title: Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity.
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.
authors.affiliation: Department of Genomics of Common Disease, School of Public Health Inperial College, London, W12 ONN, UK.
authors.forename: Julia S
authors.initials: JS
authors.lastname: El-Sayed Moustafa
authors.forename: Hariklia
authors.initials: H
authors.lastname: Eleftherohorinou
authors.forename: Adam J
authors.initials: AJ
authors.lastname: de Smith
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Andersson-Assarsson
authors.forename: Alexessander Couto
authors.initials: AC
authors.lastname: Alves
authors.forename: Eleni
authors.initials: E
authors.lastname: Hadjigeorgiou
authors.forename: Robin G
authors.initials: RG
authors.lastname: Walters
authors.forename: Julian E
authors.initials: JE
authors.lastname: Asher
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bottolo
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Buxton
authors.forename: Rob
authors.initials: R
authors.lastname: Sladek
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.forename: Sophie
authors.initials: S
authors.lastname: Visvikis-Siest
authors.forename: Peter
authors.initials: P
authors.lastname: Jacobson
authors.forename: Lars
authors.initials: L
authors.lastname: Sjöström
authors.forename: Lena M S
authors.initials: LM
authors.lastname: Carlsson
authors.forename: Andrew
authors.initials: A
authors.lastname: Walley
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Alexandra I F
authors.initials: AI
authors.lastname: Blakemore
authors.forename: Lachlan J M
authors.initials: LJ
authors.lastname: Coin
mesh_terms: D000273:Adipose Tissue / Q000502:physiology; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002898:Chromosomes, Human, Pair 8; D015331:Cohort Studies; D004041:Dietary Fats; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D018598:Minisatellite Repeats; D009767:Obesity, Morbid / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D004041:Dietary Fats; C578026:Dock5 protein, human; D020662:Guanine Nucleotide Exchange Factors