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Stone  et al . previously reported an association between the  TBC1D1  gene variant R125W (rs35859249) and severe obesity in women from US pedigrees. We attempted to replicate this result in 9714 French Caucasian individuals, combining family-based and general population studies. We confirmed an association with familial obesity (defined as body mass index (BMI) ≥ 97th percentile) in women from 1109 obesity-selected pedigrees (Z-score = 2.70,  P  = 0.008). Analysis of 16 microsatellite markers on chromosome 4 restricted to the 42 pedigrees carrying the  TBC1D1  R125W variant allele also revealed a suggestive evidence of linkage with obesity (maximum likelihood binomial LOD of 2.73,  P  = 0.0002) on chromosome 4p14, where resides  TBC1D1 . In contrast, R125W variant was neither associated with BMI nor with obesity in a large population-based cohort. These results confirm a putative role of  TBC1D1  R125W variant in familial obesity predisposition.

R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population