title: Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion.
abstract: A recent study identified a low-frequency variant at CCND2 associated with lower risk of type 2 diabetes, enhanced insulin response to a glucose challenge, higher height, and, paradoxically, higher BMI. We aimed to replicate the strength and effect size of these associations in independent samples and to assess the underlying mechanism. We genotyped the variant in 29,956 individuals and tested its association with type 2 diabetes and related traits. The low-frequency allele was associated with a lower risk of type 2 diabetes (OR 0.53; P = 2 × 10(-13); 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log10; P = 2 × 10(-11); n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log10; P = 5 × 10(-3); n = 13,118) but not fasting proinsulin (β = 0.01 log10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (β = 1.38 cm; P = 6 × 10(-9); n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m(2); P = 0.02; n = 24,807), estimated in four population-based samples, was less than in the original publication where the effect estimate was biased by analyzing case subjects with type 2 diabetes and control subjects without diabetes separately. Our study establishes that a low-frequency allele in CCND2 halves the risk of type 2 diabetes primarily through enhanced insulin secretion.
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: University of Eastern Finland, Kuopio, Finland.
authors.forename: Alena
authors.initials: A
authors.lastname: Stancáková
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
authors.affiliation: University of Eastern Finland, Kuopio, Finland.
authors.forename: Jagadish
authors.initials: J
authors.lastname: Vangipurapu
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Weijia
authors.initials: W
authors.lastname: Xie
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Wood
authors.affiliation: CNR Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
authors.affiliation: CNR Institute of Biomedical Engineering, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Valgerdur
authors.initials: V
authors.lastname: Steinthorsdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Guðbjartsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.affiliation: Genetics of Diabetes, University of Exeter Medical School, Exeter, U.K.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, U.K.
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.affiliation: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K. National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K.
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.affiliation: University of Eastern Finland, Kuopio, Finland Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K. t.m.frayling@ex.ac.uk.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
mesh_terms: D000483:Alleles; D015992:Body Mass Index; D056742:Cyclin D2 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion
chemical_list: C080336:CCND2 protein, human; D056742:Cyclin D2; D007328:Insulin