Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity

Authors: El-Sayed Moustafa, Julia S.; Eleftherohorinou, Hariklia; de Smith, Adam J.; Andersson-Assarsson, Johanna C.; Couto Alves, Alexessander; Hadjigeorgiou, Eleni; Walters, Robin G.; Asher, Julian E.; Bottolo, Leonardo; Buxton, Jessica L.; Sladek, Rob; Meyre, David; Dina, Christian; Visvikis-Siest, Sophie; Jacobson, Peter; Sjöström, Lars; Carlsson, Lena M.S.; Walley, Andrew; Falchi, Mario; Froguel, Philippe; Blakemore, Alexandra I.F.; Coin, Lachlan J.M.

Source: Human Molecular Genetics, Volume 21, Number 16, 15 August 2012 , pp. 3727-3738(12)

Publisher: Oxford University Press

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Abstract:

Variable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (P_empirical= 8.9 × 10⁻⁸ and P= 3.1 × 10⁻³, respectively) which we estimate explains ∼0.8% of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46% of the variance (P_combined= 1.6 × 10⁻³). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P= 0.027) and both VNTRs (P_empirical= 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies.

Document Type: Research article

DOI: http://dx.doi.org/10.1093/hmg/dds187

Publication date: 2012-08-15

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Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity

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