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

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

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3727-3738
Number of pages12
JournalHuman Molecular Genetics
Volume21
Issue number16
DOIs
Publication statusPublished - 15 Aug 2012

Keywords

  • Adipose Tissue
  • Adult
  • Case-Control Studies
  • Child
  • Chromosomes, Human, Pair 8
  • Cohort Studies
  • Dietary Fats
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Minisatellite Repeats
  • Obesity, Morbid
  • Sequence Deletion

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