Title

The genetic architecture of type 2 diabetes.

Authors

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 R Robertson
N William Rayner
Pablo Cingolani
Adam E Locke
Juan Fernandez Tajes
Heather M Highland
Josee Dupuis
Peter S Chines
Cecilia M Lindgren
Christopher Hartl
Anne U Jackson
Han Chen
Jeroen R Huyghe
Martijn van de Bunt
Richard D Pearson
Ashish Kumar
Martina Müller-Nurasyid
Niels Grarup
Heather M Stringham
Eric R Gamazon
Jaehoon Lee
Yuhui Chen
Robert A Scott
Jennifer E Below
Peng Chen
Jinyan Huang
Min Jin Go
Michael L. Stitzel, The Jackson LaboratoryFollow
Dorota Pasko
Stephen C J Parker
Tibor V Varga
Todd Green
Nicola L Beer
Aaron G Day-Williams
Teresa Ferreira
Tasha 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 Manning
Maggie C Y Ng
Nicholette D Palmer
Beverley Balkau
Alena Stancáková
Hanna E Abboud
Heiner Boeing
Vilmantas Giedraitis
Dorairaj Prabhakaran
Omri Gottesman
James Scott
Jason Carey
Phoenix Kwan
George 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 Esten 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
Loïc Yengo
Sian-Tsung Tan
Herman A Taylor
Farook Thameem
Gregory Wilson
Tien Yin Wong
Pål Rasmus 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 J 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 Swift
Anders H Rosengren
Kathleen Stirrups
Andrew R Wood
Evelin Mihailov
Christine Blancher
Mauricio O Carneiro
Jared Maguire
Ryan Poplin
Khalid Shakir
Timothy Fennell
Mark DePristo
Martin Hrabé de Angelis
Panos Deloukas
Anette P Gjesing
Goo Jun
Peter Nilsson
Jacquelyn Murphy
Robert Onofrio
Barbara Thorand
Torben Hansen
Christa Meisinger
Frank B Hu
Bo Isomaa
Fredrik Karpe
Liming Liang
Annette Peters
Cornelia Huth
Stephen P 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 B Ebrahim
Claudia Langenberg
Paul Elliott
Kathleen A Jablonski
Donna M Lehman
Weiping Jia
Ronald C W Ma
Toni I Pollin
Manjinder 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 Singh 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
Timothy 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
Rob Sladek
Eric S Lander
Stacey Gabriel
Noël P Burtt
Karen L Mohlke
Thomas Meitinger
Leif Groop
Goncalo Abecasis
Jose C Florez
Laura J Scott
Andrew P Morris
Hyun Min Kang
Michael Boehnke
David Altshuler
Mark I McCarthy

Document Type

Article

Publication Date

8-4-2016

Keywords

Alleles, DNA Mutational Analysis, Diabetes Mellitus, Type 2, Europe, Exome, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, Humans, Sample Size

JAX Source

Nature 2016 Aug 4; 536(7614):41-7

PMID

27398621

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. Nature 2016 Aug 4; 536(7614):41-7.