The genetic architecture of type 2 diabetes.

Nature

Authors	Christian Fuchsberger Jason Flannick Tanya Teslovich Anubha Mahajan Vineeta Agarwala Kyle Gaulton Clement Ma Pierre Fontanillas Loukas Moutsianas Davis McCarthy Manuel Rivas John Perry Xueling Sim Thomas Blackwell Neil Robertson N William Rayner Pablo Cingolani Adam Locke Juan Tajes Heather Highland Josée Dupuis Peter Chines Cecilia Lindgren Christopher Hartl Anne Jackson Han Chen Jeroen Huyghe Martijn van de Bunt Richard Pearson Ashish Kumar Martina Müller-Nurasyid Niels Grarup Heather Stringham Eric Gamazon Jaehoon Lee Yuhui Chen Robert Scott Jennifer Below Peng Chen Jinyan Huang Min Go Michael Stitzel Dorota Pasko Stephen Parker Tibor Varga Todd Green Nicola Beer Aaron Day-Williams Teresa Ferreira Tasha Fingerlin Momoko Horikoshi Cheng Hu Iksoo Huh Mohammad Ikram Bong-Jo Kim Yongkang Kim Young Kim Min-Seok Kwon Juyoung Lee Selyeong Lee Keng-Han Lin Taylor Maxwell Yoshihiko Nagai Xu Wang Ryan Welch Joon Yoon Weihua Zhang Nir Barzilai Benjamin Voight Bok-Ghee Han Christopher Jenkinson Teemu Kuulasmaa Johanna Kuusisto Alisa Manning Maggie C Y Ng Nicholette Palmer Beverley Balkau Alena Stančáková Hanna Abboud Heiner Boeing Vilmantas Giedraitis Dorairaj Prabhakaran Omri Gottesman James Scott Jason Carey Phoenix Kwan George Grant Joshua Smith Benjamin Neale Shaun Purcell Adam Butterworth Joanna Howson Heung Lee Yingchang Lu Soo-Heon Kwak Wei Zhao John Danesh Vincent Lam Kyong Park Danish Saleheen Wing So Claudia Tam Uzma Afzal David Aguilar Rector Arya Tin Aung Edmund Chan Carmen Navarro Ching-Yu Cheng Domenico Palli Adolfo Correa Joanne Curran Denis Rybin Vidya Farook Sharon Fowler Barry Freedman Michael Griswold Daniel Hale Pamela Hicks Chiea-Chuen Khor Satish Kumar Benjamin Lehne Dorothee Thuillier Wei Lim Jianjun Liu Yvonne van der Schouw Marie Loh Solomon Musani Sobha Puppala William Scott Loic Yengo Sian-Tsung Tan Herman Taylor Farook Thameem Gregory Wilson Tien Wong Pål Njølstad Jonathan Levy Massimo Mangino Lori Bonnycastle Thomas Schwarzmayr Joao Fadista Gabriela Surdulescu Christian Herder Christopher Groves Thomas Wieland Jette Bork-Jensen Ivan Brandslund Cramer Christensen Heikki Koistinen Alex Doney Leena Kinnunen Tõnu Esko Andrew Farmer Liisa Hakaste Dylan Hodgkiss Jasmina Kravic Valeriya Lyssenko Mette Hollensted Marit Jørgensen Torben Jørgensen Claes Ladenvall Johanne 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 Swift Anders Rosengren Kathleen Stirrups Andrew Wood Evelin Mihailov Christine Blancher Mauricio Carneiro Jared Maguire Ryan Poplin Khalid Shakir Timothy Fennell Mark DePristo Martin de Angelis Panos Deloukas Anette Gjesing Goo Jun Peter Nilsson Jacquelyn Murphy Robert Onofrio Barbara Thorand Torben Hansen Christa Meisinger Frank Hu Bo Isomaa Fredrik Karpe Liming Liang Annette Peters Cornelia Huth Stephen O'Rahilly Colin Palmer Oluf Pedersen Rainer Rauramaa Jaakko Tuomilehto Veikko Salomaa Richard Watanabe Ann-Christine Syvänen Richard Bergman Dwaipayan Bharadwaj Erwin Bottinger Yoon Cho Giriraj Chandak Juliana Chan Kee Chia Mark Daly Shah Ebrahim Claudia Langenberg Paul Elliott Kathleen Jablonski Donna Lehman Weiping Jia Ronald Ma Toni Pollin Manjinder Sandhu Nikhil Tandon Philippe Froguel Inês Barroso Yik Teo Eleftheria Zeggini Ruth Loos Kerrin Small Janina Ried Ralph DeFronzo Harald Grallert Benjamin Glaser Andres Metspalu Nicholas Wareham Mark Walker Eric Banks Christian Gieger Erik Ingelsson Hae Im Thomas Illig Paul Franks Gemma Buck Joseph Trakalo David Buck Inga Prokopenko Reedik Mägi Lars Lind Yossi Farjoun Katharine Owen Anna Gloyn Konstantin Strauch Tiinamaija Tuomi Jaspal Kooner Jong-Young Lee Taesung Park Peter Donnelly Andrew Morris Andrew Hattersley Donald Bowden Francis Collins Gil Atzmon John Chambers Timothy Spector Markku Laakso Tim Strom Graeme Bell John Blangero Ravindranath Duggirala E Shyong Tai Gilean McVean Craig Hanis James Wilson Mark Seielstad Timothy Frayling James Meigs Nancy Cox Rob Sladek Eric Lander Stacey Gabriel Noel Burtt Karen Mohlke Thomas Meitinger Leif Groop Goncalo Abecasis Jose Florez Laura Scott Andrew Morris Hyun Kang Michael Boehnke David Altshuler Mark McCarthy
Keywords	Humans Genetic Predisposition to Disease Alleles Genome-Wide Association Study Genetic Variation DNA Mutational Analysis Exome Diabetes Mellitus, Type 2 Sample Size Europe Genotyping Techniques
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.
Year of Publication	2016
Journal	Nature
Volume	536
Issue	7614
Pages	41-7
Date Published	2016 08 04
ISSN	1476-4687
DOI	10.1038/nature18642
PubMed ID	27398621
PubMed Central ID	PMC5034897
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Grant list	R01 DK093757 / DK / NIDDK NIH HHS / United States U01 DK085501 / DK / NIDDK NIH HHS / United States U01 HG005773 / HG / NHGRI NIH HHS / United States 095552 / Wellcome Trust / United Kingdom R01 AG042188 / AG / NIA NIH HHS / United States K12CA139160 / CA / NCI NIH HHS / United States P60DK20595 / DK / NIDDK NIH HHS / United States U01DK085501 / DK / NIDDK NIH HHS / United States HHSN268201300046C / PHS HHS / International DK093757 / DK / NIDDK NIH HHS / United States R00 DK092251 / DK / NIDDK NIH HHS / United States R00 DK099240 / DK / NIDDK NIH HHS / United States 1RC2DK088389 / DK / NIDDK NIH HHS / United States 090532 / Wellcome Trust / United Kingdom U54 MD007588 / MD / NIMHD NIH HHS / United States R01 AG046949 / AG / NIA NIH HHS / United States MR/K002414/1 / Medical Research Council / United Kingdom U54 HG003067 / HG / NHGRI NIH HHS / United States U01 DK085524 / DK / NIDDK NIH HHS / United States K24DK080140 / DK / NIDDK NIH HHS / United States DK085524 / DK / NIDDK NIH HHS / United States R01DK066358 / DK / NIDDK NIH HHS / United States U01 DK085545 / DK / NIDDK NIH HHS / United States 100956 / Wellcome Trust / United Kingdom R01 DK106236 / DK / NIDDK NIH HHS / United States SP/04/002 / British Heart Foundation / United Kingdom P01AG027734 / AG / NIA NIH HHS / United States R01 DK098032 / DK / NIDDK NIH HHS / United States U01DK085526 / DK / NIDDK NIH HHS / United States R01 DK072193 / DK / NIDDK NIH HHS / United States G0700931 / Medical Research Council / United Kingdom SP/09/002 / British Heart Foundation / United Kingdom U54HG003067 / HG / NHGRI NIH HHS / United States HHSN268201300048C / HL / NHLBI NIH HHS / United States MC_UU_12012/5 / Medical Research Council / United Kingdom 098017 / Wellcome Trust / United Kingdom T32 GM007753 / GM / NIGMS NIH HHS / United States R01MH090937 / MH / NIMH NIH HHS / United States MR/L01341X/1 / Medical Research Council / United Kingdom 095101 / Wellcome Trust / United Kingdom R01DK062370 / DK / NIDDK NIH HHS / United States MC_UU_12015/1 / Medical Research Council / United Kingdom 084723 / Wellcome Trust / United Kingdom 092447 / Wellcome Trust / United Kingdom R01 DK101478 / DK / NIDDK NIH HHS / United States R01 HL102830 / HL / NHLBI NIH HHS / United States DK072193 / DK / NIDDK NIH HHS / United States R01 DK073541 / DK / NIDDK NIH HHS / United States P30AG038072 / AG / NIA NIH HHS / United States HHSN268201300049C / HL / NHLBI NIH HHS / United States R01 DK066358 / DK / NIDDK NIH HHS / United States CIHR / Canada 085475 / Wellcome Trust / United Kingdom 064890 / Wellcome Trust / United Kingdom 086596 / Wellcome Trust / United Kingdom R01MH101820 / MH / NIMH NIH HHS / United States G0900747-‐91070 / Medical Research Council / United Kingdom RC2 DK088389 / DK / NIDDK NIH HHS / United States P30DK020595 / DK / NIDDK NIH HHS / United States K24 DK080140 / DK / NIDDK NIH HHS / United States R01DK098032 / DK / NIDDK NIH HHS / United States HHSN268201300049C / PHS HHS / International HHSN268201300047C / HL / NHLBI NIH HHS / United States U01 DK085526 / DK / NIDDK NIH HHS / United States RC2DK088389 / DK / NIDDK NIH HHS / United States R00DK092251 / DK / NIDDK NIH HHS / United States HHSN268201300050C / HL / NHLBI NIH HHS / United States 090367 / Wellcome Trust / United Kingdom 098051 / Wellcome Trust / United Kingdom U01 DK085584 / DK / NIDDK NIH HHS / United States DK085584 / DK / NIDDK NIH HHS / United States DK085545 / DK / NIDDK NIH HHS / United States G0601966 / Medical Research Council / United Kingdom P01 AG027734 / AG / NIA NIH HHS / United States U01 DK078616 / DK / NIDDK NIH HHS / United States DK088389 / DK / NIDDK NIH HHS / United States DK085526 / DK / NIDDK NIH HHS / United States DK098032 / DK / NIDDK NIH HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States P30 AG038072 / AG / NIA NIH HHS / United States 1R01AG042188 / AG / NIA NIH HHS / United States DK085501 / DK / NIDDK NIH HHS / United States R01 MH101820 / MH / NIMH NIH HHS / United States U01HG005773 / HG / NHGRI NIH HHS / United States T32GM007753 / GM / NIGMS NIH HHS / United States 083948 / Wellcome Trust / United Kingdom RG/14/5/30893 / British Heart Foundation / United Kingdom HHSN268201300046C / HL / NHLBI NIH HHS / United States HHSN268201300047C / PHS HHS / International 098381 / Wellcome Trust / United Kingdom G0800270 / Medical Research Council / United Kingdom R01DK073541 / DK / NIDDK NIH HHS / United States R01 MH090937 / MH / NIMH NIH HHS / United States R01AG046949 / AG / NIA NIH HHS / United States G0601261 / Medical Research Council / United Kingdom RC2-‐DK088389 / DK / NIDDK NIH HHS / United States R01HL102830 / HL / NHLBI NIH HHS / United States P30 DK020595 / DK / NIDDK NIH HHS / United States HHSN268201300050C / PHS HHS / International P60 DK020595 / DK / NIDDK NIH HHS / United States HHSN268201300048C / PHS HHS / International
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