title: Variation in BMPR1B, TGFRB1 and BMPR2 and control of dizygotic twinning.
abstract: Genes in the TGF9 signaling pathway play important roles in the regulation of ovarian follicle growth and ovulation rate. Mutations in three genes in this pathway, growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and the bone morphogenetic protein receptor B 1 (BMPRB1), influence dizygotic (DZ) twinning rates in sheep. To date, only variants in GDF9 and BMP15, but not their receptors transforming growth factor ß receptor 1 (TGFBR1), bone morphogenetic protein receptor 2 (BMPR2) and BMPR1B, have been investigated with respect to their roles in human DZ twinning. We screened for rare and novel variants in TGFBR1, BMPR2 and BMPR1B in mothers of dizygotic twins (MODZT) from twin-dense families, and assessed association between genotyped and imputed variants and DZ twinning in another large sample of MODZT. Three novel variants were found: a deep intronic variant in BMPR2, and one intronic and one non-synonymous exonic variant in BMPRB1 which would result in the replacement of glutamine by glutamic acid at amino acid position 294 (p.Gln294Glu). None of these variants were predicted to have major impacts on gene function. However, the p.Gln294Glu variant changes the same amino acid as a sheep BMPR1B functional variant and may have functional consequences. Six BMPR1B variants were marginally associated with DZ twinning in the larger case-control sample, but these were no longer significant once multiple testing was taken into account. Our results suggest that variation in the TGF9 signaling pathway type II receptors has limited effects on DZ twinning rates in humans.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Hien T T
authors.initials: HT
authors.lastname: Luong
authors.forename: Justin
authors.initials: J
authors.lastname: Chaplin
authors.forename: Allan F
authors.initials: AF
authors.lastname: McRae
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.forename: Chantal
authors.initials: C
authors.lastname: Hoekstra
authors.forename: David L
authors.initials: DL
authors.lastname: Duffy
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Jodie N
authors.initials: JN
authors.lastname: Painter
mesh_terms: D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D004247:DNA / Q000032:analysis / Q000235:genetics; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction; D014429:Twins, Dizygotic / Q000235:genetics*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C498214:BMPR1B protein, human; C498218:BMPR2 protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human