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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The UK Biobank resource with deep phenotyping and genomic data
Clare Bycroft,Colin Freeman,Desislava Petkova,Desislava Petkova,Gavin Band,Lloyd T. Elliott,Kevin Sharp,Allan Motyer,Damjan Vukcevic,Olivier Delaneau,Olivier Delaneau,Jared O'Connell,Adrian Cortes,Adrian Cortes,Samantha Welsh,Alan Young,Mark Effingham,Gil McVean,Stephen Leslie,Naomi E. Allen,Peter Donnelly,Jonathan Marchini +21 more
TL;DR: Deep phenotype and genome-wide genetic data from 500,000 individuals from the UK Biobank is described, describing population structure and relatedness in the cohort, and imputation to increase the number of testable variants to 96 million.
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Global aetiology and epidemiology of type 2 diabetes mellitus and its complications.
TL;DR: An updated view of the global epidemiology of type 2 diabetes mellitus, as well as dietary, lifestyle and other risk factors for T2DM and its complications are provided.
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10 Years of GWAS Discovery: Biology, Function, and Translation
Peter M. Visscher,Naomi R. Wray,Qian Zhang,Pamela Sklar,Mark I. McCarthy,Matthew A. Brown,Jian Yang +6 more
TL;DR: The remarkable range of discoveriesGWASs has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics are reviewed.
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Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations
Amit Khera,Mark Chaffin,Krishna G. Aragam,Mary E. Haas,Carolina Roselli,Seung Hoan Choi,Pradeep Natarajan,Eric S. Lander,Steven A. Lubitz,Steven A. Lubitz,Patrick T. Ellinor,Patrick T. Ellinor,Sekar Kathiresan +12 more
TL;DR: Genome-wide polygenic risk scores derived from GWAS data for five common diseases can identify subgroups of the population with risk approaching or exceeding that of a monogenic mutation.
Journal ArticleDOI
Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.
Anubha Mahajan,Daniel Taliun,Matthias Thurner,Neil R. Robertson,Jason M. Torres,N. William Rayner,N. William Rayner,Anthony Payne,Valgerdur Steinthorsdottir,Robert A. Scott,Niels Grarup,James P. Cook,Ellen M. Schmidt,Matthias Wuttke,Chloé Sarnowski,Reedik Mägi,Jana Nano,Christian Gieger,Stella Trompet,Cécile Lecoeur,Michael Preuss,Bram P. Prins,Xiuqing Guo,Lawrence F. Bielak,Jennifer E. Below,Donald W. Bowden,John C. Chambers,Young-Jin Kim,Maggie C.Y. Ng,Lauren E. Petty,Xueling Sim,Weihua Zhang,Weihua Zhang,Amanda J. Bennett,Jette Bork-Jensen,Chad M. Brummett,Mickaël Canouil,Kai-Uwe Ec Kardt,Krista Fischer,Sharon L.R. Kardia,Florian Kronenberg,Kristi Läll,Ching-Ti Liu,Adam E. Locke,Jian'an Luan,Ioanna Ntalla,Vibe Nylander,Sebastian Schönherr,Claudia Schurmann,Loic Yengo,Erwin P. Bottinger,Ivan Brandslund,Cramer Christensen,George Dedoussis,Jose C. Florez,Ian Ford,Oscar H. Franco,Timothy M. Frayling,Vilmantas Giedraitis,Sophie Hackinger,Andrew T. Hattersley,Christian Herder,M. Arfan Ikram,Martin Ingelsson,Marit E. Jørgensen,Marit E. Jørgensen,Torben Jørgensen,Torben Jørgensen,Jennifer Kriebel,Johanna Kuusisto,Symen Ligthart,Cecilia M. Lindgren,Cecilia M. Lindgren,Allan Linneberg,Allan Linneberg,Valeriya Lyssenko,Valeriya Lyssenko,Vasiliki Mamakou,Thomas Meitinger,Karen L. Mohlke,Andrew D. Morris,Andrew D. Morris,Girish N. Nadkarni,James S. Pankow,Annette Peters,Naveed Sattar,Alena Stančáková,Konstantin Strauch,Kent D. Taylor,Barbara Thorand,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Unnur Thorsteinsdottir,Jaakko Tuomilehto,Daniel R. Witte,Josée Dupuis,Patricia A. Peyser,Eleftheria Zeggini,Ruth J. F. Loos,Philippe Froguel,Philippe Froguel,Erik Ingelsson,Erik Ingelsson,Lars Lind,Leif Groop,Leif Groop,Markku Laakso,Francis S. Collins,J. Wouter Jukema,Colin N. A. Palmer,Harald Grallert,Andres Metspalu,Abbas Dehghan,Abbas Dehghan,Anna Köttgen,Gonçalo R. Abecasis,James B. Meigs,Jerome I. Rotter,Jonathan Marchini,Oluf Pedersen,Torben Hansen,Torben Hansen,Claudia Langenberg,Nicholas J. Wareham,Kari Stefansson,Kari Stefansson,Anna L. Gloyn,Andrew P. Morris,Andrew P. Morris,Andrew P. Morris,Michael Boehnke,Mark I. McCarthy +131 more
TL;DR: Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.
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