title: TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition.
abstract: The molecular etiology of obesity predisposition is largely unknown. Here, we present evidence that genetic variation in TBC1D1 confers risk for severe obesity in females. We identified a coding variant (R125W) in TBC1D1 that segregated with the disease in 4p15-14-linked obesity pedigrees. In cases derived from pedigrees with the strongest linkage evidence, the variant was significantly associated with obesity (P=0.000007) and chromosomes carrying R125W accounted for the majority of the evidence that originally linked 4p15-14 with the disease. In addition, by selecting families that segregated R125W with obesity, we were able to generate highly significant linkage evidence for an obesity predisposition locus at 4q34-35. This result provides additional and confirming evidence that R125W affects obesity susceptibility, delimits the location of an obesity gene at 4q34-35 and identifies a gene/gene interaction that influences the risk for obesity predisposition. Finally, although the function of TBC1D1 is unknown, the protein is structurally similar to a known regulator of insulin-mediated Glut4 translocation.
authors.affiliation: Myriad Genetics, Inc., Salt City, UT 84108, USA. sstone@myriad.com
authors.forename: Steven
authors.initials: S
authors.lastname: Stone
authors.forename: Victor
authors.initials: V
authors.lastname: Abkevich
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Russell
authors.forename: Robyn
authors.initials: R
authors.lastname: Riley
authors.forename: Kirsten
authors.initials: K
authors.lastname: Timms
authors.forename: Thanh
authors.initials: T
authors.lastname: Tran
authors.forename: Deborah
authors.initials: D
authors.lastname: Trem
authors.forename: David
authors.initials: D
authors.lastname: Frank
authors.forename: Srikanth
authors.initials: S
authors.lastname: Jammulapati
authors.forename: Chris D
authors.initials: CD
authors.lastname: Neff
authors.forename: Diana
authors.initials: D
authors.lastname: Iliev
authors.forename: Richard
authors.initials: R
authors.lastname: Gress
authors.forename: Gongping
authors.initials: G
authors.lastname: He
authors.forename: Georges C
authors.initials: GC
authors.lastname: Frech
authors.forename: Ted D
authors.initials: TD
authors.lastname: Adams
authors.forename: Mark H
authors.initials: MH
authors.lastname: Skolnick
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Lanchbury
authors.forename: Alexander
authors.initials: A
authors.lastname: Gutin
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.forename: Donna
authors.initials: D
authors.lastname: Shattuck
mesh_terms: D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D009765:Obesity / Q000209:etiology / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D043222:Ubiquitin Thiolesterase
chemical_list: D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D010450:Endopeptidases; C473330:USP6 protein, human; D043222:Ubiquitin Thiolesterase