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

• Published in: The American Journal of Human Genetics
• 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 R B, Martin, Nicholas G, Stefánsson, Hreinn, Stefánsson, Kari, Boomsma, Dorret I
• Other Authors: 1 Free Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands 2 deCODE Genet, IS-101 Reykjavik, Iceland 3 Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia 4 QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia 5 Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA 6 Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia 7 Avera Inst Human Genet, Sioux Falls, SD 57108 USA 8 Wellcome Trust Ctr Human Genet, Oxford OX3 TBN, England 9 Vrije U Univ, Med Ctr GGZ inGeest, Dept Psychiat, NL-1081 HL Amsterdam, Netherlands 10 Vrije U Univ, Med Ctr GGZ inGeest, EMGO Inst Hlth & Care Res, NL-1081 HL Amsterdam, Netherlands 11 Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00014 Helsinki, Finland 12 Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland 13 Natl Inst Hlth & Welfare, Helsinki 00014, Finland 14 Kings Coll London, Med Res Council, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England 15 Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England 16 Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden 17 ASTAR, Lab Human Genet & Embryol, Inst Med Biol, Singapore 138648, Singapore 18 Acad Med Ctr, Amsterdam Reprod & Dev, Reprod Biol Lab Q3 119, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands 19 Baylor Coll Med, Div Maternal Fetal Med, Dept Obstet & Gynecol, Houston, TX 77030 USA 20 Baylor Coll Med, Div Maternal Fetal Med, Dept Mol & Human Genet, Houston, TX 77030 USA 21 Baylor Coll Med, Div Maternal Fetal Med, Dept Mol & Cell Biol, Houston, TX 77030 USA 22 Texas Childrens Hosp, Houston, TX 77030 USA 23 Landspitali Natl Univ Hosp Iceland, Dept Clin Biochem, IS-101 Reykjavik, Iceland 24 Iceland Med Ctr Laeknasetrid, Lab Mjodd RAM, IS-101 Reykjavik, Iceland 25 Akureyri Hosp, Dept Clin Biochem, IS-109 Akureyri, Iceland 26 Vrije Univ Amsterdam, Med Ctr, Dept Obstet Gynecol & Reprod Med, NL-1007 MB Amsterdam, Netherlands 27 Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 0QQ, England 28 EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands
• Format: Article in Journal/Newspaper
• Language: English
• Published: Cell Press 2016
• Subjects: Frjósemi; Konur; Tvíburar; MAB12; Fertility; Female; Twins; Dizygotic; Iceland
• Online Access: http://hdl.handle.net/2336/613063; https://doi.org/10.1016/j.ajhg.2016.03.008

To access publisher's full text version of this article click on the hyperlink at the bottom of the page 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.