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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
TL;DR: This study shows that in patients undergoing MV repair for degenerative MR, preoperative AF has a major negative impact on the early and late survival.
Abstract: Objective: There is conflictingevidence with regardto the impact of preoperative atrialfibrillation(AF) on the post mitral valve (MV) repair on the early and late outcome. Methods: A total of 349 patients undergoing various MVrepair procedures for degenerative mitral regurgitation (MR) between 1997and 2003were studied.Preoperatively, 152(44%) of these patientswere in AF and 197(56%) patientswere in sinusrhythm (SR).The clinical features and the outcome in these two cohorts of patients were compared. Results: The patients in the AF group were older than their counterparts in the SR group (66 7v s 62 9 years) (p = 0.01), had a higher mean NYHA class score (2.4 0.6 vs 2.2 0.7) (p = 0.04) and were more likely to have impaired left ventricular function (60% vs 36%) (p < 0.0001). A similar proportion of patients in the AF (38%) and SR (30%) groups had additional cardiac surgical procedures (p = 0.12). Operative mortality was 3.9% in AF group versus 0.5% in SR group (p = 0.04), and operative morbidity was 27% versus 17%, respectively (p = 0.03). At latest follow up, 4% of patients that were in SR preoperatively developed AF; conversely, 2% of the patients in the AF group converted to SR. The rates of recurrent grade II or III MR (4% vs 5%) (p = 0.8) and MV re-operation (2.6% vs 2.5%) (p = 1.0) were similar in the AF and SR groups. Kaplan—Meier survival at 7 years was 75 6% versus 90 3% (p = 0.005). On Cox proportional hazards regression model, impaired LV function [(p = 0.02), hazard ratio 0.25 (95% confidence intervals (C.I.) 0.078—0.84)] and AF [(p = 0.03), hazard ratio 2.70 (95% C.I. 1.09—6.68)] were significant adverse predictors of survival. Conclusions: This study shows that in patients undergoing MV repair for degenerative MR, preoperative AF has a major negative impact on the early and late survival. # 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

48 citations

Journal ArticleDOI
TL;DR: It is concluded that renalmiR-181a has pleiotropic effects on pathways relevant to blood pressure regulation and that circulating levels of miR- 181a are both a measurable proxy of renal miR -181a expression and a novel biochemical correlate of blood pressure.
Abstract: MicroRNA-181a binds to the 3′ untranslated region of messenger RNA (mRNA) for renin, a rate-limiting enzyme of the renin-angiotensin system. Our objective was to determine whether this molecular interaction translates into a clinically meaningful effect on blood pressure and whether circulating miR-181a is a measurable proxy of blood pressure. In 200 human kidneys from the TRANScriptome of renaL humAn TissuE (TRANSLATE) study, renal miR-181a was the sole negative predictor of renin mRNA and a strong correlate of circulating miR-181a. Elevated miR-181a levels correlated positively with systolic and diastolic blood pressure in TRANSLATE, and this association was independent of circulating renin. The association between serum miR-181a and systolic blood pressure was replicated in 199 subjects from the Genetic Regulation of Arterial Pressure of Humans In the Community (GRAPHIC) study. Renal immunohistochemistry and in situ hybridization showed that colocalization of miR-181a and renin was most prominent in collecting ducts where renin is not released into the systemic circulation. Analysis of 69 human kidneys characterized by RNA sequencing revealed that miR-181a was associated with downregulation of four mitochondrial pathways and upregulation of 41 signaling cascades of adaptive immunity and inflammation. We conclude that renal miR-181a has pleiotropic effects on pathways relevant to blood pressure regulation and that circulating levels of miR-181a are both a measurable proxy of renal miR-181a expression and a novel biochemical correlate of blood pressure.

48 citations

Journal ArticleDOI
TL;DR: The data show that patients with AAA have shorter leukocyte telomere length compared to controls, which suggests that vascular biological aging may have a role in the pathogenesis of AAA.

48 citations

Journal ArticleDOI
TL;DR: Of the hundreds of thousands single-nucleotide polymorphisms studied across the genome the same locus showed the strongest association with CAD in all 4 studies, as illustrated by a direct comparison of the data from the Wellcome Trust Case Control Consortium and the Cardiogenics Consortium.
Abstract: The middle of 2007 saw what may, with time, turn out to be the single most important discovery in the genetics of cardiovascular diseases Within a few weeks, 4 independent genomewide association studies reported the association of the same locus on chromosome 9p21 with coronary artery disease (CAD) and myocardial infarction (MI)1–4 In fact, of the hundreds of thousands single-nucleotide polymorphisms studied across the genome the same locus showed the strongest association with CAD in all 4 studies, as illustrated by a direct comparison of the data from the Wellcome Trust Case Control Consortium and the Cardiogenics Consortium4 The finding has led to a plethora of further studies that have largely confirmed the association of the 9p21 locus with CAD and MI in both case–control and cohort studies and in multiple ethnic groups5–12 9p21 represents the most replicated locus for CAD and MI to date The risk allele as currently defined, until causal variants are identified, is common (allele frequency of almost 50%) and associated with a 20% to 30% increased risk per copy The effect of the 9p21 locus on CAD and MI risk is unaltered by adjustment for traditional cardiovascular risk factors5,6 and indeed studies in healthy populations have found no explanatory effect of the 9p21 locus on CAD risk via blood pressure, cholesterol levels, body mass index, or smoking behavior13 Article see p 85 The chromosome 9p21 locus is intriguing for several reasons First, it is a region well known in cancer genetics as one of the most common sites of deletions leading to hereditary forms of cutaneous malignant melanoma14 Second, the association signal for CAD maps to a segment with no known protein coding genes4 Indeed, the most strongly associated single-nucleotide polymorphisms lie almost a 100 kb from the …

47 citations

Journal ArticleDOI
Evangelos Evangelou1, Evangelos Evangelou2, He Gao2, Congying Chu3, Georgios Ntritsos1, Paul Blakeley2, Andrew R. Butts4, Raha Pazoki2, Hideaki Suzuki5, Hideaki Suzuki2, Fotios Koskeridis1, Andrianos M. Yiorkas6, Andrianos M. Yiorkas2, Ibrahim Karaman2, Joshua Elliott2, Qiang Luo7, Qiang Luo8, Stefanie Aeschbacher9, Traci M. Bartz10, Sebastian E. Baumeister11, Sebastian E. Baumeister12, Peter S. Braund13, Peter S. Braund14, Michael R. Brown15, Jennifer A. Brody10, Toni-Kim Clarke16, Niki Dimou1, Jessica D. Faul17, Georg Homuth11, Anne U. Jackson17, Katherine A. Kentistou16, Peter K. Joshi16, Rozenn N. Lemaitre10, Penelope A. Lind18, Leo-Pekka Lyytikäinen, Massimo Mangino19, Massimo Mangino3, Yuri Milaneschi20, Christopher P. Nelson13, Christopher P. Nelson14, Ilja M. Nolte21, Mia-Maria Perälä22, Ozren Polasek23, David J. Porteous16, Scott M. Ratliff17, Jennifer A. Smith17, Alena Stančáková24, Alexander Teumer25, Samuli Tuominen26, Sébastien Thériault27, Sébastien Thériault28, Jagadish Vangipurapu24, John Whitfield18, Alexis C. Wood29, Jie Yao30, Bing Yu15, Wei Zhao17, Dan E. Arking31, Juha Auvinen32, Chunyu Liu33, Minna Männikkö32, Lorenz Risch34, Jerome I. Rotter35, Harold Snieder21, Juha Veijola32, Alexandra I. F. Blakemore6, Alexandra I. F. Blakemore2, Michael Boehnke17, Harry Campbell16, David Conen28, Johan G. Eriksson26, Johan G. Eriksson22, Hans J. Grabe36, Hans J. Grabe25, Xiuqing Guo30, Pim van der Harst21, Catharina A. Hartman21, Caroline Hayward16, Andrew C. Heath37, Marjo-Riitta Järvelin32, Marjo-Riitta Järvelin2, Marjo-Riitta Järvelin6, Mika Kähönen38, Sharon L.R. Kardia17, Michael Kühne9, Johanna Kuusisto24, Markku Laakso24, Jari Lahti26, Terho Lehtimäki, Andrew M. McIntosh16, Karen L. Mohlke39, Alanna C. Morrison15, Nicholas G. Martin18, Albertine J. Oldehinkel21, Brenda W.J.H. Penninx20, Bruce M. Psaty40, Bruce M. Psaty10, Olli T. Raitakari41, Igor Rudan16, Nilesh J. Samani14, Nilesh J. Samani13, Laura J. Scott17, Tim D. Spector3, Niek Verweij21, David R. Weir17, James F. Wilson16, Daniel Levy42, Ioanna Tzoulaki2, Jimmy D. Bell43, Paul M. Matthews2, Adrian Rothenfluh4, Sylvane Desrivières3, Gunter Schumann44, Gunter Schumann3, Paul Elliott 
TL;DR: This article conducted a meta-analysis of genome-wide association studies of alcohol consumption from the UK Biobank, the Alcohol Genome Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake.
Abstract: Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

47 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