Identification of common genetic variants influencing spontaneous dizygotic twinning and female fertility

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., Stefansson, Hreinn, Stefansson, Kari and Boomsman, Dorret I. (2016) Identification of common genetic variants influencing spontaneous dizygotic twinning and female fertility. American Journal of Human Genetics, 98 5: 898-908. doi:10.1016/j.ajhg.2016.03.008


Author 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.
Stefansson, Hreinn
Stefansson, Kari
Boomsman, Dorret I.
Title Identification of common genetic variants influencing spontaneous dizygotic twinning and female fertility
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 1537-6605
0002-9297
Publication date 2016-05-05
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2016.03.008
Open Access Status Not Open Access
Volume 98
Issue 5
Start page 898
End page 908
Total pages 11
Place of publication Cambridge, MA, United States
Publisher Cell Press
Collection year 2017
Language eng
Formatted 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.
Keyword Spontaneous dizygotic (DZ) twinning
DZ twinning
Female fertility
Common genetic variants
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
 
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