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
Links
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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