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Nat Genet. 2014 Mar;46(3):294-8. doi: 10.1038/ng.2882. Epub 2014 Jan 26.

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

Author information

1
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
2
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
3
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
4
Steno Diabetes Center, Gentofte, Denmark.
5
Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark.
6
1] Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark. [2] Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
7
Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark.
8
Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.
9
1] Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. [2] Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [3] Faculty of Medicine, University of Aalborg, Aalborg, Denmark.
10
Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
11
Department of Endocrinology and Metabolism, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
12
Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
13
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Department of Anthropology, University of Iceland, Reykjavik, Iceland.
14
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

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)).

PMID:
24464100
DOI:
10.1038/ng.2882
[Indexed for MEDLINE]

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