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Olle Melander

Principal investigator

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Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

Author

  • Richa Saxena
  • Clara C. Elbers
  • Yiran Guo
  • Inga Peter
  • Tom R. Gaunt
  • Jessica L. Mega
  • Matthew B. Lanktree
  • Archana Tare
  • Berta Almoguera Castillo
  • Yun R. Li
  • Toby Johnson
  • Marcel Bruinenberg
  • Diane Gilbert-Diamond
  • Ramakrishnan Rajagopalan
  • Benjamin F. Voight
  • Ashok Balasubramanyam
  • John Barnard
  • Florianne Bauer
  • Jens Baumert
  • Tushar Bhangale
  • Bernhard O. Boehm
  • Peter S. Braund
  • Paul R. Burton
  • Hareesh R. Chandrupatla
  • Robert Clarke
  • Rhonda M. Cooper-DeHoff
  • Errol D. Crook
  • George Davey-Smith
  • Ian N. Day
  • Anthonius de Boer
  • Mark C. H. de Groot
  • Fotios Drenos
  • Jane Ferguson
  • Caroline S. Fox
  • Clement E. Furlong
  • Quince Gibson
  • Christian Gieger
  • Lisa A. Gilhuijs-Pederson
  • Joseph T. Glessner
  • Anuj Goel
  • Yan Gong
  • Struan F. A. Grant
  • Diederick E. Grobbee
  • Claire Hastie
  • Steve E. Humphries
  • Cecilia E. Kim
  • Mika Kivimaki
  • Marcus Kleber
  • Christa Meisinger
  • Meena Kumari
  • Taimour Y. Langaee
  • Debbie A. Lawlor
  • Mingyao Li
  • Maximilian T. Lobmeyer
  • Anke-Hilse Maitland-van der Zee
  • Matthijs F. L. Meijs
  • Cliona M. Molony
  • David A. Morrow
  • Gurunathan Murugesan
  • Solomon K. Musani
  • Christopher P. Nelson
  • Stephen J. Newhouse
  • Jeffery R. O'Connell
  • Sandosh Padmanabhan
  • Jutta Palmen
  • Sanjey R. Patel
  • Carl J. Pepine
  • Mary Pettinger
  • Thomas S. Price
  • Suzanne Rafelt
  • Jane Ranchalis
  • Asif Rasheed
  • Elisabeth Rosenthal
  • Ingo Ruczinski
  • Sonia Shah
  • Haiqing Shen
  • Guenther Silbernagel
  • Erin N. Smith
  • Annemieke W. M. Spijkerman
  • Alice Stanton
  • Michael W. Steffes
  • Barbara Thorand
  • Mieke Trip
  • Pim van der Harst
  • Daphne L. van der A
  • Erik P. A. van Iperen
  • Jessica van Setten
  • Jana V. van Vliet-Ostaptchouk
  • Niek Verweij
  • Bruce H. R. Wolffenbuttel
  • Taylor Young
  • M. Hadi Zafarmand
  • Joseph M. Zmuda
  • Michael Boehnke
  • David Altshuler
  • Mark McCarthy
  • W. H. Linda Kao
  • James S. Pankow
  • Thomas P. Cappola
  • Peter Sever
  • Neil Poulter
  • Mark Caulfield
  • Anna Dominiczak
  • Denis C. Shields
  • Deepak L. Bhatt
  • Li Zhang
  • Sean P. Curtis
  • John Danesh
  • Juan P. Casas
  • Yvonne T. van der Schouw
  • N. Charlotte Onland-Moret
  • Pieter A. Doevendans
  • Gerald W. Dorn II
  • Martin Farrall
  • Garret A. FitzGerald
  • Anders Hamsten
  • Robert Hegele
  • Aroon D. Hingorani
  • Marten H. Hofker
  • Gordon S. Huggins
  • Thomas Illig
  • Gail P. Jarvik
  • Julie A. Johnson
  • Olaf H. Klungel
  • William C. Knowler
  • Wolfgang Koenig
  • Winfried Maerz
  • James B. Meigs
  • Olle Melander
  • Patricia B. Munroe
  • Braxton D. Mitchell
  • Susan J. Bielinski
  • Daniel J. Rader
  • Muredach P. Reilly
  • Stephen S. Rich
  • Jerome I. Rotter
  • Danish Saleheen
  • Nilesh J. Samani
  • Eric E. Schadt
  • Alan R. Shuldiner
  • Roy Silverstein
  • Kandice Kottke-Marchant
  • Philippa J. Talmud
  • Hugh Watkins
  • Folkert W. Asselbergs
  • Paul I. W. de Bakker
  • Jeanne McCaffery
  • Cisca Wijmenga
  • Marc S. Sabatine
  • James G. Wilson
  • Alex Reiner
  • Donald W. Bowden
  • Hakon Hakonarson
  • David S. Siscovick
  • Brendan J. Keating

Summary, in English

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.

Department/s

  • Cardiovascular Research - Hypertension
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year

2012

Language

English

Pages

410-425

Publication/Series

American Journal of Human Genetics

Volume

90

Issue

3

Document type

Journal article

Publisher

Cell Press

Topic

  • Medical Genetics

Status

Published

Research group

  • Cardiovascular Research - Hypertension

ISBN/ISSN/Other

  • ISSN: 0002-9297