TY - JOUR
T1 - Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility
AU - Mbarek, Hamdi
AU - Steinberg, Stacy
AU - Nyholt, Dale R.
AU - Gordon, Scott D.
AU - Miller, Michael B.
AU - McRae, Allan F.
AU - Hottenga, Jouke Jan
AU - Day, Felix R.
AU - Willemsen, Gonneke
AU - De Geus, Eco J.
AU - Davies, Gareth E.
AU - Martin, Hilary C.
AU - Penninx, Brenda W.
AU - Jansen, Rick
AU - McAloney, Kerrie
AU - Vink, Jacqueline M.
AU - Kaprio, Jaakko
AU - Plomin, Robert
AU - Spector, Tim D.
AU - Magnusson, Patrik K.
AU - Reversade, Bruno
AU - Harris, R. Alan
AU - Aagaard, Kjersti
AU - Kristjansson, Ragnar P.
AU - Olafsson, Isleifur
AU - Eyjolfsson, Gudmundur Ingi
AU - Sigurdardottir, Olof
AU - Iacono, William G.
AU - Lambalk, Cornelis B.
AU - Montgomery, Grant W.
AU - McGue, Matt
AU - Ong, Ken K.
AU - Perry, John R.B.
AU - Martin, Nicholas G.
AU - Stefánsson, Hreinn
AU - Stefánsson, Kari
AU - Boomsma, Dorret I.
N1 - Generated from Scopus record by KAUST IRTS on 2023-02-15
PY - 2016/5/5
Y1 - 2016/5/5
N2 - 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.
AB - 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.
UR - https://linkinghub.elsevier.com/retrieve/pii/S000292971630043X
UR - http://www.scopus.com/inward/record.url?scp=84964614196&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2016.03.008
DO - 10.1016/j.ajhg.2016.03.008
M3 - Article
SN - 0002-9297
VL - 98
SP - 898
EP - 908
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -