Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Robert A Scott, Vasiliki Lagou, Ryan P Welch, Eleanor Wheeler, May E Montasser, Jian'an Luan, Reedik Mägi, Rona J Strawbridge, Emil Rehnberg, Stefan Gustafsson, Stavroula Kanoni, Laura J Rasmussen-Torvik, Loïc Yengo, Cecile Lecoeur, Dmitry Shungin, Serena Sanna, Carlo Sidore, Paul C D Johnson, J Wouter Jukema, Toby JohnsonAnubha Mahajan, Niek Verweij, Gudmar Thorleifsson, Jouke-Jan Hottenga, Sonia Shah, Albert V Smith, Bengt Sennblad, Christian Gieger, Perttu Salo, Markus Perola, Nicholas J Timpson, David M Evans, Beate St Pourcain, Ying Wu, Jeanette S Andrews, Jennie Hui, Lawrence F Bielak, Wei Zhao, Momoko Horikoshi, Pau Navarro, Aaron Isaacs, Jeffrey R O'Connell, Kathleen Stirrups, Veronique Vitart, Caroline Hayward, Tõnu Esko, Evelin Mihailov, Ross M Fraser, Tove Fall, Benjamin F Voight, DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Original languageEnglish
Pages (from-to)991-1005
Number of pages15
JournalNature Genetics
Volume44
Issue number9
DOIs
Publication statusPublished - Sep 2012
Externally publishedYes

Keywords

  • Adult
  • Animals
  • Blood Glucose/genetics
  • Fasting/blood
  • Female
  • Gene Frequency
  • Genome-Wide Association Study/statistics & numerical data
  • Humans
  • Insulin/blood
  • Male
  • Metabolic Networks and Pathways/genetics
  • Mice
  • Osmolar Concentration
  • Quantitative Trait Loci/physiology

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