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 Jørgensen; 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

doi:10.1038/ng.2882

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

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

Authors

Valgerdur Steinthorsdottir¹, Gudmar Thorleifsson¹, Patrick Sulem¹, Hannes Helgason², Niels Grarup³, Asgeir Sigurdsson¹, Hafdis T Helgadottir¹, Hrefna Johannsdottir¹, Olafur T Magnusson¹, Sigurjon A Gudjonsson¹, Johanne M Justesen³, Marie N Harder³, Marit E Jørgensen⁴, Cramer Christensen⁵, Ivan Brandslund⁶, Annelli Sandbæk⁷, Torsten Lauritzen⁷, Henrik Vestergaard³, Allan Linneberg⁸, Torben Jørgensen⁹, Torben Hansen³, Maryam S Daneshpour¹⁰, Mohammad-Sadegh Fallah¹⁰, Astradur B Hreidarsson¹¹, Gunnar Sigurdsson¹¹, Fereidoun Azizi¹², Rafn Benediktsson¹¹, Gisli Masson¹, Agnar Helgason¹³, Augustine Kong², Daniel F Gudbjartsson², Oluf Pedersen³, Unnur Thorsteinsdottir¹⁴, Kari Stefansson¹⁴

Affiliations

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.

PMID: 24464100
DOI: 10.1038/ng.2882

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)).

Publication types

Letter
Research Support, Non-U.S. Gov't

MeSH terms

Amidine-Lyases / genetics*
Body Height / genetics
Body Weight / genetics
Case-Control Studies
Cyclin D2 / genetics*
Denmark
Diabetes Mellitus, Type 2 / genetics*
Diabetes Mellitus, Type 2 / pathology
Female
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation*
Genome-Wide Association Study
Homeodomain Proteins / genetics*
Humans
Iceland
Iran
Male
Mixed Function Oxygenases / genetics*
Polymorphism, Single Nucleotide
Risk Factors
Trans-Activators / genetics*

Substances

CCND2 protein, human
Cyclin D2
Homeodomain Proteins
Trans-Activators
pancreatic and duodenal homeobox 1 protein
Mixed Function Oxygenases
PAM protein, human
Amidine-Lyases

Associated data

GEO/GPL3991
GEO/GSE7965