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

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Hanieh Yaghootkar, Alena Stancáková, Rachel M Freathy, Jagadish Vangipurapu, Michael N Weedon, Weijia Xie, Andrew R Wood, Ele Ferrannini, Andrea Mari, Susan M Ring, Debbie A Lawlor, George Davey Smith, Torben Jørgensen, Torben Hansen, Oluf Pedersen, Valgerdur Steinthorsdottir, Daniel F Guðbjartsson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari Stefansson & 7 others Andrew T Hattersley, Mark Walker, Andrew D Morris, Mark I McCarthy, Colin N A Palmer, Markku Laakso, Timothy M Frayling

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/m2; 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.
Original languageEnglish
Issue number6
Pages (from-to)2279-85
Number of pages7
Publication statusPublished - Jun 2015

    Research areas

  • Alleles, Body Mass Index, Cyclin D2, Diabetes Mellitus, Type 2, Gene Frequency, Genotype, Humans, Insulin

ID: 150711521