Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility

Hamdi Mbarek, Stacy Steinberg, Dale R. Nyholt, Scott D. Gordon, Michael B. Miller, Allan F. McRae, Jouke Jan Hottenga, Felix R. Day, Gonneke Willemsen, Eco J. De Geus, Gareth E. Davies, Hilary C. Martin, Brenda W. Penninx, Rick Jansen, Kerrie McAloney, Jacqueline M. Vink, Jaakko Kaprio, Robert Plomin, Tim D. Spector, Patrik K. MagnussonBruno Reversade, R. Alan Harris, Kjersti Aagaard, Ragnar P. Kristjansson, Isleifur Olafsson, Gudmundur Ingi Eyjolfsson, Olof Sigurdardottir, William G. Iacono, Cornelis B. Lambalk, Grant W. Montgomery, Matt McGue, Ken K. Ong, John R B Perry, Nicholas G. Martin, Hreinn Stefánsson, Kari Stefánsson, Dorret I. Boomsma

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10-9, and rs17293443 in SMAD3, p = 1.57 × 10-8) and replicated (p = 3 × 10-3 and p = 1.44 × 10-4, respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.

Original languageEnglish (US)
Pages (from-to)898-908
Number of pages11
JournalAmerican Journal of Human Genetics
Volume98
Issue number5
DOIs
StatePublished - May 5 2016

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    Mbarek, H., Steinberg, S., Nyholt, D. R., Gordon, S. D., Miller, M. B., McRae, A. F., Hottenga, J. J., Day, F. R., Willemsen, G., De Geus, E. J., Davies, G. E., Martin, H. C., Penninx, B. W., Jansen, R., McAloney, K., Vink, J. M., Kaprio, J., Plomin, R., Spector, T. D., ... Boomsma, D. I. (2016). Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility. American Journal of Human Genetics, 98(5), 898-908. https://doi.org/10.1016/j.ajhg.2016.03.008