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

El-Sayed Moustafa, J.S., Eleftherohorinou, H., De Smith, A.J., Andersson-Assarsson, J.C., Couto Alves, A., Hadjigeorgiou, E., Walters, R.G., Asher, J.E., Bottolo, L., Buxton, J.L., Sladek, R., Meyre, D., Dina, C., Visvikis-Siest, S., Jacobson, P., Sjöström, L., Carlsson, L.M., Walley, A., Falchi, M., Froguel, P., Blakemore, A.I. and Coin, L.J. (2012) Novel association approach for variable number tandem repeats (VNTR) identifies DOCK5 as a susceptibility gene for severe obesity. Human Molecular Genetics, 21 (16), 3727–3738. (doi:10.1093/hmg/dds187).

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 (Pempirical= 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 (Pcombined= 1.6 × 10−3). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P= 0.027) and both VNTRs (Pempirical= 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.

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Contributors

Author: A. Couto Alves

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