title: Structural and population-based evaluations of TBC1D1 p.Arg125Trp.
abstract: Obesity is now a leading cause of preventable death in the industrialised world. Understanding its genetic influences can enhance insight into molecular pathogenesis and potential therapeutic targets. A non-synonymous polymorphism (rs35859249, p.Arg125Trp) in the N-terminal TBC1D1 phosphotyrosine-binding (PTB) domain has shown a replicated association with familial obesity in women. We investigated these findings in the Avon Longitudinal Study of Parents and Children (ALSPAC), a large European birth cohort of mothers and offspring, and by generating a predicted model of the structure of this domain. Structural prediction involved the use of three separate algorithms; Robetta, HHpred/MODELLER and I-TASSER. We used the transmission disequilibrium test (TDT) to investigate familial association in the ALSPAC study cohort (N = 2,292 mother-offspring pairs). Linear regression models were used to examine the association of genotype with mean measurements of adiposity (Body Mass Index (BMI), waist circumference and Dual-energy X-ray absorptiometry (DXA) assessed fat mass), and logistic regression was used to examine the association with odds of obesity. Modelling showed that the R125W mutation occurs in a location of the TBC1D1 PTB domain that is predicted to have a function in a putative protein:protein interaction. We did not detect an association between R125W and BMI (mean per allele difference 0.27 kg/m(2) (95% Confidence Interval: 0.00, 0.53) P = 0.05) or obesity (odds ratio 1.01 (95% Confidence Interval: 0.77, 1.31, P = 0.96) in offspring after adjusting for multiple comparisons. Furthermore, there was no evidence to suggest that there was familial association between R125W and obesity (χ(2) = 0.06, P = 0.80). Our analysis suggests that R125W in TBC1D1 plays a role in the binding of an effector protein, but we find no evidence that the R125W variant is related to mean BMI or odds of obesity in a general population sample.
authors.affiliation: Bristol Genetic Epidemiology Laboratories, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom. Tom.G.Richardson@bristol.ac.uk
authors.forename: Tom G
authors.initials: TG
authors.lastname: Richardson
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Thomas
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sessions
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Tavaré
authors.forename: Ian N M
authors.initials: IN
authors.lastname: Day
mesh_terms: D050154:Adiposity / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics*; D015992:Body Mass Index; D002648:Child; D015331:Cohort Studies; D005190:Family; D005260:Female; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008958:Models, Molecular; D010641:Phenotype; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012984:Software; D040681:Structural Homology, Protein
chemical_list: D020690:GTPase-Activating Proteins; C526441:TBC1D1 protein, human