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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

Lookup NU author(s): Professor Mark Walker


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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 x 10(-13); 6,647 case vs. 12,645 control subjects), higher disposition index (beta = 0.07 log10; P = 2 x 10(-11); n = 13,028), and higher Matsuda index of insulin sensitivity (beta = 0.02 10g10; P = 5 x 10(-3); n = 13,118) but not fasting proinsulin (beta = 0.01 log10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (beta = 1.38 cm; P = 6 x 10(-9) n = 13,927), but the association of the variant with BMI (beta = 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.

Publication metadata

Author(s): Yaghootkar H, Stancakova A, Freathy RM, Vangipurapu J, Weedon MN, Xie WJ, Wood AR, Ferrannini E, Mari A, Ring SM, Lawlor DA, Smith GD, Jorgensen T, Hansen T, Pedersen O, Steinthorsdottir V, Gudbjartsson DF, Thorleifsson G, Thorsteinsdottir U, Stefanssonn K, Hattersley AT, Walker M, Morris AD, McCarthy MI, Palmer CNA, Laakso M, Frayling TM

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2015

Volume: 64

Issue: 6

Pages: 2279-2285

Print publication date: 01/06/2015

Online publication date: 21/05/2015

Acceptance date: 13/01/2015

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association


DOI: 10.2337/db14-1456


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Funder referenceFunder name
Academy of Finland
Becket Foundation
Danish Centre for Health Technology Assessment
Danish Pharmaceutical Association
Ib Henriksen Foundation
Lundbeck Foundation
Ministry of Internal Affairs and Health
Novo Nordisk Foundation
PhD School of Molecular Metabolism
Research Foundation of Copenhagen County
Sigrid Juselius Foundation
University of Bristol
University of Eastern Finland
University of Southern Denmark
Augustinus Foundation
Copenhagen Graduate School of Health and Medical Sciences
Danish Agency for Science, Technology and Innovation
Danish Heart Foundation
Danish Research Council
Novo Nordisk Foundation Center for Basic Metabolic Research
072960/z/03/zWellcome Trust
085541/Z/08/ZWellcome Trust
092731Wellcome Trust
099177/z12/zWellcome Trust
323195European Research Council
SP/07 1008/24066
SZ-50371European Research Council