Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes

Nat Genet. 2014 Mar;46(3):294-8. doi: 10.1038/ng.2882. Epub 2014 Jan 26.

Abstract

Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidine-Lyases / genetics*
  • Body Height / genetics
  • Body Weight / genetics
  • Case-Control Studies
  • Cyclin D2 / genetics*
  • Denmark
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome-Wide Association Study
  • Homeodomain Proteins / genetics*
  • Humans
  • Iceland
  • Iran
  • Male
  • Mixed Function Oxygenases / genetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Trans-Activators / genetics*

Substances

  • CCND2 protein, human
  • Cyclin D2
  • Homeodomain Proteins
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Mixed Function Oxygenases
  • PAM protein, human
  • Amidine-Lyases

Associated data

  • GEO/GPL3991
  • GEO/GSE7965