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

Research output: Contribution to journalJournal articleResearchpeer-review

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 Jørgensen & 14 others Torben 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

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
Issue number3
Pages (from-to)294-300
Number of pages7
Publication statusPublished - 26 Jan 2014

ID: 97378188