Open Access
The genetic architecture of type 2 diabetes
Christian Fuchsberger,Jason Flannick,Tanya M. Teslovich,Anubha Mahajan,Vineeta Agarwala,Kyle J. Gaulton,Clement Ma,Pierre Fontanillas,Loukas Moutsianas,Davis J. McCarthy,Manuel A. Rivas,John R. B. Perry,Xueling Sim,Thomas W. Blackwell,Neil Robertson,N. William Rayner,Pablo Cingolani,Adam E. Locke,Juan Fernandez Tajes,Heather M. Highland,Josée Dupuis,Peter S. Chines,Cecilia M. Lindgren,Christopher Hartl,Anne U. Jackson,Han Chen,Jeroen R. Huyghe,Martijn van de Bunt,Richard D. Pearson,Ashok Kumar,Martina Mueller-Nurasyid,Niels Grarup,Heather M. Stringham,Eric R. Gamazon,Jae-Hoon Lee,Yi Chen,Robert A. Scott,Jennifer E. Below,Peng Chen,Jinyan Huang,Min Jin Go,Michael L. Stitzel,Dorota Pasko,Stephen C. J. Parker,Tibor V. Varga,Todd Green,Nicola L. Beer,Aaron G. Day-Williams,Teresa Ferreira,Tasha E. Fingerlin,Momoko Horikoshi,Cheng Hu,Iksoo Huh,Mohammad Kamran Ikram,Bong-Jo Kim,Yongkang Kim,Young-Jin Kim,Min-Seok Kwon,Juyoung Lee,Selyeong Lee,Keng-Han Lin,Taylor J. Maxwell,Yoshihiko Nagai,Xu Wang,Ryan P. Welch,Joon Yoon,Weihua Zhang,Nir Barzilai,Benjamin F. Voight,Bok-Ghee Han,Christopher P. Jenkinson,Teemu Kuulasmaa,Johanna Kuusisto,Alisa K. Manning,Maggie C.Y. Ng,Nicholette D. Palmer,Beverley Balkau,Alena Stančáková,Hanna E. Abboud,Heiner Boeing,Vilmantas Giedraitis,Dorairaj Prabhakaran,Omri Gottesman,James Scott,Jason Carey,Phoenix Kwan,George B. Grant,Joshua D. Smith,Benjamin M. Neale,Shaun Purcell,Adam S. Butterworth,Joanna M. M. Howson,Heung Man Lee,Yingchang Lu,Soo Heon Kwak,Wei Zhao,John Danesh,Vincent K. L. Lam,Kyong Soo Park,Danish Saleheen,Wing-Yee So,Claudia H. T. Tam,Uzma Afzal,David Aguilar,Rector Arya,Tin Aung,Edmund Chan,Carmen Navarro,Ching-Yu Cheng,Domenico Palli,Adolfo Correa,Joanne E. Curran,Denis Rybin,Vidya S. Farook,Sharon P. Fowler,Barry I. Freedman,Michael Griswold,Daniel E. Hale,Pamela J. Hicks,Chiea Chuen Khor,Satish Kumar,Benjamin Lehne,Dorothée Thuillier,Wei-Yen Lim,Jianjun Liu,Yvonne T. van der Schouw,Marie Loh,Solomon K. Musani,Sobha Puppala,William R. Scott,Loic Yengo,Sian-Tsung Tan,Herman A. Taylor,Farook Thameem,Gregory P. Wilson,Tien Yin Wong,Pål R. Njølstad,Jonathan C. Levy,Massimo Mangino,Lori L. Bonnycastle,Thomas Schwarzmayr,João Fadista,Gabriela L. Surdulescu,Christian Herder,Christopher J. Groves,Thomas Wieland,Jette Bork-Jensen,Ivan Brandslund,Cramer Christensen,Heikki A. Koistinen,Alex S. F. Doney,Leena Kinnunen,Tõnu Esko,Andrew Farmer,Liisa Hakaste,Dylan Hodgkiss,Jasmina Kravic,Valeriya Lyssenko,Mette Hollensted,Marit E. Jørgensen,Torben Jørgensen,Claes Ladenvall,Johanne Marie Justesen,Annemari Käräjämäki,Jennifer Kriebel,Wolfgang Rathmann,Lars Lannfelt,Torsten Lauritzen,Narisu Narisu,Allan Linneberg,Olle Melander,Lili Milani,Matt Neville,Marju Orho-Melander,Lu Qi,Qibin Qi,Michael Roden,Olov Rolandsson,Amy J. Swift,Anders Rosengren,Kathleen Stirrups,Andrew R. Wood,Evelin Mihailov,Christine Blancher,Mauricio O. Carneiro,Jared Maguire,Ryan Poplin,Khalid Shakir,Timothy R. Fennell,Mark A. DePristo,Martin Hrabé de Angelis,Panos Deloukas,Anette P. Gjesing,Goo Jun,Peter M. Nilsson,Jacquelyn Murphy,Robert C. Onofrio,Barbara Thorand,Torben Hansen,Christa Meisinger,Frank B. Hu,Bo Isomaa,Fredrik Karpe,Liming Liang,Annette Peters,Cornelia Huth,Stephen O'Rahilly,Colin N. A. Palmer,Oluf Pedersen,Rainer Rauramaa,Jaakko Tuomilehto,Veikko Salomaa,Richard M. Watanabe,Ann-Christine Syvänen,Richard N. Bergman,Dwaipayan Bharadwaj,Erwin P. Bottinger,Yoon Shin Cho,Giriraj R. Chandak,Juliana C.N. Chan,Kee Seng Chia,Mark J. Daly,Shah Ebrahim,Claudia Langenberg,Paul Elliott,Kathleen A. Jablonski,Donna M. Lehman,Weiping Jia,Ronald C.W. Ma,Toni I. Pollin,Manjinder S. Sandhu,Nikhil Tandon,Philippe Froguel,Inês Barroso,Yik Ying Teo,Eleftheria Zeggini,Ruth J. F. Loos,Kerrin S. Small,Janina S. Ried,Ralph A. DeFronzo,Harald Grallert,Benjamin Glaser,Andres Metspalu,Nicholas J. Wareham,Mark Walker,Eric Banks,Christian Gieger,Erik Ingelsson,Hae Kyung Im,Thomas Illig,Paul W. Franks,Gemma Buck,Joseph Trakalo,David Buck,Inga Prokopenko,Reedik Mägi,Lars Lind,Yossi Farjoun,Katharine R. Owen,Anna L. Gloyn,Konstantin Strauch,Tiinamaija Tuomi,Jaspal S. Kooner,Jong-Young Lee,Taesung Park,Peter Donnelly,Andrew D. Morris,Andrew T. Hattersley,Donald W. Bowden,Francis S. Collins,Gil Atzmon,John C. Chambers,Tim D. Spector,Markku Laakso,Tim M. Strom,Graeme I. Bell,John Blangero,Ravindranath Duggirala,E. Shyong Tai,Gilean McVean,Craig L. Hanis,James G. Wilson,Mark Seielstad,Timothy M. Frayling,James B. Meigs,Nancy J. Cox,Robert Sladek,Eric S. Lander,Stacey Gabriel,Noël P. Burtt,Karen L. Mohlke,Thomas Meitinger,Leif Groop,Gonçalo R. Abecasis,Jose C. Florez,Laura J. Scott,Andrew P. Morris,Hyun Min Kang,Michael Boehnke,David Altshuler,Mark I. McCarthy +300 more
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TLDR
Large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes, but most fell within regions previously identified by genome-wide association studies.Abstract:
The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.read more
Citations
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Posted ContentDOI
Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants
Justin B. Miller,Elizabeth Ward,Lyndsay A. Staley,Jeff Stevens,Craig C. Teerlink,Justina P Tavana,Matthew Cloward,Madeline Page,Louisa Dayton,Lisa A. Cannon-Albright,John S. K. Kauwe +10 more
TL;DR: This unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity.
Dissertation
Pipeline design to identify key features and perform classification on response/predisposition large-scale genetic data
Valdés Graterol,María Gabriela +1 more
TL;DR: This work proposes a state-of-the-art, scalable and flexible alternative to the classical GWAS approach, based on machine learning techniques, to analyze large-scale data and discover epistatic and non-epistatic polygenic variants in complex diseases.
Book ChapterDOI
Genetically Altered Mice as an Approach for the Investigation of Obesity and Metabolic Disease
Rebecca Dumbell,Roger D. Cox +1 more
Proceedings ArticleDOI
PAS-SNP: iOS App with GWAS SNP-Disease Database for Personalized Genomics Research: PAS-SNP for GWAS SNP-Disease
TL;DR: Non-profit, academic and publicly available iOS application, PAS-SNP, is presented, which invites global users to freely download it on iPhone & iPad devices, effortlessly adopt it's easy to use interface and search for SNPs, genes and related diseases.
Proceedings ArticleDOI
Risk prediction using common and rare genetic variants: Application to Type 2 diabetes
Sunghwan Bae,Taesung Park +1 more
TL;DR: This study constructed risk prediction models, such as stepwise linear regression, least absolute shrinkage and selection operator, Elastic-Net and support vector machine, and compared prediction accuracy by calculating the area under the curve to show that the performance using both common and rare variants was better than either the common variants only or the rare variants only.
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