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- Title
Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes.
- Authors
Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Sulem, Patrick; Helgason, Hannes; Grarup, Niels; Sigurdsson, Asgeir; Helgadottir, Hafdis T; Johannsdottir, Hrefna; Magnusson, Olafur T; Gudjonsson, Sigurjon A; Justesen, Johanne M; Harder, Marie N; Jørgensen, Marit E; Christensen, Cramer; Brandslund, Ivan; Sandbæk, Annelli; Lauritzen, Torsten; Vestergaard, Henrik; Linneberg, Allan; Jørgensen, Torben
- 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/m2 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).
- Subjects
CARBOHYDRATE intolerance; BODY mass index; TYPE 2 diabetes; ICELANDERS; GENETICS
- Publication
Nature Genetics, 2014, Vol 46, Issue 3, p294
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.2882