Journal
HUMAN MOLECULAR GENETICS
Volume 21, Issue 16, Pages 3727-3738Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds187
Keywords
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Funding
- Imperial College Department of Medicine
- Wellcome Trust [WT088431MA, 079534/z/06/z]
- European Commission [223367]
- Diabetes UK
- Caisse Nationale d'Assurance Maladies des Travailleurs Salaries (CNAM)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Region Lorraine
- Communaute Urbaine du Grand Nancy
- Universite de Lorraine
- BioIntelligence project
- Swedish Research Council [K2010-55X-11285-13]
- Swedish Foundation for Strategic Research
- Swedish Diabetes Foundation
- Swedish federal government
- Wellcome Trust [079534/Z/06/Z] Funding Source: Wellcome Trust
- MRC [G1002084] Funding Source: UKRI
- Diabetes UK [08/0003775] Funding Source: researchfish
- Medical Research Council [G1002084] Funding Source: researchfish
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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 approximate to 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.
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