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
Citations
More filters
Journal ArticleDOI
Common Inherited Variation in Mitochondrial Genes Is Not Enriched for Associations with Type 2 Diabetes or Related Glycemic Traits
Ayellet V. Segrè,Magic Investigators,Leif Groop,Vamsi K. Mootha,Mark J. Daly,Mark J. Daly,David Altshuler +6 more
TL;DR: The results suggest that common variants affecting nuclear-encoded mitochondrial genes have at most a small genetic contribution to T2D susceptibility.
Journal ArticleDOI
An Environment-Wide Association Study (EWAS) on Type 2 Diabetes Mellitus
TL;DR: Despite difficulty in ascertaining causality, the potential for novel factors of large effect associated with T2D justify the use of EWAS to create hypotheses regarding the broad contribution of the environment to disease.
Journal ArticleDOI
Meta-analysis in genome-wide association studies
TL;DR: This review discusses the key methodological issues in the set-up, information gathering and processing, and analysis of meta-analyses of genome-wide association datasets, and illustrates the application ofMeta-analysis methods in the elucidation of common genetic variants associated with Type 2 diabetes.
Journal ArticleDOI
Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p
Helen M. Broadbent,John F. Peden,Stefan Lorkowski,Anuj Goel,Halit Ongen,Fiona R. Green,Robert Clarke,Rory Collins,Maria Grazia Franzosi,Gianni Tognoni,Udo Seedorf,Stephan Rust,Per Eriksson,Anders Hamsten,Martin Farrall,Hugh Watkins +15 more
TL;DR: A simultaneous test of CAD and diabetes susceptibility with CAD and T2D-associated SNPs indicated that these associations were independent of each other.
Journal ArticleDOI
Translating molecular discoveries into new therapies for atherosclerosis.
Daniel J. Rader,Alan Daugherty +1 more
TL;DR: Clinical trials have confirmed that certain lipoproteins and the renin–angiotensin–aldosterone system are important in the pathogenesis of atherosclerotic cardiovascular disease, and that interventions targeted towards these are beneficial.
References
More filters
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.
Related Papers (5)
A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
Laura J. Scott,Karen L. Mohlke,Lori L. Bonnycastle,Cristen J. Willer,Yun Li,William L. Duren,Michael R. Erdos,Heather M. Stringham,Peter S. Chines,Anne U. Jackson,Ludmila Prokunina-Olsson,Chia-Jen Ding,Amy J. Swift,Narisu Narisu,Tianle Hu,Randall Pruim,Rui Xiao,Xiao-Yi Li,Karen N. Conneely,Nancy Riebow,Andrew G. Sprau,Maurine Tong,Peggy P. White,Kurt N. Hetrick,Michael W. Barnhart,Craig W. Bark,Janet L. Goldstein,Lee Watkins,Fang Xiang,Jouko Saramies,Thomas A. Buchanan,Richard M. Watanabe,Timo T. Valle,Leena Kinnunen,Gonçalo R. Abecasis,Elizabeth W. Pugh,Kimberly F. Doheny,Richard N. Bergman,Jaakko Tuomilehto,Francis S. Collins,Michael Boehnke +40 more
Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes
Eleftheria Zeggini,Michael N. Weedon,Cecilia M. Lindgren,Timothy M. Frayling,Katherine S. Elliott,Hana Lango,Nicholas J. Timpson,John R. B. Perry,Nigel W. Rayner,Rachel M. Freathy,Jeffrey C. Barrett,Beverley M. Shields,Andrew P. Morris,Sian Ellard,Christopher J. Groves,Lorna W. Harries,Jonathan Marchini,Katharine R. Owen,Beatrice Knight,Lon R. Cardon,Mark Walker,Graham A. Hitman,Andrew D. Morris,Alex S. F. Doney,Mark I. McCarthy,Andrew T. Hattersley +25 more
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
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
Paul Burton,David Clayton,Lon R. Cardon,Nicholas John Craddock,Panos Deloukas,Audrey Duncanson,Dominic P. Kwiatkowski,Mark I. McCarthy,Willem H. Ouwehand,Nilesh J. Samani,John A. Todd,Peter Donnelly,Jeffrey C. Barrett,Dan Davison,Doug Easton,David M. Evans,H. T. Leung,Jonathan Marchini,Andrew P. Morris,Chris C. A. Spencer,Martin D. Tobin,Antony P. Attwood,James P. Boorman,Barbara Cant,Ursula Everson,Judith M. Hussey,Jennifer Jolley,Alexandra S. Knight,Kerstin Koch,Elizabeth Meech,Sarah Nutland,Christopher Prowse,Helen Stevens,Niall C. Taylor,Graham R. Walters,Neil Walker,Nicholas A. Watkins,Thilo Winzer,Richard Jones,Wendy L. McArdle,Susan M. Ring,David P. Strachan,Marcus Pembrey,Gerome Breen,David St Clair,Sian Caesar,Katherine Gordon-Smith,Lisa Jones,Christine Fraser,Elaine K. Green,Detelina Grozeva,Marian L. Hamshere,Peter Holmans,Ian Jones,George Kirov,Valentina Moskvina,Ivan Nikolov,Michael Conlon O'Donovan,Michael John Owen,David A. Collier,Amanda Elkin,Anne Farmer,Richard Williamson,Peter McGuffin,Allan H. Young,I. Nicol Ferrier,Stephen G. Ball,Anthony J. Balmforth,Jennifer H. Barrett,D. Timothy Bishop,Mark M. Iles,Azhar Maqbool,Nadira Yuldasheva,Alistair S. Hall,Peter S. Braund,Richard J. Dixon,Massimo Mangino,Suzanne Stevens,John R. Thompson,Francesca Bredin,Mark Tremelling,Miles Parkes,Hazel E. Drummond,Charlie W. Lees,Elaine R. Nimmo,Jack Satsangi,Sheila A. Fisher,Alastair Forbes,Cathryn M. Lewis,Clive M. Onnie,Natalie J. Prescott,Jeremy D. Sanderson,Christopher G. Mathew,Jamie Barbour,M. Khalid Mohiuddin,Catherine E. Todhunter,John C. Mansfield,Tariq Ahmad,Fraser Cummings,Derek P. Jewell,John Webster,Morris J. Brown,G. Mark Lathrop,John M. C. Connell,Anna F. Dominiczak,Carolina A. Braga Marcano,Beverley Burke,Richard Dobson,Johannie Gungadoo,Kate L. Lee,Patricia B. Munroe,Stephen Newhouse,Abiodun Onipinla,Chris Wallace,Mingzhan Xue,Mark J. Caulfield,Martin Farrall,Anne Barton,Ian N. Bruce,Hannah Donovan,Steve Eyre,Paul D. Gilbert,Samantha L. Hider,Anne Hinks,Sally John,Catherine Potter,Alan J. Silman,Deborah P M Symmons,Wendy Thomson,Jane Worthington,David B. Dunger,Barry Widmer,Timothy M. Frayling,Rachel M. Freathy,Hana Lango,John R. B. Perry,Beverley M. Shields,Michael N. Weedon,Andrew T. Hattersley,Graham A. Hitman,Mark Walker,Kate S. Elliott,Christopher J. Groves,Cecilia M. Lindgren,Nigel W. Rayner,Nicholas J. Timpson,Eleftheria Zeggini,Melanie J. Newport,Giorgio Sirugo,Emily J. Lyons,Fredrik O. Vannberg,Adrian V. S. Hill,Linda A. Bradbury,C Farrar,J J Pointon,Paul Wordsworth,Matthew A. Brown,Jayne A. Franklyn,Joanne M. Heward,Matthew J. Simmonds,Stephen C. L. Gough,Sheila Seal,Michael R. Stratton,Nazneen Rahman,Maria Ban,An Goris,Stephen Sawcer,Alastair Compston,David J. Conway,Muminatou Jallow,Kirk A. Rockett,Suzannah Bumpstead,Amy Chaney,Kate Downes,Mohammed J. R. Ghori,Rhian Gwilliam,Sarah E. Hunt,Michael Inouye,Andrew Keniry,Emma King,Ralph McGinnis,Simon C. Potter,Rathi Ravindrarajah,Pamela Whittaker,Claire Widden,David Withers,Niall Cardin,Teresa Ferreira,Joanne Pereira-Gale,Ingileif B. Hallgrímsdóttir,Bryan Howie,Zhan Su,Yik Ying Teo,Damjan Vukcevic,David Bentley,A Compston +195 more
Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.
Struan F.A. Grant,Gudmar Thorleifsson,Inga Reynisdottir,Rafil Benediktsson,Andrei Manolescu,Jesus Sainz,Agnar Helgason,Hreinn Stefansson,Valur Emilsson,Anna Helgadottir,Unnur Styrkarsdottir,Kristinn P. Magnusson,G. Bragi Walters,Ebba Palsdottir,Thorbjorg Jonsdottir,Thorunn Gudmundsdottir,Arnaldur Gylfason,Jona Saemundsdottir,Robert L. Wilensky,Muredach P. Reilly,Daniel J. Rader,Yu Z. Bagger,Claus Christiansen,Vilmundur Gudnason,Gunnar Sigurdsson,Unnur Thorsteinsdottir,Jeffrey R. Gulcher,Augustine Kong,Kari Stefansson +28 more