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Laura M. Raffield

Bio: Laura M. Raffield is an academic researcher from University of North Carolina at Chapel Hill. The author has contributed to research in topics: Genome-wide association study & Medicine. The author has an hindex of 23, co-authored 124 publications receiving 1948 citations. Previous affiliations of Laura M. Raffield include Medical University of South Carolina & Wake Forest University.

Papers published on a yearly basis

Papers
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Journal ArticleDOI
14 Oct 2020-Nature
TL;DR: Analysis of high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine programme enables simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells.
Abstract: Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

300 citations

Journal ArticleDOI
Dragana Vuckovic1, Erik L. Bao2, Parsa Akbari1, Caleb A. Lareau2, Abdou Mousas3, Tao Jiang1, Ming-Huei Chen, Laura M. Raffield4, Manuel Tardaguila5, Jennifer E. Huffman6, Scott C. Ritchie1, Karyn Megy1, Hannes Ponstingl5, Christopher J. Penkett1, Patrick K. Albers5, Emilie M. Wigdor5, Saori Sakaue7, Arden Moscati8, Regina Manansala9, Ken Sin Lo3, Huijun Qian4, Masato Akiyama10, Traci M. Bartz11, Yoav Ben-Shlomo12, Andrew D Beswick12, Jette Bork-Jensen13, Erwin P. Bottinger8, Jennifer A. Brody11, Frank J. A. van Rooij14, Kumaraswamy Naidu Chitrala15, Peter W.F. Wilson16, Hélène Choquet17, John Danesh, Emanuele Di Angelantonio, Niki Dimou18, Jingzhong Ding19, Paul Elliott20, Tõnu Esko21, Michele K. Evans15, Stephan B. Felix22, James S. Floyd11, Linda Broer14, Niels Grarup13, Michael H. Guo23, Qi Guo24, Andreas Greinacher22, Jeffrey Haessler25, Torben Hansen13, J. M. M. Howson1, Wei Huang26, Eric Jorgenson17, Tim Kacprowski27, Mika Kähönen28, Yoichiro Kamatani29, Masahiro Kanai2, Savita Karthikeyan24, Fotios Koskeridis30, Leslie A. Lange31, Terho Lehtimäki, Allan Linneberg13, Yongmei Liu32, Leo-Pekka Lyytikäinen, Ani Manichaikul33, Koichi Matsuda29, Karen L. Mohlke4, Nina Mononen, Yoshinori Murakami29, Girish N. Nadkarni8, Kjell Nikus28, Nathan Pankratz34, Oluf Pedersen13, Michael Preuss8, Bruce M. Psaty11, Olli T. Raitakari35, Stephen S. Rich33, Benjamin Rodriguez, Jonathan D. Rosen4, Jerome I. Rotter36, Petra Schubert6, Cassandra N. Spracklen4, Praveen Surendran5, Hua Tang37, Jean-Claude Tardif3, Mohsen Ghanbari38, Uwe Völker22, Henry Völzke22, Nicholas A. Watkins39, Stefan Weiss22, VA Million Veteran Program5, Na Cai5, Kousik Kundu5, Stephen B. Watt5, Klaudia Walter5, Alan B. Zonderman15, Kelly Cho40, Yun Li4, Ruth J. F. Loos8, Julian C. Knight41, Michel Georges42, Oliver Stegle43, Evangelos Evangelou20, Yukinori Okada7, David J. Roberts44, Michael Inouye, Andrew D. Johnson, Paul L. Auer9, William J. Astle1, Alexander P. Reiner11, Adam S. Butterworth, Willem H. Ouwehand1, Guillaume Lettre3, Vijay G. Sankaran21, Vijay G. Sankaran2, Nicole Soranzo 
03 Sep 2020-Cell
TL;DR: The results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

284 citations

01 Jan 2019
TL;DR: Trans-ancestry meta-analysis of estimated glomerular filtration rate (eGFR) from 1,046,070 individuals identifies 264 associated loci, providing a resource of molecular targets for translational research of chronic kidney disease.
Abstract: Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.Trans-ancestry meta-analysis of estimated glomerular filtration rate (eGFR) from 1,046,070 individuals identifies 264 associated loci, providing a resource of molecular targets for translational research of chronic kidney disease.

243 citations

Journal ArticleDOI
Ming-Huei Chen, Laura M. Raffield1, Abdou Mousas2, Saori Sakaue3, Jennifer E. Huffman4, Arden Moscati5, Bhavi Trivedi6, Tao Jiang7, Parsa Akbari8, Dragana Vuckovic9, Erik L. Bao10, Xue Zhong11, Regina Manansala12, Véronique Laplante13, Minhui Chen14, Ken Sin Lo2, Huijun Qian1, Caleb A. Lareau10, Mélissa Beaudoin2, Karen A. Hunt6, Masato Akiyama15, Traci M. Bartz16, Yoav Ben-Shlomo17, Andrew D Beswick17, Jette Bork-Jensen18, Erwin P. Bottinger5, Jennifer A. Brody16, Frank J. A. van Rooij19, Kumaraswamynaidu Chitrala20, Kelly Cho21, Hélène Choquet22, Adolfo Correa23, John Danesh, Emanuele Di Angelantonio8, Niki Dimou24, Jingzhong Ding25, Paul Elliott26, Tõnu Esko27, Michele K. Evans20, James S. Floyd16, Linda Broer19, Niels Grarup18, Michael H. Guo28, Andreas Greinacher29, Jeffrey Haessler30, Torben Hansen18, Joanna M. M. Howson7, Qin Qin Huang9, Wei Huang31, Eric Jorgenson22, Tim Kacprowski32, Mika Kähönen33, Yoichiro Kamatani34, Masahiro Kanai10, Savita Karthikeyan7, Fotis Koskeridis35, Leslie A. Lange36, Terho Lehtimäki, Markus M. Lerch29, Allan Linneberg18, Yongmei Liu37, Leo-Pekka Lyytikäinen, Ani Manichaikul38, Hilary C. Martin9, Koichi Matsuda34, Karen L. Mohlke1, Nina Mononen, Yoshinori Murakami34, Girish N. Nadkarni5, Matthias Nauck29, Kjell Nikus33, Willem H. Ouwehand39, Nathan Pankratz40, Oluf Pedersen18, Michael Preuss5, Bruce M. Psaty16, Olli T. Raitakari41, David J. Roberts8, Stephen S. Rich38, Benjamin Rodriguez, Jonathan D. Rosen1, Jerome I. Rotter42, Petra Schubert4, Cassandra N. Spracklen1, Praveen Surendran7, Hua Tang43, Jean-Claude Tardif2, Richard C. Trembath44, Mohsen Ghanbari45, Uwe Völker29, Henry Völzke29, Nicholas A. Watkins39, Alan B. Zonderman20, VA Million Veteran Program46, Peter W.F. Wilson46, Yun Li1, Adam S. Butterworth8, Jean-François Gauchat13, Charleston W. K. Chiang14, Bingshan Li11, Ruth J. F. Loos5, William J. Astle8, Evangelos Evangelou26, David A. van Heel6, Vijay G. Sankaran10, Yukinori Okada3, Nicole Soranzo9, Andrew D. Johnson, Alexander P. Reiner16, Paul L. Auer12, Guillaume Lettre2, Guillaume Lettre13 
03 Sep 2020-Cell
TL;DR: The clinical significance and predictive value of trans-ethnic variants in multiple populations are explored, genetic architecture and the effect of natural selection on these blood phenotypes between populations are compared and the value of a more global representation of populations in genetic studies is highlighted.

233 citations

Journal ArticleDOI
Adrienne Tin1, Jonathan Marten2, Victoria L. Halperin Kuhns3, Yong Li4  +248 moreInstitutions (77)
TL;DR: A trans-ancestry genome-wide association study of serum urate levels identifies 183 loci that improve the prediction of gout in an independent cohort of 334,880 individuals, and implicates the kidney and liver as key target organs and prioritize potential causal genes.
Abstract: Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

214 citations


Cited by
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Book ChapterDOI
01 Jan 2010

5,842 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: This year's edition of the Statistical Update includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association’s 2020 Impact Goals.
Abstract: Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovas...

5,078 citations

01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

4,409 citations

Journal ArticleDOI
TL;DR: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascul...
Abstract: Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascul...

3,034 citations