Variation in bone morphogenetic protein 15 is not associated with spontaneous human dizygotic twinning

Human Reproduction, Oct 2008

BACKGROUND Spontaneous dizygotic (DZ) twinning in humans is under genetic control. In sheep, heterozygous loss of function mutations in bone morphogenetic protein 15 (BMP15) increase ovulation and hence twinning rates. METHODS To investigate the role of BMP15 in human twinning, we typed 14 common variants, 4 rare novel variants initially detected by sequencing 279 mothers of DZ twins (MODZT) and 17 variants previously associated with premature ovarian failure (POF) in 933 DZ twinning families. We also typed five additional POF associated GDF9 variants. RESULTS There was some evidence for association between DZ twinning and a common intronic BMP15 variant (rs3897937), but this was not significant after correction for multiple testing. Three of the four novel variants (p.Pro174Ser, p.Ala311Thr and p.Arg392Thr) occurred in 1–5 MODZT but were not detected in 1512 controls. We also detected three POF associated mutations in both BMP15 and GDF9 at low frequencies in MODZT and controls. CONCLUSIONS We conclude that neither rare nor common BMP15 variants play a significant role in the variation in human DZ twinning.

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Variation in bone morphogenetic protein 15 is not associated with spontaneous human dizygotic twinning

Zhen Zhen Zhao 2 Jodie N. Painter 1 James S. Palmer 2 Penelope M. Webb 0 Nicholas K. Hayward 4 David C. Whiteman 0 Dorret I. Boomsma 3 Nicholas G. Martin 1 David L. Duffy 1 Grant W. Montgomery 2 0 Cancer and Population Studies, Queensland Institute of Medical Research , Brisbane , Australia 1 Genetic Epidemiology, Queensland Institute of Medical Research , Brisbane , Australia 2 Molecular Epidemiology, Queensland Institute of Medical Research, Royal Brisbane Hospital , 300 Herston Rd, Brisbane, QLD 4029 , Australia 3 Biological Psychology Department, Free University , Amsterdam , The Netherlands 4 Oncogenomics, Queensland Institute of Medical Research , Brisbane , Australia BACKGROUND: Spontaneous dizygotic (DZ) twinning in humans is under genetic control. In sheep, heterozygous loss of function mutations in bone morphogenetic protein 15 (BMP15) increase ovulation and hence twinning rates. METHODS: To investigate the role of BMP15 in human twinning, we typed 14 common variants, 4 rare novel variants initially detected by sequencing 279 mothers of DZ twins (MODZT) and 17 variants previously associated with premature ovarian failure (POF) in 933 DZ twinning families. We also typed five additional POF associated GDF9 variants. RESULTS: There was some evidence for association between DZ twinning and a common intronic BMP15 variant (rs3897937), but this was not significant after correction for multiple testing. Three of the four novel variants (p.Pro174Ser, p.Ala311Thr and p.Arg392Thr) occurred in 1 - 5 MODZT but were not detected in 1512 controls. We also detected three POF associated mutations in both BMP15 and GDF9 at low frequencies in MODZT and controls. CONCLUSIONS: We conclude that neither rare nor common BMP15 variants play a significant role in the variation in human DZ twinning. Introduction The transforming growth factor signalling pathway within the ovary is critical for the regulation of ovarian function, ovulation rate and fertility (Moore et al., 2004; Shimasaki et al., 2004). Two genes in this pathway are growth differentiation factor 9 (GDF9) on chromosome 5 and bone morphogenetic protein 15 (BMP15) on the X chromosome. Loss of function of Gdf9 in female mice blocks folliculogenesis during early follicle development and leads to infertility (McGrath et al., 1995). In sheep, the effects of mutations in both GDF9 and BMP15 are sensitive to copy number. Heterozygous mutations in both genes increase the frequency of twins and higher order multiples, whereas homozygous loss of function mutations results in ovarian dysgenesis and infertility (Galloway et al., 2000; Hanrahan et al., 2004). This pathway is also essential for human fertility (Di Pasquale et al., 2004). Two sisters with hypergonadotrophic ovarian failure due to ovarian dysgenesis were found to carry a nonconservative amino acid substitution in the pro region of BMP15 (p.Tyr235Cys) which acts in a dominant negative fashion by altering BMP15 processing (Di Pasquale et al., 2004). Rare variants in both BMP15 and GDF9 contribute to premature ovarian failure (POF) (Di Pasquale et al., 2004, 2006; Dixit et al., 2005, 2006; Laissue et al., 2006). Additionally, we found that some mothers of spontaneous dizygotic (DZ) twins (MODZT) carry rare deletions and missense mutations in the coding region of GDF9 that are significantly associated with twinning (Montgomery et al., 2004; Palmer et al., 2006). BMP15 is expressed in oocytes in several mammalian species (Laitinen et al., 1998; Galloway et al., 2000; Otsuka et al., 2000). The protein has six conserved cysteine residues characteristic of the TGFb superfamily, but lacks the additional cysteine residue that strengthens dimerization in other members of the bone morphogenetic protein family (Vitt et al., 2001). BMP15 stimulates granulosa cell proliferation (Otsuka et al., 2000), inhibits follicle-stimulating hormone receptor (FSHR) expression (Otsuka et al., 2001) and stimulates KIT ligand expression (Otsuka and Shimasaki, 2002). Five different heterozygous mutations in the coding region of BMP15 in different lines of sheep increase ovulation rate and litter size (McNatty et al., 2004). It is unknown if variants in BMP15 contribute to variation in human twinning. The human BMP15 sequence has a number of variants that alter the predicted protein sequence, including rs41308602 (c.308A.G) located in the second position of codon 103 of the preproprotein that changes the amino acid from an asparagine to a serine. We hypothesized that variation in BMP15 may contribute to the variation in human twinning and genotyped common variants identified from the literature and public databases in families of MODZT and controls. We also searched for rare variants by conducting a mutation screen of the coding region of the BMP15 gene in a subset of MODZT and typed these novel variants in additional families to determine whether these are associated with DZ twinning. Further, we typed rare BMP15 and GDF9 variants (...truncated)


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Zhen Zhen Zhao, Jodie N. Painter, James S. Palmer, Penelope M. Webb, Nicholas K. Hayward, David C. Whiteman, Dorret I. Boomsma, Nicholas G. Martin, David L. Duffy, Grant W. Montgomery. Variation in bone morphogenetic protein 15 is not associated with spontaneous human dizygotic twinning, Human Reproduction, 2008, pp. 2372-2379, 23/10, DOI: 10.1093/humrep/den268