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

Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Patrick Sulem, Hannes Helgason, Niels Grarup, Asgeir Sigurdsson, Hafdis T. Helgadottir, Hrefna Johannsdottir, Olafur T. Magnusson, Sigurjon A. Gudjonsson, Johanne M. Justesen, Marie N. Harder, Marit E. Jørgensen, Cramer Christensen, Ivan Brandslund, Annelli Sandbæk, Torsten Lauritzen, Henrik Vestergaard, Allan Linneberg, Torben JørgensenTorben Hansen, Maryam S. Daneshpour, Mohammad Sadegh Fallah, Astradur B. Hreidarsson, Gunnar Sigurdsson, Fereidoun Azizi, Rafn Benediktsson, Gisli Masson, Agnar Helgason, Augustine Kong, Daniel F. Gudbjartsson, Oluf Pedersen, Unnur Thorsteinsdottir*, Kari Stefansson

*Corresponding author for this work

Research output: Contribution to journalLetterpeer-review

240 Citations (Scopus)

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).

Original languageEnglish
JournalNature Genetics
Volume46
Issue number3
Pages (from-to)294-298
Number of pages5
ISSN1061-4036
DOIs
Publication statusPublished - 1 Jan 2014

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