Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Angli Xue(The University of Queensland), Yang Wu(The University of Queensland), Zhihong Zhu(The University of Queensland), Futao Zhang(The University of Queensland), Kathryn E. Kemper(The University of Queensland), Zhili Zheng(The University of Queensland), Loïc Yengo(The University of Queensland), Luke R. Lloyd‐Jones(The University of Queensland), Julia Sidorenko(The University of Queensland), Yeda Wu(The University of Queensland), Mawussé Agbessi(Ontario Institute for Cancer Research), Habibul Ahsan(Chicago Department of Public Health), Isabel Alves(Ontario Institute for Cancer Research), Anand Kumar Andiappan(Agency for Science, Technology and Research), Philip Awadalla(Ontario Institute for Cancer Research), Alexis Battle(Johns Hopkins University), Frank Beutner(Leipzig Heart Institute), Marc Jan Bonder(University Medical Center Groningen), Dorret I. Boomsma(Vrije Universiteit Amsterdam), Mark Christiansen(University of Washington), Annique Claringbould(University Medical Center Groningen), Patrick Deelen(University Medical Center Groningen), Tõnu Esko(University of Tartu), Marie-Julie Favé(Ontario Institute for Cancer Research), Lude Franke(University Medical Center Groningen), Timothy M. Frayling(University of Exeter), Sina A. Gharib(University of Washington), Gregory Gibson(Georgia Institute of Technology), Gibran Hemani(University of Bristol), Rick Jansen(Vrije Universiteit Amsterdam), Mika Kähönen(Tampere University), Anette Kalnapenkis(University of Tartu), Silva Kasela(University of Tartu), Johannes Kettunen(University of Helsinki), Yungil Kim(Johns Hopkins University), Holger Kirsten(Leipzig University), Péter Kovács(IFB Adiposity Diseases), Knut Krohn(Leipzig University), Jaanika Kronberg-Guzman(University of Tartu), Viktorija Kukushkina(University of Tartu), Zoltán Kutalik(University of Lausanne), Bernett Lee(Agency for Science, Technology and Research), Terho Lehtimäki(Tampere University), Markus Loeffler(Leipzig University), Urko M. Marigorta(Georgia Institute of Technology), Andres Metspalu(University of Tartu), Lili Milani(University of Tartu), Martina Müller‐Nurasyid(Helmholtz Zentrum München), Matthias Nauck(Universitätsmedizin Greifswald), Michel G. Nivard(Vrije Universiteit Amsterdam), Brenda W.J.H. Penninx(Vrije Universiteit Amsterdam), Markus Perola(University of Helsinki), Natalia Pervjakova(University of Tartu), Brandon L. Pierce(Chicago Department of Public Health), Joseph E. Powell(The University of Queensland), Holger Prokisch(Helmholtz Zentrum München), Bruce M. Psaty(University of Washington), Olli T. Raitakari(University of Turku), Susan M. Ring(University of Bristol), Samuli Ripatti(University of Helsinki), Olaf Rötzschke(Agency for Science, Technology and Research), Sina Rüeger(University of Lausanne), Ashis Saha(Johns Hopkins University), Markus Scholz(Leipzig University), Katharina Schramm(Helmholtz Zentrum München), Ilkka Seppälä(Tampere University), Michael Stümvoll(IFB Adiposity Diseases), Patrick Sullivan(Karolinska Institutet), Alexander Teumer(Universitätsmedizin Greifswald), Joachim Thiery(Leipzig University), Tong Lin(Chicago Department of Public Health), Anke Tönjes(Leipzig University), Jenny van Dongen(Vrije Universiteit Amsterdam), Joyce B. J. van Meurs(Erasmus University Rotterdam), Joost Verlouw(Erasmus University Rotterdam), Uwe Völker(Universitätsmedizin Greifswald), Urmo Võsa(University Medical Center Groningen), Hanieh Yaghootkar(University of Exeter), Biao Zeng(Georgia Institute of Technology), Allan F. McRae(The University of Queensland), Peter M. Visscher(The University of Queensland), Jian Zeng(The University of Queensland), Jian Yang(The University of Queensland)
Nature Communications
July 23, 2018
10.1038/s41467-018-04951-w
Cited by 1,015Open Access
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Abstract

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.

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