factor for cardiovascular disease To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis We replicated findings in an independent set of 68,368 individuals of European ancestry Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2 Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules In summary, we identified previously unknown loci associated with BP Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification

158 citations

Journal ArticleDOI
Gregory T. Jones, Gerard Tromp1, Helena Kuivaniemi1, Solveig Gretarsdottir2, Annette F. Baas3, Betti Giusti4, Ewa Strauss, Femke N G van 't Hof, Tom R. Webb5, Robert Erdman1, Marylyn D. Ritchie6, James R. Elmore7, Anurag Verma6, Sarah A. Pendergrass6, Iftikhar J. Kullo1, Zi Ye1, Peggy L. Peissig8, Omri Gottesman9, Omri Gottesman10, Shefali S. Verma6, Jennifer Malinowski11, Laura J. Rasmussen-Torvik12, Kenneth M. Borthwick1, Diane T. Smelser1, David R. Crosslin13, Mariza de Andrade1, Evan J. Ryer14, Catherine A. McCarty15, E.P. Bottinger10, Jennifer A. Pacheco12, Dana C. Crawford, David Carrell16, Glenn S. Gerhard17, David P. Franklin18, David J. Carey1, Victoria L Phillips, Michael J.A. Williams, Wenhua Wei, Ross D. Blair, Andrew Hill19, Thodor M. Vasudevan, David R. Lewis14, Ian Thomson, J Krysa, Geraldine B. Hill, Justin A. Roake, Tony R. Merriman20, Grzegorz Oszkinis, Silvia Galora4, Claudia Saracini4, Rosanna Abbate4, Rosanna Abbate2, Raffaele Pulli, Carlo Pratesi, Athanasios Saratzis5, Ana Raquel Verissimo5, Suzannah Bumpstead20, Stephen A. Badger21, Rachel E. Clough22, Gillian Cockerill23, Hany Hafez24, D. Julian A. Scott25, T. Simon Futers25, Simon P. R. Romaine25, Katherine I Bridge25, Kathryn J. Griffin25, Marc A. Bailey25, Alberto Smith, Matthew M. Thompson23, Frank M. van Bockxmeer26, Stefan E Matthiasson27, Gudmar Thorleifsson2, Gudmar Thorleifsson1, Unnur Thorsteinsdottir2, Jan D. Blankensteijn28, Joep A.W. Teijink29, Joep A.W. Teijink30, Cisca Wijmenga, Jacqueline de Graaf31, Lambertus A. Kiemeney31, Jes S. Lindholt32, Anne Hughes33, Declan Bradley, Kathleen Stirrups, Jonathan Golledge34, Paul Norman26, Janet T. Powell35, Steve E. Humphries5, Stephen E. Hamby36, Alison H. Goodall5, Christopher P. Nelson5, Natzi Sakalihasan37, Audrey Courtois4, Robert E. Ferrell38, Per Eriksson39, Lasse Folkersen39, Anders Franco-Cereceda, John D. Eicher40, Andrew D. Johnson40, Christer Betsholtz41, Arno Ruusalepp42, Arno Ruusalepp43, Oscar Franzén11, Oscar Franzén42, Eric E. Schadt11, Johan Björkegren, Leonard Lipovich42, Leonard Lipovich40, Anne M. Drolet, Eric L. G. Verhoeven44, Clark J. Zeebregts45, Robert H. Geelkerken31, Marc R.H.M. van Sambeek29, Steven M.M. van Sterkenburg, Jean-Paul P.M. de Vries, K. Stefansson2, John R. Thompson, Paul I.W. de Bakker3, Panos Deloukas, Robert D. Sayers, Seamus C. Harrison, Andre M. van Rij, Nilesh J. Samani5, Matthew J. Bown5 
TL;DR: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
Abstract: RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

158 citations

Journal ArticleDOI
TL;DR: The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomeres length.
Abstract: ObjectivesHuman age-dependent telomere attrition and telomere shortening are associated with several age-associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length. Design and MethodsLeucocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. Follow-up data were available at two time-points up to 2007. Leucocyte telomere length was measured, on between one and three separate occasions, in a total of 16783 DNA samples. Multilevel growth models were created to identify the factors that influence leucocyte telomere dynamics. ResultsWe observed an average attrition rate of 0.470.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39-60) years at baseline. Annual telomere attrition rate increased with age (P ConclusionsSmoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age-associated diseases.

157 citations

Journal ArticleDOI
TL;DR: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories, and it is proposed to establish a common set of physical telomere length standards to improve comparability of telomeres length estimates between laboratories.
Abstract: Background: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories. Methods: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques. Results: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63-0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant (P = 0.06). Gel-based and PCR-based techniques were not different in accuracy. Conclusions: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories.

157 citations

01 Jan 2017
TL;DR: Radiofrequency ablation of the left atrium during mitral valve surgery for continuous atrial fibrillation significantly increases the rate of sinus rhythm restoration 1 year postoperatively, improving patient exercise capacity.
Abstract: CONTEXT Although left atrial radiofrequency ablation (RFA) is increasingly used for the treatment of chronic atrial fibrillation during mitral valve surgery, its efficacy to restore sinus rhythm and any resulting benefits have not been examined in the context of an adequately powered randomized trial. OBJECTIVE To determine whether intraoperative RFA of the left atrium increases the long-term restoration of sinus rhythm and improves exercise capacity. DESIGN, SETTING, AND PATIENTS Randomized, double-blind trial performed in a single UK tertiary referral center with enrollment between December 2001 and November 2003. A total of 101 patients referred for mitral valve surgery with at least 6 months' history of uninterrupted atrial fibrillation were assessed for eligibility; 97 were enrolled. Patients were followed up for 12 months. INTERVENTION Patients were randomly assigned to undergo mitral valve surgery and RFA of the left atrium (n = 49) or mitral valve surgery alone (controls; n = 48). MAIN OUTCOME MEASURES The primary outcome measure was presence of sinus rhythm at 12 months; secondary measures were patient functional status and exercise capacity (assessed by shuttle-walk test), left atrial contractility, and left atrial and left ventricular dimension and function and plasma levels of B-type natriuretic peptide. RESULTS At 12 months, sinus rhythm was present in 20 (44.4%) of 45 RFA patients and in 2 (4.5%) of 44 controls (rate ratio, 9.8; 95% CI, 2.4-86.3; P<.001). Restoration of sinus rhythm in the RFA group was accompanied by a greater improvement in mean (SD) shuttle-walk distance compared with controls (+94 [102] m vs +48 [82] m; P = .003) and a greater reduction in the plasma level of B-type natriuretic peptide (-104 [87] fmol/mL vs -51 [82] fmol/mL; P = .03). Patients randomized to receive RFA had similar rates of postoperative complications and deaths as control patients. CONCLUSIONS Radiofrequency ablation of the left atrium during mitral valve surgery for continuous atrial fibrillation significantly increases the rate of sinus rhythm restoration 1 year postoperatively, improving patient exercise capacity. On the basis of its efficacy and safety, routine use of RFA of the left atrium during mitral valve surgery may be justified. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00238706.

157 citations


Cited by
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28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal ArticleDOI
Giuseppe Mancia1, Robert Fagard, Krzysztof Narkiewicz, Josep Redon, Alberto Zanchetti, Michael Böhm, Thierry Christiaens, Renata Cifkova, Guy De Backer, Anna F. Dominiczak, Maurizio Galderisi, Diederick E. Grobbee, Tiny Jaarsma, Paulus Kirchhof, Sverre E. Kjeldsen, Stéphane Laurent, Athanasios J. Manolis, Peter M. Nilsson, Luis M. Ruilope, Roland E. Schmieder, Per Anton Sirnes, Peter Sleight, Margus Viigimaa, Bernard Waeber, Faiez Zannad, Michel Burnier, Ettore Ambrosioni, Mark Caufield, Antonio Coca, Michael H. Olsen, Costas Tsioufis, Philippe van de Borne, José Luis Zamorano, Stephan Achenbach, Helmut Baumgartner, Jeroen J. Bax, Héctor Bueno, Veronica Dean, Christi Deaton, Çetin Erol, Roberto Ferrari, David Hasdai, Arno W. Hoes, Juhani Knuuti, Philippe Kolh2, Patrizio Lancellotti, Aleš Linhart, Petros Nihoyannopoulos, Massimo F Piepoli, Piotr Ponikowski, Juan Tamargo, Michal Tendera, Adam Torbicki, William Wijns, Stephan Windecker, Denis Clement, Thierry C. Gillebert, Enrico Agabiti Rosei, Stefan D. Anker, Johann Bauersachs, Jana Brguljan Hitij, Mark J. Caulfield, Marc De Buyzere, Sabina De Geest, Geneviève Derumeaux, Serap Erdine, Csaba Farsang, Christian Funck-Brentano, Vjekoslav Gerc, Giuseppe Germanò, Stephan Gielen, Herman Haller, Jens Jordan, Thomas Kahan, Michel Komajda, Dragan Lovic, Heiko Mahrholdt, Jan Östergren, Gianfranco Parati, Joep Perk, Jorge Polónia, Bogdan A. Popescu, Zeljko Reiner, Lars Rydén, Yuriy Sirenko, Alice Stanton, Harry A.J. Struijker-Boudier, Charalambos Vlachopoulos, Massimo Volpe, David A. Wood 
TL;DR: In this article, a randomized controlled trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly people was presented. But the authors did not discuss the effect of the combination therapy in patients living with systolic hypertension.
Abstract: ABCD : Appropriate Blood pressure Control in Diabetes ABI : ankle–brachial index ABPM : ambulatory blood pressure monitoring ACCESS : Acute Candesartan Cilexetil Therapy in Stroke Survival ACCOMPLISH : Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension ACCORD : Action to Control Cardiovascular Risk in Diabetes ACE : angiotensin-converting enzyme ACTIVE I : Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events ADVANCE : Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation AHEAD : Action for HEAlth in Diabetes ALLHAT : Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack ALTITUDE : ALiskiren Trial In Type 2 Diabetes Using Cardio-renal Endpoints ANTIPAF : ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation APOLLO : A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People ARB : angiotensin receptor blocker ARIC : Atherosclerosis Risk In Communities ARR : aldosterone renin ratio ASCOT : Anglo-Scandinavian Cardiac Outcomes Trial ASCOT-LLA : Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm ASTRAL : Angioplasty and STenting for Renal Artery Lesions A-V : atrioventricular BB : beta-blocker BMI : body mass index BP : blood pressure BSA : body surface area CA : calcium antagonist CABG : coronary artery bypass graft CAPPP : CAPtopril Prevention Project CAPRAF : CAndesartan in the Prevention of Relapsing Atrial Fibrillation CHD : coronary heart disease CHHIPS : Controlling Hypertension and Hypertension Immediately Post-Stroke CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease—EPIdemiology collaboration CONVINCE : Controlled ONset Verapamil INvestigation of CV Endpoints CT : computed tomography CV : cardiovascular CVD : cardiovascular disease D : diuretic DASH : Dietary Approaches to Stop Hypertension DBP : diastolic blood pressure DCCT : Diabetes Control and Complications Study DIRECT : DIabetic REtinopathy Candesartan Trials DM : diabetes mellitus DPP-4 : dipeptidyl peptidase 4 EAS : European Atherosclerosis Society EASD : European Association for the Study of Diabetes ECG : electrocardiogram EF : ejection fraction eGFR : estimated glomerular filtration rate ELSA : European Lacidipine Study on Atherosclerosis ESC : European Society of Cardiology ESH : European Society of Hypertension ESRD : end-stage renal disease EXPLOR : Amlodipine–Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine–Atenolol Combination FDA : U.S. Food and Drug Administration FEVER : Felodipine EVent Reduction study GISSI-AF : Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation HbA1c : glycated haemoglobin HBPM : home blood pressure monitoring HOPE : Heart Outcomes Prevention Evaluation HOT : Hypertension Optimal Treatment HRT : hormone replacement therapy HT : hypertension HYVET : HYpertension in the Very Elderly Trial IMT : intima-media thickness I-PRESERVE : Irbesartan in Heart Failure with Preserved Systolic Function INTERHEART : Effect of Potentially Modifiable Risk Factors associated with Myocardial Infarction in 52 Countries INVEST : INternational VErapamil SR/T Trandolapril ISH : Isolated systolic hypertension JNC : Joint National Committee JUPITER : Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin LAVi : left atrial volume index LIFE : Losartan Intervention For Endpoint Reduction in Hypertensives LV : left ventricle/left ventricular LVH : left ventricular hypertrophy LVM : left ventricular mass MDRD : Modification of Diet in Renal Disease MRFIT : Multiple Risk Factor Intervention Trial MRI : magnetic resonance imaging NORDIL : The Nordic Diltiazem Intervention study OC : oral contraceptive OD : organ damage ONTARGET : ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial PAD : peripheral artery disease PATHS : Prevention And Treatment of Hypertension Study PCI : percutaneous coronary intervention PPAR : peroxisome proliferator-activated receptor PREVEND : Prevention of REnal and Vascular ENdstage Disease PROFESS : Prevention Regimen for Effectively Avoiding Secondary Strokes PROGRESS : Perindopril Protection Against Recurrent Stroke Study PWV : pulse wave velocity QALY : Quality adjusted life years RAA : renin-angiotensin-aldosterone RAS : renin-angiotensin system RCT : randomized controlled trials RF : risk factor ROADMAP : Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention SBP : systolic blood pressure SCAST : Angiotensin-Receptor Blocker Candesartan for Treatment of Acute STroke SCOPE : Study on COgnition and Prognosis in the Elderly SCORE : Systematic COronary Risk Evaluation SHEP : Systolic Hypertension in the Elderly Program STOP : Swedish Trials in Old Patients with Hypertension STOP-2 : The second Swedish Trial in Old Patients with Hypertension SYSTCHINA : SYSTolic Hypertension in the Elderly: Chinese trial SYSTEUR : SYSTolic Hypertension in Europe TIA : transient ischaemic attack TOHP : Trials Of Hypertension Prevention TRANSCEND : Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease UKPDS : United Kingdom Prospective Diabetes Study VADT : Veterans' Affairs Diabetes Trial VALUE : Valsartan Antihypertensive Long-term Use Evaluation WHO : World Health Organization ### 1.1 Principles The 2013 guidelines on hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology …

14,173 citations

Journal ArticleDOI
Adam Auton1, Gonçalo R. Abecasis2, David Altshuler3, Richard Durbin4  +514 moreInstitutions (90)
01 Oct 2015-Nature
TL;DR: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.
Abstract: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

12,661 citations

Journal ArticleDOI
Paul Burton1, David Clayton2, Lon R. Cardon, Nicholas John Craddock3  +192 moreInstitutions (4)
07 Jun 2007-Nature
TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

9,244 citations

Journal ArticleDOI
Monkol Lek, Konrad J. Karczewski1, Konrad J. Karczewski2, Eric Vallabh Minikel2, Eric Vallabh Minikel1, Kaitlin E. Samocha, Eric Banks1, Timothy Fennell1, Anne H. O’Donnell-Luria2, Anne H. O’Donnell-Luria3, Anne H. O’Donnell-Luria1, James S. Ware, Andrew J. Hill4, Andrew J. Hill2, Andrew J. Hill1, Beryl B. Cummings1, Beryl B. Cummings2, Taru Tukiainen2, Taru Tukiainen1, Daniel P. Birnbaum1, Jack A. Kosmicki, Laramie E. Duncan1, Laramie E. Duncan2, Karol Estrada2, Karol Estrada1, Fengmei Zhao2, Fengmei Zhao1, James Zou1, Emma Pierce-Hoffman2, Emma Pierce-Hoffman1, Joanne Berghout5, David Neil Cooper6, Nicole A. Deflaux7, Mark A. DePristo1, Ron Do, Jason Flannick2, Jason Flannick1, Menachem Fromer, Laura D. Gauthier1, Jackie Goldstein2, Jackie Goldstein1, Namrata Gupta1, Daniel P. Howrigan2, Daniel P. Howrigan1, Adam Kiezun1, Mitja I. Kurki1, Mitja I. Kurki2, Ami Levy Moonshine1, Pradeep Natarajan, Lorena Orozco, Gina M. Peloso1, Gina M. Peloso2, Ryan Poplin1, Manuel A. Rivas1, Valentin Ruano-Rubio1, Samuel A. Rose1, Douglas M. Ruderfer8, Khalid Shakir1, Peter D. Stenson6, Christine Stevens1, Brett Thomas1, Brett Thomas2, Grace Tiao1, María Teresa Tusié-Luna, Ben Weisburd1, Hong-Hee Won9, Dongmei Yu, David Altshuler1, David Altshuler10, Diego Ardissino, Michael Boehnke11, John Danesh12, Stacey Donnelly1, Roberto Elosua, Jose C. Florez2, Jose C. Florez1, Stacey Gabriel1, Gad Getz1, Gad Getz2, Stephen J. Glatt13, Christina M. Hultman14, Sekar Kathiresan, Markku Laakso15, Steven A. McCarroll1, Steven A. McCarroll2, Mark I. McCarthy16, Mark I. McCarthy17, Dermot P.B. McGovern18, Ruth McPherson19, Benjamin M. Neale1, Benjamin M. Neale2, Aarno Palotie, Shaun Purcell8, Danish Saleheen20, Jeremiah M. Scharf, Pamela Sklar, Patrick F. Sullivan21, Patrick F. Sullivan14, Jaakko Tuomilehto22, Ming T. Tsuang23, Hugh Watkins16, Hugh Watkins17, James G. Wilson24, Mark J. Daly1, Mark J. Daly2, Daniel G. MacArthur2, Daniel G. MacArthur1 
18 Aug 2016-Nature
TL;DR: The aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC) provides direct evidence for the presence of widespread mutational recurrence.
Abstract: Large-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) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This 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 have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having 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.

8,758 citations