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

Jason Flannick; Josep M. Mercader; Christian Fuchsberger; Miriam S. Udler; Anubha Mahajan; Jennifer Wessel; Tanya M. Teslovich; Lizz Caulkins; Ryan Koesterer; Francisco Barajas-Olmos; Thomas W. Blackwell; Eric Boerwinkle; Jennifer A. Brody; Federico Centeno-Cruz; Ling Chen; Siying Chen; Cecilia Contreras-Cubas; Emilio Cordova; Adolfo Correa; Maria Cortes; Ralph A. DeFronzo; Lawrence Dolan; Kimberly L. Drews; Amanda Elliott; James S. Floyd; Stacey Gabriel; Maria Eugenia Garay-Sevilla; Humberto Garcia-Ortiz; Myron Gross; Sohee Han; Nancy L. Heard-Costa; Anne U. Jackson; Marit E. Jorgensen; Hyun Min Kang; Megan Kelsey; Bong-Jo Kim; Heikki A. Koistinen; Johanna Kuusisto; Joseph B. Leader; Allan Linneberg; Ching-Ti Liu; Jianjun Liu; Valeriya Lyssenko; Alisa K. Manning; Anthony Marcketta; Juan Manuel Malacara-Hernandez; Angelica Martinez-Hernandez; Karen Matsuo; Elizabeth Mayer-Davis; Elvia Mendoza-Caamal; Karen L. Mohlke; Alanna C. Morrison; Anne Ndungu; Maggie C. Y. Ng; Colm O'Dushlaine; Anthony J. Payne; Catherine Pihoker; Wendy S. Post; Michael Preuss; Bruce M. Psaty; Ramachandran S. Vasan; N. William Rayner; Alexander P. Reiner; Cristina Revilla-Monsalve; Neil R. Robertson; Nicola Santoro; Claudia Schurmann; Wing Yee So; Xavier Soberon; Heather M. Stringham; Tim M. Strom; Claudia H. T. Tam; Farook Thameem; Brian Tomlinson; Jason M. Torres; Russell P. Tracy; Rob M. van Dam; Marijana Vujkovic; Shuai Wang; Ryan P. Welch; Daniel R. Witte; Tien-Yin Wong; Gil Atzmon; Nir Barzilai; John Blangero; Lori L. Bonnycastle; Donald W. Bowden; John C. Chambers; Edmund Chan; Ching-Yu Cheng; Yoon Shin Cho; Francis S. Collins; Paul S. De Vries; Ravindranath Duggirala; Benjamin Glaser; Clicerio Gonzalez; Ma Elena Gonzalez; Leif Groop; Jaspal Singh Kooner; Soo Heon Kwak; Markku Laakso; Donna M. Lehman; Peter Nilsson; Timothy D. Spector; E. Shyong Tai; Tiinamaija Tuomi; Jaakko Tuomilehto; James G. Wilson; Carlos A. Aguilar-Salinas; Erwin Bottinger; Brian Burke; David J. Carey; Juliana C. N. Chan; Josee Dupuis; Philippe Frossard; Susan R. Heckbert; Mi Yeong Hwang; Young Jin Kim; H. Lester Kirchner; Jong-Young Lee; Juyoung Lee; Ruth J. F. Loos; Ronald C. W. Ma; Andrew D. Morris; Christopher J. O'Donnell; Colin N. A. Palmer; James Pankow; Kyong Soo Park; Asif Rasheed; Danish Saleheen; Xueling Sim; Kerrin S. Small; Yik Ying Teo; Christopher Haiman; Craig L. Hanis; Brian E. Henderson; Lorena Orozco; Teresa Tusie-Luna; Frederick E. Dewey; Aris Baras; Christian Gieger; Thomas Meitinger; Konstantin Strauch; Leslie Lange; Niels Grarup; Torben Hansen; Oluf Pedersen; Philip Zeitler; Dana Dabelea; Goncalo Abecasis; Graeme I. Bell; Nancy J. Cox; Mark Seielstad; Rob Sladek; James B. Meigs; Steve S. Rich; Jerome I. Rotter; David Altshuler; Noel P. Burtt; Laura J. Scott; Andrew P. Morris; Jose C. Florez; Mark I. McCarthy; Michael Boehnke; DiscovEHR Collaboration

doi:10.1038/s41586-019-1231-2

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

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

Jason Flannick, Josep M. Mercader, Christian Fuchsberger, Miriam S. Udler, Anubha Mahajan, Jennifer Wessel, Tanya M. Teslovich, Lizz Caulkins, Ryan Koesterer, Francisco Barajas-Olmos, …

Nature (London), Vol.570(7759), pp.71-76

06/2019

DOI: https://doi.org/10.1038/s41586-019-1231-2

PMCID: PMC6699738

PMID: 31118516

Abstract

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

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 x 10(-3)) and candidate genes from knockout mice (P = 5.2 x 10(-3)). 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.

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Title: Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
Creators - without role: Jason Flannick - Broad Institute
Josep M. Mercader - Broad Institute
Christian Fuchsberger - Biostat
Miriam S. Udler - Broad Institute
Anubha Mahajan - University of Oxford
Jennifer Wessel - Indiana University
Tanya M. Teslovich - Regeneron
Lizz Caulkins - Broad Institute
Ryan Koesterer - Broad Institute
Francisco Barajas-Olmos - College Station Medical Center
Thomas W. Blackwell - Biostat
Eric Boerwinkle - Supreme Council Of Health
Jennifer A. Brody - University of Washington
Federico Centeno-Cruz - College Station Medical Center
Ling Chen - Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA
Siying Chen - Biostat
Cecilia Contreras-Cubas - College Station Medical Center
Emilio Cordova - College Station Medical Center
Adolfo Correa - University of Mississippi
Maria Cortes - Broad Institute
Ralph A. DeFronzo - College Station Medical Center
Lawrence Dolan - College Station Medical Center
Kimberly L. Drews - George Washington University
Amanda Elliott - Broad Institute
James S. Floyd - University of Washington
Stacey Gabriel - Broad Institute
Maria Eugenia Garay-Sevilla - University of Chicago
Humberto Garcia-Ortiz - College Station Medical Center
Myron Gross - University of Minnesota
Sohee Han - Natl Inst Hlth, Ctr Genome Sci, Div Genome Res, Cheongju, Chungcheongbuk, South Korea
Nancy L. Heard-Costa - Boston University
Anne U. Jackson - Biostat
Marit E. Jorgensen - Steno Diabet Ctr Copenhagen, Gentofte, Denmark
Hyun Min Kang - Biostat
Megan Kelsey - George Washington University
Bong-Jo Kim - Natl Inst Hlth, Ctr Genome Sci, Div Genome Res, Cheongju, Chungcheongbuk, South Korea
Heikki A. Koistinen - Natl Inst Hlth & Welf, Dept Publ Hlth Solut, Helsinki, Finland
Johanna Kuusisto - University of Eastern Finland
Joseph B. Leader - Geisinger Hlth Syst, Danville, PA USA
Allan Linneberg - University of Copenhagen
Ching-Ti Liu - Boston University
Jianjun Liu - Genome Institute of Singapore
Valeriya Lyssenko - Lund University
Alisa K. Manning - Supreme Council Of Health
Anthony Marcketta - Regeneron
Juan Manuel Malacara-Hernandez - University of Chicago
Angelica Martinez-Hernandez - College Station Medical Center
Karen Matsuo - Biostat
Elizabeth Mayer-Davis - Univ N Carolina, Chapel Hill, NC 27515 USA
Elvia Mendoza-Caamal - College Station Medical Center
Karen L. Mohlke - Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA
Alanna C. Morrison - Supreme Council Of Health
Anne Ndungu - University of Oxford
Maggie C. Y. Ng - Supreme Council Of Health
Colm O'Dushlaine - Regeneron
Anthony J. Payne - University of Oxford
Catherine Pihoker - Seattle Childrens Hosp, Seattle, WA USA
Wendy S. Post - Johns Hopkins University
Michael Preuss - Supreme Council Of Health
Bruce M. Psaty - University of Washington
Ramachandran S. Vasan - Framingham Heart Study
N. William Rayner - University of Oxford
Alexander P. Reiner - University of Washington
Cristina Revilla-Monsalve - Inst Mexicano Seguro Social SXXI, Mexico City, DF, Mexico
Neil R. Robertson - University of Oxford
Nicola Santoro - Yale University
Claudia Schurmann - Supreme Council Of Health
Wing Yee So - Chinese University of Hong Kong
Xavier Soberon - College Station Medical Center
Heather M. Stringham - Biostat
Tim M. Strom - Tech Univ Munich, Inst Human Genet, Munich, Germany
Claudia H. T. Tam - Chinese University of Hong Kong
Farook Thameem - Kuwait University
Brian Tomlinson - Chinese University of Hong Kong
Jason M. Torres - University of Oxford
Russell P. Tracy - University of Vermont
Rob M. van Dam - Supreme Council Of Health
Marijana Vujkovic - Biostat
Shuai Wang - Boston University
Ryan P. Welch - Biostat
Daniel R. Witte - Aarhus University
Tien-Yin Wong - Singapore Eye Research Institute
Gil Atzmon - Albert Einstein College of Medicine
Nir Barzilai - Albert Einstein College of Medicine
John Blangero - The University of Texas Rio Grande Valley
Lori L. Bonnycastle - College Station Medical Center
Donald W. Bowden - Supreme Council Of Health
John C. Chambers - Biostat
Edmund Chan - Supreme Council Of Health
Ching-Yu Cheng - Duke-NUS Medical School
Yoon Shin Cho - Hallym University
Francis S. Collins - College Station Medical Center
Paul S. De Vries - Supreme Council Of Health
Ravindranath Duggirala - The University of Texas Rio Grande Valley
Benjamin Glaser - Hadassah
Clicerio Gonzalez - Inst Nacl Salud Publ, Unidad Diabet & Riesgo Cardiovasc, Cuernavaca, Morelos, Mexico
Ma Elena Gonzalez - Ctr Estudios Diabet, Mexico City, DF, Mexico
Leif Groop - Lund University
Jaspal Singh Kooner - Lung Institute
Soo Heon Kwak - College Station Medical Center
Markku Laakso - University of Eastern Finland
Donna M. Lehman - College Station Medical Center
Peter Nilsson - Lund University
Timothy D. Spector - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
E. Shyong Tai - Supreme Council Of Health
Tiinamaija Tuomi - University of Helsinki
Jaakko Tuomilehto - Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland
James G. Wilson - University of Mississippi
Carlos A. Aguilar-Salinas - College Station Medical Center
Erwin Bottinger - Supreme Council Of Health
Brian Burke - George Washington University
David J. Carey - Geisinger Hlth Syst, Danville, PA USA
Juliana C. N. Chan - Chinese University of Hong Kong
Josee Dupuis - Framingham Heart Study
Philippe Frossard - Ctr Noncommunicable Dis, Karachi, Pakistan
Susan R. Heckbert - University of Washington
Mi Yeong Hwang - Natl Inst Hlth, Ctr Genome Sci, Div Genome Res, Cheongju, Chungcheongbuk, South Korea
Young Jin Kim - Natl Inst Hlth, Ctr Genome Sci, Div Genome Res, Cheongju, Chungcheongbuk, South Korea
H. Lester Kirchner - Geisinger Hlth Syst, Danville, PA USA
Jong-Young Lee - Convergence
Juyoung Lee - Natl Inst Hlth, Ctr Genome Sci, Div Genome Res, Cheongju, Chungcheongbuk, South Korea
Ruth J. F. Loos - Supreme Council Of Health
Ronald C. W. Ma - Chinese University of Hong Kong
Andrew D. Morris - Supreme Council Of Health
Christopher J. O'Donnell - Supreme Council Of Health
Colin N. A. Palmer - Supreme Council Of Health
James Pankow - University of Minnesota
Kyong Soo Park - Lung Institute
Asif Rasheed - Ctr Noncommunicable Dis, Karachi, Pakistan
Danish Saleheen - Biostat
Xueling Sim - Supreme Council Of Health
Kerrin S. Small - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Yik Ying Teo - Supreme Council Of Health
Christopher Haiman - Supreme Council Of Health
Craig L. Hanis - Supreme Council Of Health
Brian E. Henderson - Supreme Council Of Health
Lorena Orozco - College Station Medical Center
Teresa Tusie-Luna - College Station Medical Center
Frederick E. Dewey - Regeneron
Aris Baras - Regeneron
Christian Gieger - Helmholtz Zentrum München
Thomas Meitinger - Tech Univ Munich, Inst Human Genet, Munich, Germany
Konstantin Strauch - Helmholtz Zentrum München
Leslie Lange - University of Colorado Denver
Niels Grarup - University of Copenhagen
Torben Hansen - University of Copenhagen
Oluf Pedersen - University of Copenhagen
Philip Zeitler - College Station Medical Center
Dana Dabelea - Supreme Council Of Health
Goncalo Abecasis - Biostat
Graeme I. Bell - University of Chicago
Nancy J. Cox - Vanderbilt University
Mark Seielstad - College Station Medical Center
Rob Sladek - McGill University
James B. Meigs - Broad Institute
Steve S. Rich - University of Virginia
Jerome I. Rotter - Biomed Research Institute
David Altshuler - Broad Institute
Noel P. Burtt - Broad Institute
Laura J. Scott - Biostat
Andrew P. Morris - University of Oxford
Jose C. Florez - Broad Institute
Mark I. McCarthy - University of Oxford
Michael Boehnke - Biostat
DiscovEHR Collaboration
Publication Details: Nature (London), Vol.570(7759), pp.71-76
Publisher: NATURE PORTFOLIO
Number of pages: 24
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Identifiers: 9937042508331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article