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

Author

Listed:
  • Jason Flannick

    (Broad Institute
    Boston Children’s Hospital
    Harvard Medical School
    Broad Institute)

  • Josep M. Mercader

    (Broad Institute
    Broad Institute
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Christian Fuchsberger

    (University of Michigan
    Eurac Research
    University of Michigan)

  • Miriam S. Udler

    (Broad Institute
    Broad Institute
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Anubha Mahajan

    (University of Oxford
    University of Oxford)

  • Jennifer Wessel

    (Indiana University
    Indiana University
    Indiana University)

  • Tanya M. Teslovich

    (Regeneron Pharmaceuticals)

  • Lizz Caulkins

    (Broad Institute
    Broad Institute)

  • Ryan Koesterer

    (Broad Institute
    Broad Institute)

  • Francisco Barajas-Olmos

    (Instituto Nacional de Medicina Genómica)

  • Thomas W. Blackwell

    (University of Michigan
    University of Michigan)

  • Eric Boerwinkle

    (The University of Texas Health Science Center at Houston
    Baylor College of Medicine)

  • Jennifer A. Brody

    (University of Washington)

  • Federico Centeno-Cruz

    (Instituto Nacional de Medicina Genómica)

  • Ling Chen

    (Massachusetts General Hospital
    Harvard Medical School)

  • Siying Chen

    (University of Michigan
    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
    Broad Institute
    Massachusetts General Hospital
    Harvard Medical School)

  • James S. Floyd

    (University of Washington)

  • Stacey Gabriel

    (Broad Institute of MIT and Harvard)

  • Maria Eugenia Garay-Sevilla

    (The University of Chicago
    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
    National Heart Lung and Blood Institute’s Framingham Heart Study)

  • Anne U. Jackson

    (University of Michigan
    University of Michigan)

  • Marit E. Jørgensen

    (Steno Diabetes Center Copenhagen
    University of Southern Denmark
    University of Greenland)

  • Hyun Min Kang

    (University of Michigan
    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
    Helsinki University Central Hospital
    Minerva Foundation Institute for Medical Research)

  • Johanna Kuusisto

    (University of Eastern Finland
    Kuopio University Hospital)

  • Joseph B. Leader

    (Geisinger Health System)

  • Allan Linneberg

    (University of Copenhagen
    Bispebjerg and Frederiksberg Hospital
    Rigshospitalet)

  • Ching-Ti Liu

    (Boston University School of Public Health)

  • Jianjun Liu

    (Agency for Science Technology and Research
    National University of Singapore, National University Health System
    National University of Singapore)

  • Valeriya Lyssenko

    (Lund University Diabetes Centre
    University of Bergen)

  • Alisa K. Manning

    (Harvard Medical School
    Massachusetts General Hospital, Harvard University)

  • Anthony Marcketta

    (Regeneron Pharmaceuticals)

  • Juan Manuel Malacara-Hernandez

    (The University of Chicago
    The University of Chicago)

  • Angélica Martínez-Hernández

    (Instituto Nacional de Medicina Genómica)

  • Karen Matsuo

    (University of Michigan
    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
    Wake Forest School of Medicine
    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
    Kaiser Permanente Washington Health Research Institute
    University of Washington
    University of Washington)

  • Ramachandran S. Vasan

    (National Heart Lung and Blood Institute’s Framingham Heart Study
    Boston University School of Medicine)

  • N. William Rayner

    (University of Oxford
    University of Oxford
    Wellcome Trust Sanger Institute)

  • Alexander P. Reiner

    (University of Washington)

  • Cristina Revilla-Monsalve

    (Instituto Mexicano del Seguro Social SXXI)

  • Neil R. Robertson

    (University of Oxford
    University of Oxford)

  • Nicola Santoro

    (Yale University)

  • Claudia Schurmann

    (Mount Sinai School of Medicine)

  • Wing Yee So

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Xavier Soberón

    (Instituto Nacional de Medicina Genómica)

  • Heather M. Stringham

    (University of Michigan
    University of Michigan)

  • Tim M. Strom

    (Technische Universität München
    German Research Center for Environmental Health)

  • Claudia H. T. Tam

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong
    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
    University of Vermont)

  • Rob M. Dam

    (National University of Singapore, National University Health System
    National University of Singapore
    Harvard School of Public Health)

  • Marijana Vujkovic

    (University of Pennsylvania)

  • Shuai Wang

    (Boston University School of Public Health)

  • Ryan P. Welch

    (University of Michigan
    University of Michigan)

  • Daniel R. Witte

    (Aarhus University
    Danish Diabetes Academy)

  • Tien-Yin Wong

    (Singapore National Eye Centre
    Duke-NUS Medical School Singapore
    National University of Singapore, National University Health System)

  • Gil Atzmon

    (Albert Einstein College of Medicine
    University of Haifa
    Albert Einstein College of Medicine)

  • Nir Barzilai

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • John Blangero

    (University of Texas Rio Grande Valley
    South Texas Diabetes and Obesity Institute)

  • Lori L. Bonnycastle

    (National Institutes of Health)

  • Donald W. Bowden

    (Wake Forest School of Medicine
    Wake Forest School of Medicine
    Wake Forest School of Medicine)

  • John C. Chambers

    (Imperial College London
    Ealing Hospital NHS Trust
    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
    South Texas Diabetes and Obesity Institute)

  • 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
    University of Helsinki)

  • Jaspal Singh Kooner

    (Cardiovascular Sciences, Imperial College London)

  • Soo Heon Kwak

    (Seoul National University Hospital)

  • Markku Laakso

    (University of Eastern Finland
    Kuopio University Hospital)

  • 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
    National University of Singapore
    Duke-NUS Medical School Singapore)

  • Tiinamaija Tuomi

    (University of Helsinki
    Folkhälsan Research Centre
    Helsinki University Hospital
    University of Helsinki)

  • Jaakko Tuomilehto

    (National Institute for Health and Welfare
    Danube University Krems
    King Abdulaziz University
    University Hospital LaPaz, Autonomous University of Madrid)

  • 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
    The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Josée Dupuis

    (National Heart Lung and Blood Institute’s Framingham Heart Study
    Boston University School of Public Health)

  • Philippe Frossard

    (Center for Non-Communicable Diseases)

  • Susan R. Heckbert

    (University of Washington
    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
    Icahn School of Medicine at Mount Sinai)

  • Ronald C. W. Ma

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Andrew D. Morris

    (Ninewells Hospital and Medical School)

  • Christopher J. O’Donnell

    (Harvard Medical School
    VA Boston Healthcare
    Brigham and Women’s Hospital
    National Heart Lung and Blood Institute, NIH)

  • 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
    Seoul National University
    Seoul National University College of Medicine)

  • Asif Rasheed

    (Center for Non-Communicable Diseases)

  • Danish Saleheen

    (University of Pennsylvania
    Center for Non-Communicable Diseases)

  • Xueling Sim

    (National University of Singapore)

  • Kerrin S. Small

    (King’s College London)

  • Yik Ying Teo

    (National University of Singapore
    National University of Singapore
    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
    Universidad Nacional Autónoma de México)

  • Frederick E. Dewey

    (Regeneron Pharmaceuticals)

  • Aris Baras

    (Regeneron Pharmaceuticals)

  • Christian Gieger

    (German Research Center for Environmental Health
    German Center for Diabetes Research (DZD e.V.))

  • Thomas Meitinger

    (Technische Universität München
    German Research Center for Environmental Health
    Partner Site Munich Heart Alliance)

  • Konstantin Strauch

    (German Research Center for Environmental Health
    Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität)

  • 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
    University of Southern Denmark)

  • 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
    University of Michigan)

  • Graeme I. Bell

    (The University of Chicago
    The University of Chicago)

  • Nancy J. Cox

    (Vanderbilt University)

  • Mark Seielstad

    (University of California, San Francisco
    Blood Systems Research Institute)

  • Rob Sladek

    (McGill University, Montreal
    McGill University
    McGill University and Génome Québec Innovation Centre)

  • James B. Meigs

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Steve S. Rich

    (University of Virginia School of Medicine)

  • Jerome I. Rotter

    (Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center
    Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center
    Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center)

  • David Altshuler

    (Broad Institute
    Broad Institute
    Massachusetts General Hospital
    Harvard Medical School)

  • Noël P. Burtt

    (Broad Institute
    Broad Institute)

  • Laura J. Scott

    (University of Michigan
    University of Michigan)

  • Andrew P. Morris

    (University of Oxford
    University of Liverpool)

  • Jose C. Florez

    (Broad Institute
    Broad Institute
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Mark I. McCarthy

    (University of Oxford
    University of Oxford
    Oxford University Hospitals Trust)

  • Michael Boehnke

    (University of Michigan
    University of Michigan)

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.

Suggested Citation

  • 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, 2019. "Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls," Nature, Nature, vol. 570(7759), pages 71-76, June.
  • Handle: RePEc:nat:nature:v:570:y:2019:i:7759:d:10.1038_s41586-019-1231-2
    DOI: 10.1038/s41586-019-1231-2
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    1. Mingming Xing & Yang Li & Yuqi Zhang & Juemou Zhou & Danting Ma & Mengqi Zhang & Minglei Tang & Ting Ouyang & Fumiao Zhang & Xiaofeng Shi & Jianyuan Sun & Zuxin Chen & Weiping J. Zhang & Shuli Zhang &, 2024. "Paraventricular hypothalamic RUVBL2 neurons suppress appetite by enhancing excitatory synaptic transmission in distinct neurocircuits," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Jennifer L. Halford & Valerie N. Morrill & Seung Hoan Choi & Sean J. Jurgens & Giorgio Melloni & Nicholas A. Marston & Lu-Chen Weng & Victor Nauffal & Amelia W. Hall & Sophia Gunn & Christina A. Austi, 2022. "Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Aimee M. Deaton & Aditi Dubey & Lucas D. Ward & Peter Dornbos & Jason Flannick & Elaine Yee & Simina Ticau & Leila Noetzli & Margaret M. Parker & Rachel A. Hoffing & Carissa Willis & Mollie E. Plekan , 2022. "Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Xianyong Yin & Lap Sum Chan & Debraj Bose & Anne U. Jackson & Peter VandeHaar & Adam E. Locke & Christian Fuchsberger & Heather M. Stringham & Ryan Welch & Ketian Yu & Lilian Fernandes Silva & Susan K, 2022. "Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Jing Yan & Yuemei Zhang & Hairong Yu & Yicen Zong & Daixi Wang & Jiangfei Zheng & Li Jin & Xiangtian Yu & Caizhi Liu & Yi Zhang & Feng Jiang & Rong Zhang & Xiangnan Fang & Ting Xu & Mingyu Li & Jianzh, 2022. "GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    6. Qing Ma & Yini Xiao & Wenjun Xu & Menghan Wang & Sheng Li & Zhihao Yang & Minglu Xu & Tengjiao Zhang & Zhen-Ning Zhang & Rui Hu & Qiang Su & Fei Yuan & Tinghui Xiao & Xuan Wang & Qing He & Jiaxu Zhao , 2022. "ZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Stephanie O. Erjavec & Sahar Gelfman & Alexa R. Abdelaziz & Eunice Y. Lee & Isha Monga & Anna Alkelai & Iuliana Ionita-Laza & Lynn Petukhova & Angela M. Christiano, 2022. "Whole exome sequencing in Alopecia Areata identifies rare variants in KRT82," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    8. Sarah Meulebrouck & Judith Merrheim & Gurvan Queniat & Cyril Bourouh & Mehdi Derhourhi & Mathilde Boissel & Xiaoyan Yi & Alaa Badreddine & Raphaël Boutry & Audrey Leloire & Bénédicte Toussaint & Souhi, 2024. "Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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