Journal ArticleDOI
Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels
Richa Saxena,Benjamin F. Voight,Valeriya Lyssenko,Noël P. Burtt,Paul I.W. de Bakker,Hong Chen,Jeffrey J. Roix,Sekar Kathiresan,Joel N. Hirschhorn,Mark J. Daly,Thomas E. Hughes,Leif Groop,David Altshuler,Peter Almgren,Jose C. Florez,Joanne M. Meyer,Kristin Ardlie,Kristina Bengtsson Boström,Bo Isomaa,Guillaume Lettre,Ulf Lindblad,Helen N. Lyon,Olle Melander,Christopher Newton-Cheh,Peter Nilsson,Marju Orho-Melander,Lennart Råstam,Elizabeth K. Speliotes,Marja-Riitta Taskinen,Tiinamaija Tuomi,Candace Guiducci,Anna Berglund,Joyce Carlson,Lauren Gianniny,Rachel Hackett,Liselotte Hall,Johan Holmkvist,Esa Laurila,Marketa Sjögren,Maria Sterner,Aarti Surti,Margareta Svensson,Malin Svensson,Ryan Tewhey,Brendan Blumenstiel,Melissa Parkin,Matthew DeFelice,Rachel Barry,Wendy Brodeur,Jody Camarata,Nancy Chia,Mary Fava,John G. Gibbons,Bob Handsaker,Claire M. Healy,Kieu Nguyen,Casey Gates,Carrie Sougnez,Diane Gage,Marcia M. Nizzari,Stacey Gabriel,Gung-Wei Chirn,Qicheng Ma,Hemang Parikh,Delwood Richardson,Darrell O. Ricke,Shaun Purcell +66 more
TLDR
The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.Abstract:
New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D-in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1-and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.read more
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Journal ArticleDOI
Asymptotic conditional singular value decomposition for high-dimensional genomic data.
TL;DR: It is shown that under a conditional factor model for genomic data with a fixed sample size, the right singular vectors are asymptotically consistent for the unobserved latent factors as the number of features diverges, and a consistent estimator of the dimension of the underlying conditionalfactor model is proposed.
Journal ArticleDOI
From Loci to Biology Functional Genomics of Genome-Wide Association for Coronary Disease
Sylvia T. Nurnberg,Hanrui Zhang,Nicholas J. Hand,Robert C. Bauer,Danish Saleheen,Muredach P. Reilly,Daniel J. Rader +6 more
TL;DR: New biology regarding atherosclerosis and CAD will be learned through the functional genomics of these loci, and the hope is that at least some of these new pathways relevant to CAD pathogenesis will yield new therapeutic targets for the prevention and treatment of CAD.
Journal ArticleDOI
Cellular senescence mediated by p16INK4A-coupled miRNA pathways
Marita G. Overhoff,James C. Garbe,James Koh,Martha R. Stampfer,David H. Beach,Cleo L. Bishop +5 more
TL;DR: It is shown that SA-miRNAs-26b, 181a, 210 and 424 function in concert to directly repress expression of Polycomb group (PcG) proteins CBX7, embryonic ectoderm development (EED), enhancer of zeste homologue 2 (EZH2) and suppressor of zste 12 homologue (Suz12), thereby activating p16.
Journal ArticleDOI
Genetic Predisposition to Long-Term Nondiabetic Deteriorations in Glucose Homeostasis Ten-Year Follow-Up of the GLACIER Study
Frida Renström,Dmitry Shungin,Ingegerd Johansson,Jose C. Florez,Göran Hallmans,Frank B. Hu,Paul W. Franks +6 more
TL;DR: The findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular end points will help establish whether the magnitude of these changes is clinically relevant.
Journal ArticleDOI
Interaction Effect of Genetic Polymorphisms in Glucokinase (GCK) and Glucokinase Regulatory Protein (GCKR) on Metabolic Traits in Healthy Chinese Adults and Adolescents
Claudia H. T. Tam,Ronald C.W. Ma,Wing-Yee So,Ying Wang,Vincent K. L. Lam,Soren Germer,Mitchell Martin,Juliana C.N. Chan,Maggie C.Y. Ng +8 more
TL;DR: In support of the intimate relationship between glucose and lipid metabolisms, GCKR and GCK genetic polymorphisms interact to increase FPG in healthy adults and adolescents.
References
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Journal ArticleDOI
Principal components analysis corrects for stratification in genome-wide association studies
Alkes L. Price,Alkes L. Price,Nick Patterson,Robert M. Plenge,Robert M. Plenge,Michael E. Weinblatt,Nancy A. Shadick,David Reich,David Reich +8 more
TL;DR: This work describes a method that enables explicit detection and correction of population stratification on a genome-wide scale and uses principal components analysis to explicitly model ancestry differences between cases and controls.
Journal ArticleDOI
A haplotype map of the human genome
John W. Belmont,Andrew Boudreau,Suzanne M. Leal,Paul Hardenbol,Shiran Pasternak,David A. Wheeler,Thomas D. Willis,Fuli Yu,Huanming Yang,Gao Yang,H. B. Hu,Weitao Hu,Chaohua Li,Wei Lin,Siqi Liu,Hao Pan,Xiaoli Tang,Jian Wang,Wei Wang,Jun Yu,Bo Zhang,Qingrun Zhang,Hongbin Zhao,Jun Zhou,Rachel Barry,Brendan Blumenstiel,Amy L. Camargo,Matthew Defelice,Maura Faggart,Mary Goyette,Supriya Gupta,Jamie Moore,Huy Nguyen,Melissa Parkin,Jessica Roy,Erich Stahl,Ellen Winchester,David Altshuler,Yan Shen,Zhijian Yao,Wei Huang,Xun Chu,Yungang He,Li Jin,Yangfan Liu,Yayun Shen,Weiwei Sun,Haifeng Wang,Yi Wang,Ying Wang,Xiaoyan Xiong,Liang Xu,Mary M.Y. Waye,Stephen Kwok-Wing Tsui,Hong Xue,J. Tze Fei Wong,Launa M. Galver,Jian-Bing Fan,Sarah S. Murray,Arnold Oliphant,Mark S. Chee,Alexandre Montpetit,Fanny Chagnon,Vincent Ferretti,Martin Leboeuf,Jean François Olivier,Michael S. Phillips,Stéphanie Roumy,Clémentine Sallée,Andrei Verner,Thomas J. Hudson,Kelly A. Frazer,Dennis G. Ballinger,David R. Cox,David A. Hinds,Laura L. Stuve,Pui-Yan Kwok,Dongmei Cai,Daniel C. Koboldt,Raymond D. Miller,Ludmila Pawlikowska,Patricia Taillon-Miller,Ming Xiao,Lap-Chee Tsui,William Mak,Pak C. Sham,You-Qiang Song,Paul K.H. Tam,Yusuke Nakamura,Takahisa Kawaguchi,Takuya Kitamoto,Takashi Morizono,Atsushi Nagashima,Yozo Ohnishi,Akihiro Sekine,Toshihiro Tanaka,Panos Deloukas,Christine P. Bird,Marcos Delgado,Emmanouil T. Dermitzakis,Rhian Gwilliam,Sarah E. Hunt,Jonathan Morrison,Don Powell,Barbara E. Stranger,Pamela Whittaker,David R. Bentley,Paul I.W. de Bakker,Jeffrey C. Barrett,Ben Fry,Julian Maller,Steve McCarroll,Nick Patterson,Itsik Pe'er,Shaun Purcell,Daniel J. Richter,Pardis C. Sabeti,Richa Saxena,Stephen F. Schaffner,Patrick Varilly,Lincoln Stein,Lalitha Krishnan,Albert V. Smith,Gudmundur A. Thorisson,Aravinda Chakravarti,Peter E. Chen,David J. Cutler,Carl S. Kashuk,Shin Lin,Gonçalo R. Abecasis,Weihua Guan,Heather M. Munro,Zhaohui S. Qin,Daryl J. Thomas,Gilean McVean,Leonardo Bottolo,Susana Eyheramendy,Colin Freeman,Jonathan Marchini,Simon Myers,Chris C. A. Spencer,Matthew Stephens,Peter Donnelly,Lon R. Cardon,Geraldine M. Clarke,David M. Evans,Andrew P. Morris,Bruce S. Weir,Tatsuhiko Tsunoda,James C. Mullikin,Stephen T. Sherry,Michael Feolo,Houcan Zhang,Changqing Zeng,Hui Zhao,Ichiro Matsuda,Yoshimitsu Fukushima,Darryl Macer,Eiko Suda,Charles N. Rotimi,Clement Adebamowo,Ike Ajayi,Toyin Aniagwu,Patricia A. Marshall,Chibuzor Nkwodimmah,Charmaine D.M. Royal,Mark Leppert,Missy Dixon,Andy Peiffer,Renzong Qiu,Alastair Kent,Kazuto Kato,Norio Niikawa,Isaac F. Adewole,Bartha Maria Knoppers,Morris W. Foster,Ellen Wright Clayton,Jessica Watkin,Richard A. Gibbs,Donna M. Muzny,Lynne V. Nazareth,Erica Sodergren,George M. Weinstock,Imtiaz Yakub,Stacey Gabriel,Robert C. Onofrio,Liuda Ziaugra,Bruce W. Birren,Mark J. Daly,Richard K. Wilson,Lucinda Fulton,Jane Rogers,John Burton,Nigel P. Carter,C M Clee,Mark Griffiths,Matthew C. Jones,Kirsten McLay,Robert W. Plumb,Mark T. Ross,Sarah Sims,David Willey,Zhu Chen,Hua Han,L. Kang,Martin Godbout,John C. Wallenburg,Paul L'Archevêque,Guy Bellemare,Koji Saeki,Hongguang Wang,Daochang An,Hongbo Fu,Qing Li,Zhen Wang,Renwu Wang,Arthur L. Holden,Lisa D. Brooks,Jean E. McEwen,Christianne R. Bird,Mark S. Guyer,Patrick J. Nailer,Vivian Ota Wang,Jane Peterson,Michael Shi,Jack Spiegel,Lawrence M. Sung,Jonathan Witonsky,Lynn F. Zacharia,Francis S. Collins,Karen Kennedy,Ruth Jamieson,John Stewart +232 more
TL;DR: A public database of common variation in the human genome: more than one million single nucleotide polymorphisms for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted.
Journal ArticleDOI
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease
Jean-Pierre Hugot,Mathias Chamaillard,Mathias Chamaillard,Habib Zouali,Suzanne Lesage,Jean-Pierre Cézard,Jacques Belaiche,Sven Almer,Curt Tysk,Colm O'Morain,Miquel A. Gassull,Vibeke Binder,Yigael Finkel,Antoine Cortot,Robert Modigliani,Pierre Laurent-Puig,C. Gower-Rousseau,J. Macry,Jean-Frederic Colombel,Mourad Sahbatou,Gilles Thomas,Gilles Thomas +21 more
TL;DR: It is suggested that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn’s disease that can now be further investigated.
Journal ArticleDOI
A genome-wide association study identifies novel risk loci for type 2 diabetes
Robert Sladek,Ghislain Rocheleau,Johan Rung,Christian Dina,Lishuang Shen,David Serre,Philippe Boutin,Daniel Vincent,Alexandre Belisle,Samy Hadjadj,Beverley Balkau,Barbara Heude,Guillaume Charpentier,Thomas J. Hudson,Thomas J. Hudson,Alexandre Montpetit,Alexey V. Pshezhetsky,Marc Prentki,Barry I. Posner,David J. Balding,David Meyre,Constantin Polychronakos,Philippe Froguel,Philippe Froguel +23 more
TL;DR: Four loci containing variants that confer type 2 diabetes risk are identified and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
Journal ArticleDOI
A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene
Richard H. Duerr,Kent D. Taylor,Steven R. Brant,Steven R. Brant,John D. Rioux,John D. Rioux,Mark S. Silverberg,Mark J. Daly,Mark J. Daly,A. Hillary Steinhart,Clara Abraham,Miguel Regueiro,Anne M. Griffiths,Themistocles Dassopoulos,Alain Bitton,Huiying Yang,Stephan R. Targan,Lisa W. Datta,Emily O. Kistner,L. Philip Schumm,Annette Lee,Peter K. Gregersen,M. Michael Barmada,Jerome I. Rotter,Dan L. Nicolae,Judy H. Cho +25 more
TL;DR: A highly significant association is found between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23, which prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.
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