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

• Main 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 RB, Martin, Nicholas G, Stefánsson, Hreinn, Stefánsson, Kari, Boomsma, Dorret I
• Format: Article in Journal/Newspaper
• Language: English
• Published: Elsevier BV 2016
• Subjects: Anxiety; Case-Control Studies; Depression; Family; Female; Fertility; Follicle Stimulating Hormone; Genetic Variation; Genome-Wide Association Study; Humans; Longitudinal Studies; Male; Mothers; Polycystic Ovary Syndrome; Pregnancy; Twins; Dizygotic; Iceland
• Online Access: https://www.repository.cam.ac.uk/handle/1810/256026

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. Support for the Netherlands Twin Register was obtained from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007); Royal Netherlands Academy of Science ...