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 Córdova, Adolfo Correa, Maria Cortes, Ralph A. DeFronzo, Lawrence Dolan, Kimberly L. Drews, Amanda Elliott, James S. Floyd, Stacey Gabriel, Maria Eugenia Garay-Sevilla, Humberto García-Ortiz, Myron Gross, Sohee Han, Nancy L. Heard-Costa, Anne U. Jackson, Marit E. Jørgensen, 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, Angélica Martínez-Hernández, 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 Soberón, Heather M. Stringham, Tim M. Strom, Claudia H. T. Tam, Farook Thameem, Brian Tomlinson, Jason M. Torres, Russell P. Tracy, Rob M. 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. 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, Josée 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 Tusié-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, Noël P. Burtt, Laura J. Scott, Andrew P. Morris, Jose C. Florez, Mark I. McCarthy and Michael Boehnke
Additional contact information
Jason Flannick: Broad Institute
Josep M. Mercader: Broad Institute
Christian Fuchsberger: University of Michigan
Miriam S. Udler: Broad Institute
Anubha Mahajan: University of Oxford
Jennifer Wessel: Indiana University
Tanya M. Teslovich: Regeneron Pharmaceuticals
Lizz Caulkins: Broad Institute
Ryan Koesterer: Broad Institute
Francisco Barajas-Olmos: Instituto Nacional de Medicina Genómica
Thomas W. Blackwell: University of Michigan
Eric Boerwinkle: The University of Texas Health Science Center at Houston
Jennifer A. Brody: University of Washington
Federico Centeno-Cruz: Instituto Nacional de Medicina Genómica
Ling Chen: Massachusetts General Hospital
Siying Chen: University of Michigan
Cecilia Contreras-Cubas: Instituto Nacional de Medicina Genómica
Emilio Córdova: Instituto Nacional de Medicina Genómica
Adolfo Correa: University of Mississippi Medical Center
Maria Cortes: Broad Institute of MIT and Harvard
Ralph A. DeFronzo: University of Texas Health Science Center
Lawrence Dolan: Cincinnati Children’s Hospital Medical Center
Kimberly L. Drews: George Washington University
Amanda Elliott: Broad Institute
James S. Floyd: University of Washington
Stacey Gabriel: Broad Institute of MIT and Harvard
Maria Eugenia Garay-Sevilla: The University of Chicago
Humberto García-Ortiz: Instituto Nacional de Medicina Genómica
Myron Gross: University of Minnesota
Sohee Han: Center for Genome Science, National Institute of Health
Nancy L. Heard-Costa: Boston University School of Medicine
Anne U. Jackson: University of Michigan
Marit E. Jørgensen: Steno Diabetes Center Copenhagen
Hyun Min Kang: University of Michigan
Megan Kelsey: George Washington University
Bong-Jo Kim: Center for Genome Science, National Institute of Health
Heikki A. Koistinen: National Institute for Health and Welfare
Johanna Kuusisto: University of Eastern Finland
Joseph B. Leader: Geisinger Health System
Allan Linneberg: University of Copenhagen
Ching-Ti Liu: Boston University School of Public Health
Jianjun Liu: Agency for Science Technology and Research
Valeriya Lyssenko: Lund University Diabetes Centre
Alisa K. Manning: Harvard Medical School
Anthony Marcketta: Regeneron Pharmaceuticals
Juan Manuel Malacara-Hernandez: The University of Chicago
Angélica Martínez-Hernández: Instituto Nacional de Medicina Genómica
Karen Matsuo: University of Michigan
Elizabeth Mayer-Davis: University of North Carolina Chapel Hill
Elvia Mendoza-Caamal: Instituto Nacional de Medicina Genómica
Karen L. Mohlke: University of North Carolina Chapel Hill
Alanna C. Morrison: The University of Texas Health Science Center at Houston
Anne Ndungu: University of Oxford
Maggie C. Y. Ng: Wake Forest School of Medicine
Colm O’Dushlaine: Regeneron Pharmaceuticals
Anthony J. Payne: University of Oxford
Catherine Pihoker: Seattle Children’s Hospital
Wendy S. Post: Johns Hopkins University
Michael Preuss: Mount Sinai School of Medicine
Bruce M. Psaty: University of Washington
Ramachandran S. Vasan: National Heart Lung and Blood Institute’s Framingham Heart Study
N. William Rayner: University of Oxford
Alexander P. Reiner: University of Washington
Cristina Revilla-Monsalve: Instituto Mexicano del Seguro Social SXXI
Neil R. Robertson: University of Oxford
Nicola Santoro: Yale University
Claudia Schurmann: Mount Sinai School of Medicine
Wing Yee So: The Chinese University of Hong Kong
Xavier Soberón: Instituto Nacional de Medicina Genómica
Heather M. Stringham: University of Michigan
Tim M. Strom: Technische Universität München
Claudia H. T. Tam: The Chinese University of Hong Kong
Farook Thameem: Faculty of Medicine, Kuwait University
Brian Tomlinson: The Chinese University of Hong Kong
Jason M. Torres: University of Oxford
Russell P. Tracy: University of Vermont
Rob M. Dam: National University of Singapore, National University Health System
Marijana Vujkovic: University of Pennsylvania
Shuai Wang: Boston University School of Public Health
Ryan P. Welch: University of Michigan
Daniel R. Witte: Aarhus University
Tien-Yin Wong: Singapore National Eye Centre
Gil Atzmon: Albert Einstein College of Medicine
Nir Barzilai: Albert Einstein College of Medicine
John Blangero: University of Texas Rio Grande Valley
Lori L. Bonnycastle: National Institutes of Health
Donald W. Bowden: Wake Forest School of Medicine
John C. Chambers: Imperial College London
Edmund Chan: National University of Singapore, National University Health System
Ching-Yu Cheng: Duke-NUS Medical School
Yoon Shin Cho: Hallym University
Francis S. Collins: National Institutes of Health
Paul S. Vries: The University of Texas Health Science Center at Houston
Ravindranath Duggirala: University of Texas Rio Grande Valley
Benjamin Glaser: Hadassah-Hebrew University Medical Center
Clicerio Gonzalez: Instituto Nacional de Salud Pública
Ma Elena Gonzalez: Centro de Estudios en Diabetes
Leif Groop: Lund University Diabetes Centre
Jaspal Singh Kooner: Cardiovascular Sciences, Imperial College London
Soo Heon Kwak: Seoul National University Hospital
Markku Laakso: University of Eastern Finland
Donna M. Lehman: University of Texas Health Science Center
Peter Nilsson: Medicine, Lund University
Timothy D. Spector: King’s College London
E. Shyong Tai: National University of Singapore, National University Health System
Tiinamaija Tuomi: University of Helsinki
Jaakko Tuomilehto: National Institute for Health and Welfare
James G. Wilson: University of Mississippi Medical Center
Carlos A. Aguilar-Salinas: Instituto Nacional de Ciencias Medicas y Nutricion
Erwin Bottinger: Mount Sinai School of Medicine
Brian Burke: George Washington University
David J. Carey: Geisinger Health System
Juliana C. N. Chan: The Chinese University of Hong Kong
Josée Dupuis: National Heart Lung and Blood Institute’s Framingham Heart Study
Philippe Frossard: Center for Non-Communicable Diseases
Susan R. Heckbert: University of Washington
Mi Yeong Hwang: Center for Genome Science, National Institute of Health
Young Jin Kim: Center for Genome Science, National Institute of Health
H. Lester Kirchner: Geisinger Health System
Jong-Young Lee: Chungbuk National University
Juyoung Lee: Center for Genome Science, National Institute of Health
Ruth J. F. Loos: Mount Sinai School of Medicine
Ronald C. W. Ma: The Chinese University of Hong Kong
Andrew D. Morris: Ninewells Hospital and Medical School
Christopher J. O’Donnell: Harvard Medical School
Colin N. A. Palmer: Medical Research Institute, Ninewells Hospital and Medical School
James Pankow: University of Minnesota
Kyong Soo Park: Cardiovascular Sciences, Imperial College London
Asif Rasheed: Center for Non-Communicable Diseases
Danish Saleheen: University of Pennsylvania
Xueling Sim: National University of Singapore
Kerrin S. Small: King’s College London
Yik Ying Teo: National University of Singapore
Christopher Haiman: University of Southern California
Craig L. Hanis: The University of Texas Health Science Center at Houston
Brian E. Henderson: University of Southern California
Lorena Orozco: Instituto Nacional de Medicina Genómica
Teresa Tusié-Luna: Instituto Nacional de Ciencias Medicas y Nutricion
Frederick E. Dewey: Regeneron Pharmaceuticals
Aris Baras: Regeneron Pharmaceuticals
Christian Gieger: German Research Center for Environmental Health
Thomas Meitinger: Technische Universität München
Konstantin Strauch: German Research Center for Environmental Health
Leslie Lange: University of Colorado Denver
Niels Grarup: Faculty of Health and Medical Sciences, University of Copenhagen
Torben Hansen: Faculty of Health and Medical Sciences, University of Copenhagen
Oluf Pedersen: Faculty of Health and Medical Sciences, University of Copenhagen
Philip Zeitler: University of Colorado Anschutz Medical Campus
Dana Dabelea: Colorado School of Public Health
Goncalo Abecasis: University of Michigan
Graeme I. Bell: The University of Chicago
Nancy J. Cox: Vanderbilt University
Mark Seielstad: University of California, San Francisco
Rob Sladek: McGill University, Montreal
James B. Meigs: Broad Institute of MIT and Harvard
Steve S. Rich: University of Virginia School of Medicine
Jerome I. Rotter: Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center
David Altshuler: Broad Institute
Noël P. Burtt: Broad Institute
Laura J. Scott: University of Michigan
Andrew P. Morris: University of Oxford
Jose C. Florez: Broad Institute
Mark I. McCarthy: University of Oxford
Michael Boehnke: University of Michigan

Nature, 2019, vol. 570, issue 7759, 71-76

Abstract: 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 × 10−3) and candidate genes from knockout mice (P = 5.2 × 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.

Date: 2019
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Citations: View citations in EconPapers (8)

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DOI: 10.1038/s41586-019-1231-2

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