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

• Published in: Nature Genetics
• Main 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, Hansen, Torben, Daneshpour, Maryam S, Fallah, Mohammad-Sadegh, Hreidarsson, Astradur B, Sigurdsson, Gunnar, Azizi, Fereidoun, Benediktsson, Rafn, Masson, Gisli, Helgason, Agnar, Kong, Augustine, Gudbjartsson, Daniel F, Pedersen, Oluf, Thorsteinsdottir, Unnur, Stefansson, Kari
• Other Authors: deCODE Genet Amgen Inc, Reykjavik, Iceland Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, mark Steno Diabet Ctr, DK-2820 Gentofte, Denmark Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark Vejle Hosp, Dept Clin Biochem, Vejle, Denmark Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark Univ Aarhus, Sect Gen Practice, Dept Publ Hlth, Aarhus, Denmark Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark Aalborg Univ, Fac Med, Aalborg, Denmark Shahid Beheshti Univ Med Sci, Cellular & Mol Endocrine Res Ctr, Res Inst Endocrine Sci, Tehran, Natl Univ Hosp Iceland, Dept Endocrinol & Metab, Landspitali, Reykjavik, Iceland Shahid Beheshti Univ Med Sci, Res Inst Endocrine Sci, Endocrine Res Ctr, Tehran, Iran Univ Iceland, Dept Anthropol, Reykjavik, Iceland Univ Iceland, Fac Med, Reykjavik, Iceland
• Format: Article in Journal/Newspaper
• Language: English
• Published: Nature Publishing Group 2014
• Subjects: Amidine-Lyases; Body Height; Body Weight; Case-Control Studies; Cyclin D2; Denmark; Diabetes Mellitus; Type 2; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Homeodomain Proteins; Humans; Iceland; Iran; Male; Mixed Function Oxygenases; Polymorphism; Single Nucleotide; Risk Factors; Trans-Activators
• Online Access: http://hdl.handle.net/2336/324990; https://doi.org/10.1038/ng.2882

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. 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)). Lundbeck Foundation (Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp) Danish Council for Independent Research Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen Novo Nordisk Foundation