Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes.
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)).
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Valgerdur
V
Steinthorsdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Gudmar
G
Thorleifsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Patrick
0000000171236123
P
Sulem
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Hannes
H
Helgason
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Niels
N
Grarup
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Asgeir
A
Sigurdsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Hafdis T
HT
Helgadottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Hrefna
H
Johannsdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Olafur T
OT
Magnusson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Sigurjon A
SA
Gudjonsson
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Johanne M
JM
Justesen
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Marie N
MN
Harder
Steno Diabetes Center, Gentofte, Denmark.
Marit E
ME
Jørgensen
Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark.
Cramer
C
Christensen
1] Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark. [2] Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
Ivan
I
Brandslund
Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark.
Annelli
A
Sandbæk
Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark.
Torsten
T
Lauritzen
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Henrik
H
Vestergaard
Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.
Allan
A
Linneberg
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.
Torben
T
Jørgensen
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Torben
T
Hansen
Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Maryam S
MS
Daneshpour
Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Mohammad-Sadegh
MS
Fallah
Department of Endocrinology and Metabolism, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
Astradur B
AB
Hreidarsson
Department of Endocrinology and Metabolism, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
Gunnar
G
Sigurdsson
Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Fereidoun
F
Azizi
Department of Endocrinology and Metabolism, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
Rafn
R
Benediktsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Gisli
G
Masson
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Department of Anthropology, University of Iceland, Reykjavik, Iceland.
Agnar
A
Helgason
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Augustine
A
Kong
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Daniel F
DF
Gudbjartsson
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Oluf
O
Pedersen
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Unnur
U
Thorsteinsdottir
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Kari
K
Stefansson
D019760:Amidine-Lyases / Q000235:genetics*; D001827:Body Height / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D016022:Case-Control Studies; D056742:Cyclin D2 / Q000235:genetics*; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007055:Iceland; D007492:Iran; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D015534:Trans-Activators / Q000235:genetics*
C080336:CCND2 protein, human; D056742:Cyclin D2; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D006899:Mixed Function Oxygenases; C544787:PAM protein, human; D019760:Amidine-Lyases