Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis.

Black or African American Chromosomes, Human, X Diabetes Complications / genetics Diabetes Mellitus, Type 2 / complications Diabetic Angiopathies / genetics Europe Female Genetic Association Studies Genetic Predisposition to Disease Humans Hypoglycemic Agents / therapeutic use Male Polymorphism, Single Nucleotide Risk Assessment

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
07 2020
Historique:
received: 16 11 2019
accepted: 29 04 2020
pubmed: 17 6 2020
medline: 2 10 2020
entrez: 17 6 2020
Statut: ppublish

Résumé

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.

Identifiants

DOI: 10.1038/s41588-020-0637-y PMID: 32541925 PMC: PMC7343592
pubmed: 32541925
doi: 10.1038/s41588-020-0637-y
pii: 10.1038/s41588-020-0637-y
pmc: PMC7343592
mid: NIHMS1589535
doi:

Substances chimiques

Hypoglycemic Agents 0

Types de publication

Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

680-691

Subventions

Organisme : CSRD VA
ID : I01 CX001025
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK123704
Pays : United States
Organisme : NIAID NIH HHS
ID : R03 AI133172
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101478
Pays : United States
Organisme : CSRD VA
ID : IK2 CX001780
Pays : United States
Organisme : CSRD VA
ID : I01 CX001737
Pays : United States
Organisme : NIDDK NIH HHS
ID : R21 DK099716
Pays : United States
Organisme : BLRD VA
ID : I01 BX003362
Pays : United States
Organisme : NIDDK NIH HHS
ID : UM1 DK078616
Pays : United States
Organisme : NIDDK NIH HHS
ID : U34 DK091958
Pays : United States
Organisme : BLRD VA
ID : I01 BX004821
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK101478
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK111024
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES006694
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007734
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK087635
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK098246
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG010067
Pays : United States
Organisme : NIDDK NIH HHS
ID : UC4 DK112217
Pays : United States

Investigateurs

Mark A Atkinson (MA)
Al C Powers (AC)
Ali Naji (A)
Klaus H Kaestner (KH)
Goncalo R Abecasis (GR)
Aris Baras (A)
Michael N Cantor (MN)
Giovanni Coppola (G)
Aris N Economides (AN)
Luca A Lotta (LA)
John D Overton (JD)
Jeffrey G Reid (JG)
Alan R Shuldiner (AR)
Christina Beechert (C)
Caitlin Forsythe (C)
Erin D Fuller (ED)
Zhenhua Gu (Z)
Michael Lattari (M)
Alexander E Lopez (AE)
Thomas D Schleicher (TD)
Maria Sotiropoulos Padilla (MS)
Karina Toledo (K)
Louis Widom (L)
Sarah E Wolf (SE)
Manasi Pradhan (M)
Kia Manoochehri (K)
Ricardo H Ulloa (RH)
Xiaodong Bai (X)
Suganthi Balasubramanian (S)
Leland Barnard (L)
Andrew L Blumenfeld (AL)
Gisu Eom (G)
Lukas Habegger (L)
Alicia Hawes (A)
Shareef Khalid (S)
Evan K Maxwell (EK)
William J Salerno (WJ)
Jeffrey C Staples (JC)
Ashish Yadav (A)
Marcus B Jones (MB)
Lyndon J Mitnaul (LJ)
Samuel M Aguayo (SM)
Sunil K Ahuja (SK)
Zuhair K Ballas (ZK)
Sujata Bhushan (S)
Edward J Boyko (EJ)
David M Cohen (DM)
John Concato (J)
Joseph I Constans (JI)
Louis J Dellitalia (LJ)
Joseph M Fayad (JM)
Ronald S Fernando (RS)
Hermes J Florez (HJ)
Melinda A Gaddy (MA)
Saib S Gappy (SS)
Gretchen Gibson (G)
Michael Godschalk (M)
Jennifer A Greco (JA)
Samir Gupta (S)
Salvador Gutierrez (S)
Kimberly D Hammer (KD)
Mark B Hamner (MB)
John B Harley (JB)
Adriana M Hung (AM)
Mostaqul Huq (M)
Robin A Hurley (RA)
Pran R Iruvanti (PR)
Douglas J Ivins (DJ)
Frank J Jacono (FJ)
Darshana N Jhala (DN)
Laurence S Kaminsky (LS)
Scott Kinlay (S)
Jon B Klein (JB)
Suthat Liangpunsakul (S)
Jack H Lichy (JH)
Stephen M Mastorides (SM)
Roy O Mathew (RO)
Kristin M Mattocks (KM)
Rachel McArdle (R)
Paul N Meyer (PN)
Laurence J Meyer (LJ)
Jonathan P Moorman (JP)
Timothy R Morgan (TR)
Maureen Murdoch (M)
Xuan-Mai T Nguyen (XT)
Olaoluwa O Okusaga (OO)
Kris-Ann K Oursler (KK)
Nora R Ratcliffe (NR)
Michael I Rauchman (MI)
R Brooks Robey (RB)
George W Ross (GW)
Richard J Servatius (RJ)
Satish C Sharma (SC)
Scott E Sherman (SE)
Elif Sonel (E)
Peruvemba Sriram (P)
Todd Stapley (T)
Robert T Striker (RT)
Neeraj Tandon (N)
Gerardo Villareal (G)
Agnes S Wallbom (AS)
John M Wells (JM)
Jeffrey C Whittle (JC)
Mary A Whooley (MA)
Junzhe Xu (J)
Shing-Shing Yeh (SS)
Michaela Aslan (M)
Jessica V Brewer (JV)
Mary T Brophy (MT)
Todd Connor (T)
Dean P Argyres (DP)
Nhan V Do (NV)
Elizabeth R Hauser (ER)
Donald E Humphries (DE)
Luis E Selva (LE)
Shahpoor Shayan (S)
Brady Stephens (B)
Stacey B Whitbourne (SB)
Hongyu Zhao (H)
Jennifer Moser (J)
Jean C Beckham (JC)
Jim L Breeling (JL)
J P Casas Romero (JPC)
Grant D Huang (GD)
Rachel B Ramoni (RB)
Saiju Pyarajan (S)
Yan V Sun (YV)
Kelly Cho (K)
Peter W Wilson (PW)
Christopher J O'Donnell (CJ)
Philip S Tsao (PS)
Kyong-Mi Chang (KM)
J Michael Gaziano (JM)
Sumitra Muralidhar (S)

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Auteurs

Marijana Vujkovic (M)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0003-4924-5714

Jacob M Keaton (JM)

Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System, Nashville, TN, USA.
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.

Julie A Lynch (JA)

VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
College of Nursing and Health Sciences, University of Massachusetts, Lowell, MA, USA.
ORCID: 0000-0003-0108-2127

Donald R Miller (DR)

Edith Nourse Rogers Memorial VA Hospital, Bedford, MA, USA.
Center for Population Health, University of Massachusetts, Lowell, MA, USA.

Jin Zhou (J)

Phoenix VA Health Care System, Phoenix, AZ, USA.
Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
ORCID: 0000-0001-7983-0274

Catherine Tcheandjieu (C)

VA Palo Alto Health Care System, Palo Alto, CA, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA, USA.

Jennifer E Huffman (JE)

VA Boston Healthcare System, Boston, MA, USA.
ORCID: 0000-0002-9672-2491

Themistocles L Assimes (TL)

VA Palo Alto Health Care System, Palo Alto, CA, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
ORCID: 0000-0003-2349-0009

Kimberly Lorenz (K)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0001-8674-2942

Xiang Zhu (X)

VA Palo Alto Health Care System, Palo Alto, CA, USA.
Department of Statistics, Stanford University, Stanford, CA, USA.
ORCID: 0000-0003-1134-6413

Austin T Hilliard (AT)

VA Palo Alto Health Care System, Palo Alto, CA, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
ORCID: 0000-0002-1289-4377

Renae L Judy (RL)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Jie Huang (J)

VA Boston Healthcare System, Boston, MA, USA.
Department of Global Health, Peking University School of Public Health, Beijing, China.

Kyung M Lee (KM)

VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
ORCID: 0000-0001-8995-0448

Derek Klarin (D)

VA Boston Healthcare System, Boston, MA, USA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Vascular Surgery and Endovascular Therapy, University of Florida School of Medicine, Gainesville, FL, USA.
ORCID: 0000-0002-4636-5780

Saiju Pyarajan (S)

VA Boston Healthcare System, Boston, MA, USA.
Department of Medicine, Brigham Women's Hospital, Boston, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.

John Danesh (J)

Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Olle Melander (O)

Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.

Asif Rasheed (A)

Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan.

Nadeem H Mallick (NH)

Punjab Institute of Cardiology, Lahore, Punjab, Pakistan.
ORCID: 0000-0002-8789-147X

Shahid Hameed (S)

Punjab Institute of Cardiology, Lahore, Punjab, Pakistan.

Irshad H Qureshi (IH)

Department of Medicine, King Edward Medical University, Lahore, Punjab, Pakistan.
Mayo Hospital, Lahore, Punjab, Pakistan.

Muhammad Naeem Afzal (MN)

Department of Medicine, King Edward Medical University, Lahore, Punjab, Pakistan.
Mayo Hospital, Lahore, Punjab, Pakistan.

Uzma Malik (U)

Department of Medicine, King Edward Medical University, Lahore, Punjab, Pakistan.
Mayo Hospital, Lahore, Punjab, Pakistan.

Anjum Jalal (A)

Department of Cardiology, Faisalabad Institute of Cardiology, Faisalabad, Punjab, Pakistan.

Shahid Abbas (S)

Department of Cardiology, Faisalabad Institute of Cardiology, Faisalabad, Punjab, Pakistan.

Xin Sheng (X)

Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0002-3620-3577

Long Gao (L)

Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Klaus H Kaestner (KH)

Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Katalin Susztak (K)

Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0002-1005-3726

Yan V Sun (YV)

Atlanta VA Medical Center, Decatur, GA, USA.
Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
ORCID: 0000-0002-2838-1824

Scott L DuVall (SL)

VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
ORCID: 0000-0002-4898-3865

Kelly Cho (K)

VA Boston Healthcare System, Boston, MA, USA.
Department of Medicine, Brigham Women's Hospital, Boston, MA, USA.

Jennifer S Lee (JS)

VA Palo Alto Health Care System, Palo Alto, CA, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

J Michael Gaziano (JM)

VA Boston Healthcare System, Boston, MA, USA.
Department of Medicine, Brigham Women's Hospital, Boston, MA, USA.

Lawrence S Phillips (LS)

Atlanta VA Medical Center, Decatur, GA, USA.
Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.
ORCID: 0000-0002-6542-8046

James B Meigs (JB)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.

Peter D Reaven (PD)

Phoenix VA Health Care System, Phoenix, AZ, USA.
College of Medicine, University of Arizona, Phoenix, AZ, USA.
ORCID: 0000-0001-8923-6690

Peter W Wilson (PW)

Atlanta VA Medical Center, Decatur, GA, USA.
Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.

Todd L Edwards (TL)

Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Nashville VA Medical Center, Nashville, TN, USA.
ORCID: 0000-0003-4318-6119

Daniel J Rader (DJ)

Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0002-9245-9876

Scott M Damrauer (SM)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0001-8009-1632

Christopher J O'Donnell (CJ)

VA Boston Healthcare System, Boston, MA, USA.
Department of Medicine, Brigham Women's Hospital, Boston, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-2667-8624

Philip S Tsao (PS)

VA Palo Alto Health Care System, Palo Alto, CA, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
ORCID: 0000-0001-7274-9318

Kyong-Mi Chang (KM)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
South Texas Veterans Health Care System, San Antonio, TX, USA.
ORCID: 0000-0001-6811-9364

Benjamin F Voight (BF)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
ORCID: 0000-0002-6205-9994

Danish Saleheen (D)

Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan. ds3792@cumc.columbia.edu.
Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. ds3792@cumc.columbia.edu.
Department of Cardiology, Columbia University Irving Medical Center, New York, NY, USA. ds3792@cumc.columbia.edu.
ORCID: 0000-0001-6193-020X

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Classifications MeSH

questionsmedicales.fr › Personnes › Nord-Américains › Groupes de population aux États-Unis › Populations d'origine continentale › Noir ou Africain Américain › Discovery of 318 new risk loci for type 2...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Chromosomes › Chromosomes sexuels › Chromosome X › Chromosomes X humains › Discovery of 318 new risk loci for type 2...
questionsmedicales.fr › Maladies endocriniennes › Diabète › Complications du diabète › Discovery of 318 new risk loci for type 2...
questionsmedicales.fr › Maladies endocriniennes › Diabète › Diabète de type 2 › Discovery of 318 new risk loci for type 2...
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questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Discovery of 318 new risk loci for type 2...
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