New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Josee Dupuis, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Nicole Soranzo, Anne U. Jackson, Eleanor Wheeler, Nicole L. Glazer, Nabila Bouatia-Naji, Anna L. Gloyn, Cecilia M. Lindgren, Reedik Magi, Andrew P. Morris, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Peter HennemanHarald Grallert, Abbas Dehghan, Jouke Jan Hottenga, Christopher S. Franklin, Pau Navarro, Kijoung Song, Anuj Goel, John R. B. Perry, Josephine M. Egan, Taina Lajunen, Niels Grarup, Thomas Sparso, Alex Doney, Benjamin F. Voight, Heather M. Stringham, Man Li, Stavroula Kanoni, Peter Shrader, Christine Cavalcanti-Proenca, Meena Kumari, Lu Qi, Nicholas J. Timpson, Yoav Ben-Shlomo, Ian N. M. Day, Paul R. V. Johnson, Mika Kivimaki, Debbie A. Lawlor, George Davey Smith, Lyle J. Palmer, Shah Ebrahim, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten Procardis Consortiu, MAGIC Investigators

Research output: Contribution to journalArticle (Academic Journal)peer-review

1481 Citations (Scopus)

Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Original languageEnglish
Pages (from-to)105-U32
Number of pages15
JournalNature Genetics
Volume42
Issue number2
DOIs
Publication statusPublished - Feb 2010

Keywords

  • GENOME-WIDE ASSOCIATION
  • BETA-CELL DYSFUNCTION
  • PLASMA-GLUCOSE
  • INSULIN-SECRETION
  • TRIGLYCERIDE LEVELS
  • ESSENTIAL COMPONENTS
  • MODEL ASSESSMENT
  • COMMON VARIANTS
  • CIRCADIAN CLOCK
  • DISEASE RISK

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