Human metabolic individuality in biomedical and pharmaceutical research
Karsten Suhre,So-Youn Shin,Ann-Kristin Petersen,Robert P. Mohney,David Meredith,Brigitte Wägele,Elisabeth Altmaier,Panos Deloukas,Jeanette Erdmann,Elin Grundberg,Elin Grundberg,Christopher J Hammond,Martin Hrabé de Angelis,Gabi Kastenmüller,Anna Köttgen,Florian Kronenberg,Massimo Mangino,Christa Meisinger,Thomas Meitinger,Hans-Werner Mewes,Michael V. Milburn,Cornelia Prehn,Johannes Raffler,Janina S. Ried,Werner Römisch-Margl,Nilesh J. Samani,Kerrin S. Small,H.-Erich Wichmann,Guangju Zhai,Thomas Illig,Tim D. Spector,Jerzy Adamski,Nicole Soranzo,Christian Gieger +33 more
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TLDR
A comprehensive analysis of genotype-dependent metabolic phenotypes using a genome-wide association study with non-targeted metabolomics to identify genetic loci associated with blood metabolite concentrations and generates many new hypotheses for biomedical and pharmaceutical research.Abstract:
Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.read more
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Innovation: Metabolomics: the apogee of the omics trilogy
TL;DR: By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanism are being revealed and are shaping the understanding of cell biology, physiology and medicine.
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An atlas of genetic influences on human blood metabolites
So-Youn Shin,Eric B. Fauman,Ann-Kristin Petersen,Jan Krumsiek,Rita Santos,Jie Huang,Matthias Arnold,Idil Erte,Vincenzo Forgetta,Tsun-Po Yang,Klaudia Walter,Cristina Menni,Lu Chen,Lu Chen,Louella Vasquez,Ana M. Valdes,Ana M. Valdes,Craig L. Hyde,Vicky Wang,Daniel Ziemek,Phoebe M. Roberts,Li Xi,Elin Grundberg,Melanie Waldenberger,J. Brent Richards,Robert P. Mohney,Michael V. Milburn,Sally John,Jeff K. Trimmer,Fabian J. Theis,John P. Overington,Karsten Suhre,M. Julia Brosnan,Christian Gieger,Gabi Kastenmüller,Tim D. Spector,Nicole Soranzo +36 more
TL;DR: The most comprehensive exploration of genetic loci influencing human metabolism thus far, comprising 7,824 adult individuals from 2 European population studies, is reported, reporting genome-wide significant associations at 145 metabolic loci and their biochemical connectivity with more than 400 metabolites in human blood.
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Emerging applications of metabolomics in drug discovery and precision medicine
TL;DR: This Review discusses some of the latest technological advances in metabolomics, focusing on the application of metabolomics towards uncovering the underlying causes of complex diseases, the growing role of metabolites in drug discovery and its potential effect on precision medicine.
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HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease.
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Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?
TL;DR: The broad impact of metabolism in cellular function and how modern concepts of metabolism can inform the authors' understanding of common diseases like cancer are discussed and the prospects of developing new metabolic approaches to disease treatment are considered.
References
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PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses
Shaun Purcell,Shaun Purcell,Benjamin M. Neale,Benjamin M. Neale,Kathe Todd-Brown,Lori Thomas,Manuel A. R. Ferreira,David Bender,David Bender,Julian Maller,Julian Maller,Pamela Sklar,Pamela Sklar,Paul I.W. de Bakker,Paul I.W. de Bakker,Mark J. Daly,Mark J. Daly,Pak C. Sham +17 more
TL;DR: This work introduces PLINK, an open-source C/C++ WGAS tool set, and describes the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation, which focuses on the estimation and use of identity- by-state and identity/descent information in the context of population-based whole-genome studies.
Journal ArticleDOI
Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
Lucia A. Hindorff,Praveen Sethupathy,Heather Junkins,Erin M. Ramos,Jayashri P. Mehta,Francis S. Collins,Teri A. Manolio +6 more
TL;DR: An online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs) is developed, well-suited to guide future investigations of the role of common variants in complex disease etiology.
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A flexible and accurate genotype imputation method for the next generation of genome-wide association studies.
TL;DR: It is found that imputation accuracy can be greatly enhanced by expanding the reference panel to contain thousands of chromosomes and that IMPUTE v2 outperforms other methods in this setting at both rare and common SNPs, with overall error rates that are 15%–20% lower than those of the closest competing method.
Journal ArticleDOI
Biological, clinical and population relevance of 95 loci for blood lipids
Tanya M. Teslovich,Kiran Musunuru,Albert V. Smith,Andrew C. Edmondson,Ioannis M. Stylianou,Masahiro Koseki,James P. Pirruccello,James P. Pirruccello,James P. Pirruccello,Samuli Ripatti,Daniel I. Chasman,Cristen J. Willer,Christopher T. Johansen,Sigrid W. Fouchier,Aaron Isaacs,Gina M. Peloso,Maja Barbalić,Sally L. Ricketts,Joshua C. Bis,Yurii S. Aulchenko,Gudmar Thorleifsson,Mary F. Feitosa,John C. Chambers,Marju Orho-Melander,Olle Melander,Toby Johnson,Xiaohui Li,Xiuqing Guo,Mingyao Li,Yoon Shin Cho,Min Jin Go,Young Jin Kim,Jong-Young Lee,Taesung Park,Kyunga Kim,Xueling Sim,Rick Twee-Hee Ong,Damien C. Croteau-Chonka,Leslie A. Lange,Joshua D. Smith,Kijoung Song,Jing Hua Zhao,Xin Yuan,Jian'an Luan,Claudia Lamina,Andreas Ziegler,Weihua Zhang,Robert Y.L. Zee,Alan F. Wright,Jacqueline C. M. Witteman,James F. Wilson,Gonneke Willemsen,H.-Erich Wichmann,John Whitfield,Dawn M. Waterworth,Nicholas J. Wareham,Gérard Waeber,Peter Vollenweider,Benjamin F. Voight,Benjamin F. Voight,Veronique Vitart,André G. Uitterlinden,Manuela Uda,Jaakko Tuomilehto,John R. Thompson,Toshiko Tanaka,Ida Surakka,Heather M. Stringham,Tim D. Spector,Nicole Soranzo,Nicole Soranzo,Johannes H. Smit,Juha Sinisalo,Kaisa Silander,Eric J.G. Sijbrands,Angelo Scuteri,James Scott,David Schlessinger,Serena Sanna,Veikko Salomaa,Juha Saharinen,Chiara Sabatti,Aimo Ruokonen,Igor Rudan,Lynda M. Rose,Robert Roberts,Mark J. Rieder,Bruce M. Psaty,Peter P. Pramstaller,Irene Pichler,Markus Perola,Brenda W.J.H. Penninx,Nancy L. Pedersen,Cristian Pattaro,Alex N. Parker,Guillaume Paré,Ben A. Oostra,Christopher J. O'Donnell,Markku S. Nieminen,Deborah A. Nickerson,Grant W. Montgomery,Thomas Meitinger,Ruth McPherson,Mark I. McCarthy,Wendy L. McArdle,David Masson,Nicholas G. Martin,Fabio Marroni,Massimo Mangino,Patrik K. E. Magnusson,Gavin Lucas,Robert Luben,Ruth J. F. Loos,Marja-Liisa Lokki,Guillaume Lettre,Claudia Langenberg,Lenore J. Launer,Edward G. Lakatta,Reijo Laaksonen,Kirsten Ohm Kyvik,Florian Kronenberg,Inke R. Koenig,Kay-Tee Khaw,Jaakko Kaprio,Lee M. Kaplan,Åsa Johansson,Marjo-Riitta Järvelin,A. Cecile J.W. Janssens,Erik Ingelsson,Wilmar Igi,G. Kees Hovingh,Jouke-Jan Hottenga,Albert Hofman,Andrew A. Hicks,Christian Hengstenberg,Iris M. Heid,Caroline Hayward,Aki S. Havulinna,Nicholas D. Hastie,Tamara B. Harris,Talin Haritunians,Alistair S. Hall,Ulf Gyllensten,Candace Guiducci,Leif Groop,Leif Groop,Elena Gonzalez,Christian Gieger,Nelson B. Freimer,Luigi Ferrucci,Jeanette Erdmann,Paul Elliott,Kenechi Ejebe,Angela Doering,Anna F. Dominiczak,Serkalem Demissie,Panagiotis Deloukas,Eco J. C. de Geus,Ulf de Faire,Gabriel Crawford,Francis S. Collins,Yii-Der Ida Chen,Mark J. Caulfield,Harry Campbell,Noël P. Burtt,Lori L. Bonnycastle,Dorret I. Boomsma,S. Matthijs Boekholdt,Richard N. Bergman,Inês Barroso,Stefania Bandinelli,Christie M. Ballantyne,Themistocles L. Assimes,Themistocles L. Assimes,Thomas Quertermous,Thomas Quertermous,David Altshuler,David Altshuler,Mark Seielstad,Tien Yin Wong,E-Shyong Tai,Alan B. Feranil,Christopher W. Kuzawa,Christopher W. Kuzawa,Linda S. Adair,Herman A. Taylor,Ingrid B. Borecki,Stacey Gabriel,James G. Wilson,Hilma Holm,Unnur Thorsteinsdottir,Vilmundur Gudnason,Ronald M. Krauss,Karen L. Mohlke,Jose M. Ordovas,Patricia B. Munroe,Jaspal S. Kooner,Alan R. Tall,Robert A. Hegele,John J.P. Kastelein,Eric E. Schadt,Jerome I. Rotter,Eric Boerwinkle,David P. Strachan,Vincent Mooser,Kari Stefansson,Muredach P. Reilly,Nilesh J. Samani,Heribert Schunkert,L. Adrienne Cupples,Manjinder S. Sandhu,Manjinder S. Sandhu,Paul M. Ridker,Daniel J. Rader,Cornelia M. van Duijn,Leena Peltonen,Gonçalo R. Abecasis,Michael Boehnke,Sekar Kathiresan +218 more
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.
Journal ArticleDOI
Merlin--rapid analysis of dense genetic maps using sparse gene flow trees.
TL;DR: The multipoint engine for rapid likelihood inference (Merlin) is a computer program that uses sparse inheritance trees for pedigree analysis; it performs rapid haplotyping, genotype error detection and affected pair linkage analyses and can handle more markers than other pedigree analysis packages.
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