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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Valgerdur Steinthorsdottir
  • Gudmar Thorleifsson
  • Patrick Sulem
  • Hannes Helgason
  • Niels Grarup
  • Asgeir Sigurdsson
  • Hafdis T Helgadottir
  • Hrefna Johannsdottir
  • Olafur T Magnusson
  • Sigurjon A Gudjonsson
  • Marie N Harder
  • Marit E Jørgensen
  • Cramer Christensen
  • Ivan Brandslund
  • Annelli Sandbæk
  • Torsten Lauritzen
  • Torben Jørgensen
  • Maryam S Daneshpour
  • Mohammad-Sadegh Fallah
  • Astradur B Hreidarsson
  • Gunnar Sigurdsson
  • Fereidoun Azizi
  • Rafn Benediktsson
  • Gisli Masson
  • Agnar Helgason
  • Augustine Kong
  • Daniel F Gudbjartsson
  • Unnur Thorsteinsdottir
  • Kari Stefansson
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)).
OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind46
Udgave nummer3
Sider (fra-til)294-300
Antal sider7
ISSN1061-4036
DOI
StatusUdgivet - 26 jan. 2014

ID: 97378188