Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes.
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...
Published in: | Nature Genetics |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Other Authors: | |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Nature Publishing Group
2014
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Subjects: | |
Online Access: | http://hdl.handle.net/2336/324990 https://doi.org/10.1038/ng.2882 |
Summary: | 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 |
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