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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Consistent association of type 2 diabetes risk variants found in europeans in diverse racial and ethnic groups.
Kevin M. Waters,Daniel O. Stram,Mohamed T. Hassanein,Loic Le Marchand,Lynne R. Wilkens,Gertraud Maskarinec,Kristine R. Monroe,Laurence N. Kolonel,David Altshuler,Brian E. Henderson,Christopher A. Haiman +10 more
TL;DR: The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding “synthetic associations” of rare mutations in T2D.
Journal ArticleDOI
A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes
Janet M. Wenzlau,Yu Liu,Liping Yu,Ong Moua,Kimberly T. Fowler,Sampathkumar Rangasamy,Jay A. Walters,George S. Eisenbarth,Howard W. Davidson,John C. Hutton +9 more
TL;DR: The finding that diabetes autoimmunity can be defined by a single polymorphic residue has not previously been documented and suggests a mechanistic link between the two major forms of diabetes.
Journal ArticleDOI
Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
Jennifer Wessel,Audrey Y. Chu,Sara M. Willems,Shuai Wang,Hanieh Yaghootkar,Jennifer A. Brody,Marco Dauriz,Sridharan Raghavan,Leonard Lipovich,Bertha Hidalgo,Keolu Fox,Jennifer E. Huffman,Ping An,Yingchang Lu,Laura J. Rasmussen-Torvik,Niels Grarup,Margaret G. Ehm,Li Li,Abigail S. Baldridge,Alena Stančáková,Ravinder Abrol,Céline Besse,Anne Boland,Jette Bork-Jensen,Myriam Fornage,Daniel F. Freitag,Melissa E. Garcia,Xiuqing Guo,Hara Kazuo,Aaron Isaacs,Johanna Jakobsdottir,Leslie A. Lange,Jill Layton,Man Li,Jing Hua Zhao,Karina Meidtner,Alanna C. Morrison,Mike A. Nalls,Marjolein J. Peters,Maria Sabater-Lleal,Claudia Schurmann,Angela Silveira,Albert V. Smith,Lorraine Southam,Marcus H. Stoiber,Rona J. Strawbridge,Kent D. Taylor,Tibor V. Varga,Kristine H. Allin,Najaf Amin,Jennifer L. Aponte,Tin Aung,Caterina Barbieri,Nathan A. Bihlmeyer,Michael Boehnke,Cristina Bombieri,Donald W. Bowden,Sean M. Burns,Yuning Chen,Yii Deri Chen,Ching-Yu Cheng,Adolfo Correa,Jacek Czajkowski,Abbas Dehghan,Georg Ehret,Gudny Eiriksdottir,Stefan A. Escher,Aliki-Eleni Farmaki,Mattias Frånberg,Giovanni Gambaro,Franco Giulianini,William A. Goddard,Anuj Goel,Omri Gottesman,Megan L. Grove,Stefan Gustafsson,Yang Hai,Göran Hallmans,Jiyoung Heo,Per Hoffmann,Mohammad Kamran Ikram,Richard A. Jensen,Marit E. Jørgensen,Torben Jørgensen,Maria Karaleftheri,Chiea Chuen Khor,Andrea Kirkpatrick,Aldi T. Kraja,Johanna Kuusisto,Ethan M. Lange,I-Te Lee,Wen Jane Lee,Aaron Leong,Jiemin Liao,Chunyu Liu,Yongmei Liu,Cecilia M. Lindgren,Allan Linneberg,Giovanni Malerba,Vasiliki Mamakou,Eirini Marouli,Nisa M. Maruthur,Angela Matchan,Roberta McKean-Cowdin,Olga McLeod,Ginger A. Metcalf,Karen L. Mohlke,Donna M. Muzny,Ioanna Ntalla,Nicholette D. Palmer,Dorota Pasko,Andreas Peter,Nigel W. Rayner,Frida Renström,Kenneth Rice,Cinzia Sala,Bengt Sennblad,Ioannis Serafetinidis,Jennifer A. Smith,Nicole Soranzo,Elizabeth K. Speliotes,Eli A. Stahl,Kathleen Stirrups,Nikos Tentolouris,Anastasia Thanopoulou,Mina Torres,Michela Traglia,Emmanouil Tsafantakis,Sundas Javad,Lisa R. Yanek,Eleni Zengini,Diane M. Becker,Joshua C. Bis,James B. Brown,L. Adrienne Cupples,Torben Hansen,Erik Ingelsson,Andrew J. Karter,Carlos Lorenzo,Rasika A. Mathias,Jill M. Norris,Gina M. Peloso,Wayne Huey-Herng Sheu,Daniela Toniolo,Dhananjay Vaidya,Rohit Varma,Lynne E. Wagenknecht,Heiner Boeing,Erwin P. Bottinger,George Dedoussis,Panos Deloukas,Ele Ferrannini,Oscar H. Franco,Paul W. Franks,Richard A. Gibbs,Vilmundur Gudnason,Anders Hamsten,Tamara B. Harris,Andrew T. Hattersley,Caroline Hayward,Albert Hofman,Jan-Håkan Jansson,Claudia Langenberg,Lenore J. Launer,Daniel Levy,Ben A. Oostra,Christopher J. O'Donnell,Stephen O'Rahilly,Sandosh Padmanabhan,James S. Pankow,Ozren Polasek,Michael A. Province,Stephen S. Rich,Paul M. Ridker,Igor Rudan,Matthias B. Schulze,Blair H. Smith,André G. Uitterlinden,Mark Walker,Hugh Watkins,Tien Yin Wong,Eleftheria Zeggini,Markku Laakso,Ingrid B. Borecki,Daniel I. Chasman,Oluf Pedersen,Bruce M. Psaty,E. Shyong Tai,Cornelia M. van Duijn,Nicholas J. Wareham,Dawn M. Waterworth,Eric Boerwinkle,W. H. Linda Kao,Jose C. Florez,Ruth J. F. Loos,James G. Wilson,Timothy M. Frayling,David S. Siscovick,Josée Dupuis,Jerome I. Rotter,James B. Meigs,Robert A. Scott,Mark O. Goodarzi +202 more
TL;DR: In this article, the role of coding variation on intermediate traits for type 2 diabetes was explored by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls.
Journal ArticleDOI
Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis
John Landers,Judith Melki,Vincent Meininger,Jonathan D. Glass,Leonard H. van den Berg,Michael A. van Es,Peter C. Sapp,Peter C. Sapp,Paul W.J. van Vught,Diane McKenna-Yasek,Hylke M. Blauw,Ting Jan Cho,Meraida Polak,Lijia Shi,Anne-Marie Wills,Wendy J. Broom,Nicola Ticozzi,Nicola Ticozzi,Vincenzo Silani,Aslihan Ozoguz,Ildefonso Rodriguez-Leyva,Ildefonso Rodriguez-Leyva,Jan H. Veldink,Adrian J. Ivinson,Christiaan G J Saris,Betsy A. Hosler,Alayna Barnes-Nessa,Nicole R. Couture,John H. J. Wokke,Thomas J. Kwiatkowski,Roel A. Ophoff,Roel A. Ophoff,Simon Cronin,Orla Hardiman,Frank P. Diekstra,P. Nigel Leigh,Christopher Shaw,Claire L. Simpson,Valerie K. Hansen,John Powell,Philippe Corcia,François Salachas,Simon Heath,Pilar Galan,Franck Georges,H. Robert Horvitz,Mark Lathrop,Shaun Purcell,Ammar Al-Chalabi,Robert H. Brown,Robert H. Brown +50 more
TL;DR: Findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.
Journal ArticleDOI
Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease.
TL;DR: It is advocated that only a subset of genetic mechanisms regulating TGRLs contribute to the risk of CVD events.
References
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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.
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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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