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

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Authors
Mbarek, Hamdi
Steinberg, Stacy
Nyholt, Dale R
Gordon, Scott D
Miller, Michael B
McRae, Allan F
Hottenga, Jouke Jan
Day, Felix R
Willemsen, Gonneke
de Geus, Eco J
Davies, Gareth E
Martin, Hilary C
Penninx, Brenda W
Jansen, Rick
McAloney, Kerrie
Vink, Jacqueline M
Kaprio, Jaakko
Plomin, Robert
Spector, Tim D
Magnusson, Patrik K
Reversade, Bruno
Harris, R Alan
Aagaard, Kjersti
Kristjansson, Ragnar P
Olafsson, Isleifur
Eyjolfsson, Gudmundur Ingi
Sigurdardottir, Olof
Iacono, William G
Lambalk, Cornelis B
Montgomery, Grant W
McGue, Matt
Ong, Ken K
Perry, John R B
Martin, Nicholas G
Stefánsson, Hreinn
Stefánsson, Kari
Boomsma, Dorret I
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Issue Date
2016-05-05

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Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility. 2016, 98 (5):898-908 Am. J. Hum. Genet.
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.
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Additional Links
http://dx.doi.org/ 10.1016/j.ajhg.2016.03.008
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Archived with thanks to American journal of human genetics
ae974a485f413a2113503eed53cd6c53
10.1016/j.ajhg.2016.03.008
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