Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Nature
Authors
Jason Flannick
Josep Mercader
Christian Fuchsberger
Miriam Udler
Anubha Mahajan
Jennifer Wessel
Tanya Teslovich
Lizz Caulkins
Ryan Koesterer
Francisco Barajas-Olmos
Thomas Blackwell
Eric Boerwinkle
Jennifer Brody
Federico Centeno-Cruz
Ling Chen
Siying Chen
Cecilia Contreras-Cubas
Emilio Córdova
Adolfo Correa
Maria Cortes
Ralph DeFronzo
Lawrence Dolan
Kimberly Drews
Amanda Elliott
James Floyd
Stacey Gabriel
Maria Garay-Sevilla
Humberto García-Ortíz
Myron Gross
Sohee Han
Nancy Heard-Costa
Anne Jackson
Marit Jørgensen
Hyun Kang
Megan Kelsey
Bong-Jo Kim
Heikki Koistinen
Johanna Kuusisto
Joseph Leader
Allan Linneberg
Ching-Ti Liu
Jianjun Liu
Valeriya Lyssenko
Alisa Manning
Anthony Marcketta
Juan Malacara-Hernandez
Angélica Martínez-Hernández
Karen Matsuo
Elizabeth Mayer-Davis
Elvia Mendoza-Caamal
Karen Mohlke
Alanna Morrison
Anne Ndungu
Maggie C Y Ng
Colm O'Dushlaine
Anthony Payne
Catherine Pihoker
Broad Genomics Platform
Wendy Post
Michael Preuss
Bruce Psaty
Ramachandran Vasan
N William Rayner
Alexander Reiner
Cristina Revilla-Monsalve
Neil Robertson
Nicola Santoro
Claudia Schurmann
Wing So
Xavier Soberón
Heather Stringham
Tim Strom
Claudia Tam
Farook Thameem
Brian Tomlinson
Jason Torres
Russell Tracy
Rob van Dam
Marijana Vujkovic
Shuai Wang
Ryan Welch
Daniel Witte
Tien-Yin Wong
Gil Atzmon
Nir Barzilai
John Blangero
Lori Bonnycastle
Donald Bowden
John Chambers
Edmund Chan
Ching-Yu Cheng
Yoon Cho
Francis Collins
Paul de Vries
Ravindranath Duggirala
Benjamin Glaser
Clicerio Gonzalez
Ma Gonzalez
Leif Groop
Jaspal Kooner
Soo Kwak
Markku Laakso
Donna Lehman
Peter Nilsson
Timothy Spector
E Shyong Tai
Tiinamaija Tuomi
Jaakko Tuomilehto
James Wilson
Carlos Aguilar-Salinas
Erwin Bottinger
Brian Burke
David Carey
Juliana Chan
Josée Dupuis
Philippe Frossard
Susan Heckbert
Mi Hwang
Young Kim
H Lester Kirchner
Jong-Young Lee
Juyoung Lee
Ruth Loos
Ronald Ma
Andrew Morris
Christopher O'Donnell
Colin Palmer
James Pankow
Kyong Park
Asif Rasheed
Danish Saleheen
Xueling Sim
Kerrin Small
Yik Teo
Christopher Haiman
Craig Hanis
Brian Henderson
Lorena Orozco
Teresa Tusié-Luna
Frederick Dewey
Aris Baras
Christian Gieger
Thomas Meitinger
Konstantin Strauch
Leslie Lange
Niels Grarup
Torben Hansen
Oluf Pedersen
Philip Zeitler
Dana Dabelea
Goncalo Abecasis
Graeme Bell
Nancy Cox
Mark Seielstad
Rob Sladek
James Meigs
Steve Rich
Jerome Rotter
DiscovEHR Collaboration
CHARGE
LuCamp
ProDiGY
GOT2D
ESP
SIGMA-T2D
T2D-GENES
AMP-T2D-GENES
David Altshuler
Noel Burtt
Laura Scott
Andrew Morris
Jose Florez
Mark McCarthy
Michael Boehnke
Keywords
Animals
Female
Humans
Male
Mice
Gene Frequency
Genome-Wide Association Study
Mice, Knockout
Case-Control Studies
Exome
Diabetes Mellitus, Type 2
Whole Exome Sequencing
Decision Support Techniques
Abstract

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10) and candidate genes from knockout mice (P = 5.2 × 10). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
Year of Publication
2019
Journal
Nature
Volume
570
Issue
7759
Pages
71-76
Date Published
2019 06
ISSN
1476-4687
DOI
10.1038/s41586-019-1231-2
PubMed ID
31118516
PubMed Central ID
PMC6699738
Links
Grant list
K01 HL125751 / HL / NHLBI NIH HHS / United States
U01 HG007417 / HG / NHGRI NIH HHS / United States
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K24 DK110550 / DK / NIDDK NIH HHS / United States
U01 DK061254 / DK / NIDDK NIH HHS / United States
HHSN268201500003C / HL / NHLBI NIH HHS / United States
UL1 RR024139 / RR / NCRR NIH HHS / United States
UL1 RR024989 / RR / NCRR NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
R01 HL113323 / HL / NHLBI NIH HHS / United States
R01 AG046949 / AG / NIA NIH HHS / United States
R56 DK062370 / DK / NIDDK NIH HHS / United States
N01HC95160 / HL / NHLBI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
UL1 RR024153 / RR / NCRR NIH HHS / United States
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