TY - JOUR
T1 - Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity
AU - El-Sayed Moustafa, Julia S
AU - Eleftherohorinou, Hariklia
AU - de Smith, Adam J
AU - Andersson-Assarsson, Johanna C
AU - Alves, Alexessander Couto
AU - Hadjigeorgiou, Eleni
AU - Walters, Robin G
AU - Asher, Julian E
AU - Bottolo, Leonardo
AU - Buxton, Jessica L
AU - Sladek, Rob
AU - Meyre, David
AU - Dina, Christian
AU - Visvikis-Siest, Sophie
AU - Jacobson, Peter
AU - Sjöström, Lars
AU - Carlsson, Lena M S
AU - Walley, Andrew
AU - Falchi, Mario
AU - Froguel, Philippe
AU - Blakemore, Alexandra I F
AU - Coin, Lachlan J M
PY - 2012/8/15
Y1 - 2012/8/15
N2 - 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.
AB - 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.
KW - Adipose Tissue
KW - Adult
KW - Case-Control Studies
KW - Child
KW - Chromosomes, Human, Pair 8
KW - Cohort Studies
KW - Dietary Fats
KW - Gene Expression Regulation
KW - Genetic Predisposition to Disease
KW - Guanine Nucleotide Exchange Factors
KW - Humans
KW - Minisatellite Repeats
KW - Obesity, Morbid
KW - Sequence Deletion
U2 - 10.1093/hmg/dds187
DO - 10.1093/hmg/dds187
M3 - Article
C2 - 22595969
SN - 0964-6906
VL - 21
SP - 3727
EP - 3738
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 16
ER -