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Leslie A. Lange

Bio: Leslie A. Lange is an academic researcher from Anschutz Medical Campus. The author has contributed to research in topics: Genome-wide association study & Medicine. The author has an hindex of 72, co-authored 306 publications receiving 20582 citations. Previous affiliations of Leslie A. Lange include University of Michigan & Fred Hutchinson Cancer Research Center.


Papers
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Journal ArticleDOI
05 Aug 2010-Nature
TL;DR: The results identify several novel loci associated with plasma lipids that are also associated with CAD and provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Abstract: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

3,469 citations

Journal ArticleDOI
Daniel I. Swerdlow1, Michael V. Holmes1, Karoline Kuchenbaecker2, Engmann Jel.1, Tina Shah1, Reecha Sofat1, Yiran Guo, C Chung1, Anne Peasey1, Roman Pfister3, Simon P. Mooijaart4, Helen Ireland1, Maarten Leusink5, Claudia Langenberg3, KaWah Li1, Jutta Palmen1, Phil Howard1, Jackie A. Cooper1, Fotios Drenos1, John Hardy1, Mike A. Nalls6, Yun Li7, Gordon D.O. Lowe8, Marlene C. W. Stewart9, S. J. Bielinski10, Julian Peto11, Nicholas J. Timpson12, John Gallacher13, Malcolm G. Dunlop9, Richard S. Houlston, Ian Tomlinson14, Ioanna Tzoulaki15, Jian'an Luan2, Boer Jma.2, Nita G. Forouhi2, N. C. Onland-Moret5, Y. T. van der Schouw16, Renate B. Schnabel16, Jaroslav A. Hubacek, Růžena Kubínová, Migle Baceviciene17, Abdonas Tamosiunas17, Andrzej Pajak18, Roman Topor-Madry18, Sofia Malyutina19, Damiano Baldassarre, Bengt Sennblad20, Elena Tremoli, U de Faire21, Luigi Ferrucci21, S Bandenelli, Tetsu Tanaka21, James F. Meschia10, AB Singleton6, Gerjan Navis22, I. Mateo Leach22, Bakker Sjl.22, Ron T. Gansevoort, Ian Ford8, Stephen E. Epstein23, Mary-Susan Burnett23, Joe Devaney23, Johan Wouter Jukema4, Westendorp Rgj.5, G Jan de Borst5, Y. van der Graaf5, P A de Jong5, Mailand-van der Zee A-H.5, Olaf H. Klungel5, A. de Boer5, P. A. Doevendans5, Jeffrey W. Stephens24, Charles B. Eaton25, Jennifer G. Robinson26, JoAnn E. Manson27, F G Fowkes28, Timothy M. Frayling28, Jenna Price9, Peter H. Whincup11, Richard W Morris1, Debbie A Lawlor12, George Davey Smith12, Yoav Ben-Shlomo12, Susan Redline27, Leslie A. Lange29, Meena Kumari1, Nicholas J. Wareham2, Verschuren Wmm.30, Emelia J. Benjamin30, John C. Whittaker11, Anders Hamsten20, Frank Dudbridge11, Delaney Jac.31, Andrew Wong31, Diana Kuh31, Rebecca Hardy31, Berta Almoguera Castillo7, John Connolly7, P. van der Harst, Eric J. Brunner1, Michael Marmot1, Christina L. Wassel32, Steve E. Humphries1, P.J. Talmud1, Mika Kivimäki1, Folkert W. Asselbergs5, Mikhail I. Voevoda19, Martin Bobak1, Hynek Pikhart1, James G. Wilson33, Hakon Hakonarson7, Alexander P. Reiner34, Brendan J. Keating7, Naveed Sattar8, Aroon D. Hingorani1, Juan P. Casas11 
TL;DR: IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials and could help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses.

891 citations

Journal ArticleDOI
Jacy R Crosby1, Gina M. Peloso2, Gina M. Peloso3, Paul L. Auer4, David R. Crosslin5, Nathan O. Stitziel6, Leslie A. Lange7, Yingchang Lu8, Zheng-Zheng Tang7, He Zhang9, George Hindy10, Nicholas G. D. Masca11, Kathleen Stirrups12, Stavroula Kanoni12, Ron Do2, Ron Do3, Goo Jun9, Youna Hu9, Hyun Min Kang9, Chenyi Xue9, Anuj Goel13, Martin Farrall13, Stefano Duga14, Pier Angelica Merlini, Rosanna Asselta14, Domenico Girelli15, Oliviero Olivieri15, Nicola Martinelli15, Wu Yin16, Dermot F. Reilly16, Elizabeth K. Speliotes9, Caroline S. Fox17, Kristian Hveem18, Oddgeir L. Holmen19, Majid Nikpay20, Deborah N. Farlow3, Themistocles L. Assimes21, Nora Franceschini7, Jennifer G. Robinson22, Kari E. North7, Lisa W. Martin23, Mark A. DePristo3, Namrata Gupta3, Stefan A. Escher10, Jan-Håkan Jansson24, Natalie R. van Zuydam25, Colin N. A. Palmer25, Nicholas J. Wareham26, Werner Koch27, Thomas Meitinger27, Annette Peters, Wolfgang Lieb28, Raimund Erbel, Inke R. König29, Jochen Kruppa29, Franziska Degenhardt30, Omri Gottesman8, Erwin P. Bottinger8, Christopher J. O'Donnell17, Bruce M. Psaty5, Bruce M. Psaty31, Christie M. Ballantyne32, Christie M. Ballantyne33, Gonçalo R. Abecasis9, Jose M. Ordovas34, Jose M. Ordovas35, Olle Melander10, Hugh Watkins13, Marju Orho-Melander10, Diego Ardissino, Ruth J. F. Loos8, Ruth McPherson20, Cristen J. Willer9, Jeanette Erdmann29, Alistair S. Hall36, Nilesh J. Samani11, Panos Deloukas37, Panos Deloukas38, Panos Deloukas12, Heribert Schunkert27, James G. Wilson39, Charles Kooperberg40, Stephen S. Rich41, Russell P. Tracy42, Danyu Lin7, David Altshuler2, David Altshuler3, Stacey Gabriel3, Deborah A. Nickerson5, Gail P. Jarvik5, L. Adrienne Cupples43, L. Adrienne Cupples26, Alexander P. Reiner5, Alexander P. Reiner40, Eric Boerwinkle32, Sekar Kathiresan2, Sekar Kathiresan3 
TL;DR: Rare mutations that disrupt AP OC3 function were associated with lower levels of plasma triglycerides and APOC3, and carriers of these mutations were found to have a reduced risk of coronary heart disease.
Abstract: Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10 − 20 ), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8×10 − 10 ). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4×10 − 6 ). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)

877 citations

Journal ArticleDOI
Daniel Taliun1, Daniel N. Harris2, Michael D. Kessler2, Jedidiah Carlson1  +202 moreInstitutions (61)
10 Feb 2021-Nature
TL;DR: The Trans-Omics for Precision Medicine (TOPMed) project as discussed by the authors aims to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases.
Abstract: The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1 In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals) These rare variants provide insights into mutational processes and recent human evolutionary history The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 001% The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history

801 citations

Posted ContentDOI
Daniel Taliun1, Daniel N. Harris2, Michael D. Kessler2, Jedidiah Carlson3  +191 moreInstitutions (61)
06 Mar 2019-bioRxiv
TL;DR: The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation as well as resources and early insights from the sequence data.
Abstract: Summary paragraph The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency

662 citations


Cited by
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TL;DR: Mice adds new functionality for imputing multilevel data, automatic predictor selection, data handling, post-processing imputed values, specialized pooling routines, model selection tools, and diagnostic graphs.
Abstract: The R package mice imputes incomplete multivariate data by chained equations. The software mice 1.0 appeared in the year 2000 as an S-PLUS library, and in 2001 as an R package. mice 1.0 introduced predictor selection, passive imputation and automatic pooling. This article documents mice, which extends the functionality of mice 1.0 in several ways. In mice, the analysis of imputed data is made completely general, whereas the range of models under which pooling works is substantially extended. mice adds new functionality for imputing multilevel data, automatic predictor selection, data handling, post-processing imputed values, specialized pooling routines, model selection tools, and diagnostic graphs. Imputation of categorical data is improved in order to bypass problems caused by perfect prediction. Special attention is paid to transformations, sum scores, indices and interactions using passive imputation, and to the proper setup of the predictor matrix. mice can be downloaded from the Comprehensive R Archive Network. This article provides a hands-on, stepwise approach to solve applied incomplete data problems.

10,234 citations

Journal Article
TL;DR: For the next few weeks the course is going to be exploring a field that’s actually older than classical population genetics, although the approach it’ll be taking to it involves the use of population genetic machinery.
Abstract: So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

9,847 citations

Journal ArticleDOI
TL;DR: March 5, 2019 e1 WRITING GROUP MEMBERS Emelia J. Virani, MD, PhD, FAHA, Chair Elect On behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee.
Abstract: March 5, 2019 e1 WRITING GROUP MEMBERS Emelia J. Benjamin, MD, ScM, FAHA, Chair Paul Muntner, PhD, MHS, FAHA, Vice Chair Alvaro Alonso, MD, PhD, FAHA Marcio S. Bittencourt, MD, PhD, MPH Clifton W. Callaway, MD, FAHA April P. Carson, PhD, MSPH, FAHA Alanna M. Chamberlain, PhD Alexander R. Chang, MD, MS Susan Cheng, MD, MMSc, MPH, FAHA Sandeep R. Das, MD, MPH, MBA, FAHA Francesca N. Delling, MD, MPH Luc Djousse, MD, ScD, MPH Mitchell S.V. Elkind, MD, MS, FAHA Jane F. Ferguson, PhD, FAHA Myriam Fornage, PhD, FAHA Lori Chaffin Jordan, MD, PhD, FAHA Sadiya S. Khan, MD, MSc Brett M. Kissela, MD, MS Kristen L. Knutson, PhD Tak W. Kwan, MD, FAHA Daniel T. Lackland, DrPH, FAHA Tené T. Lewis, PhD Judith H. Lichtman, PhD, MPH, FAHA Chris T. Longenecker, MD Matthew Shane Loop, PhD Pamela L. Lutsey, PhD, MPH, FAHA Seth S. Martin, MD, MHS, FAHA Kunihiro Matsushita, MD, PhD, FAHA Andrew E. Moran, MD, MPH, FAHA Michael E. Mussolino, PhD, FAHA Martin O’Flaherty, MD, MSc, PhD Ambarish Pandey, MD, MSCS Amanda M. Perak, MD, MS Wayne D. Rosamond, PhD, MS, FAHA Gregory A. Roth, MD, MPH, FAHA Uchechukwu K.A. Sampson, MD, MBA, MPH, FAHA Gary M. Satou, MD, FAHA Emily B. Schroeder, MD, PhD, FAHA Svati H. Shah, MD, MHS, FAHA Nicole L. Spartano, PhD Andrew Stokes, PhD David L. Tirschwell, MD, MS, MSc, FAHA Connie W. Tsao, MD, MPH, Vice Chair Elect Mintu P. Turakhia, MD, MAS, FAHA Lisa B. VanWagner, MD, MSc, FAST John T. Wilkins, MD, MS, FAHA Sally S. Wong, PhD, RD, CDN, FAHA Salim S. Virani, MD, PhD, FAHA, Chair Elect On behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee

5,739 citations

Journal ArticleDOI
TL;DR: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) as discussed by the authors provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.

5,668 citations