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Am J Hum Genet. 2016 May 5;98(5):898-908. doi: 10.1016/j.ajhg.2016.03.008. Epub 2016 Apr 28.

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

Author information

1
Department of Biological Psychology, Vrije Universiteit, 1081BT Amsterdam, the Netherlands; EMGO+ Institute for Health and Care Research, 1081BT Amsterdam, the Netherlands. Electronic address: h.mbarek@vu.nl.
2
deCODE Genetics, 101 Reykjavik, Iceland.
3
Institute of Health and Biomedical Innovation, Queensland University of Technology, 4059 Brisbane, Australia; QIMR Berghofer Medical Research Institute, 4029 Brisbane, Australia.
4
QIMR Berghofer Medical Research Institute, 4029 Brisbane, Australia.
5
Department of Psychology, University of Minnesota, Minneapolis, MN 55455, USA.
6
QIMR Berghofer Medical Research Institute, 4029 Brisbane, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
7
Department of Biological Psychology, Vrije Universiteit, 1081BT Amsterdam, the Netherlands; EMGO+ Institute for Health and Care Research, 1081BT Amsterdam, the Netherlands.
8
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
9
Avera Institute for Human Genetics, Sioux Falls, SD 57108, USA.
10
Wellcome Trust Centre for Human Genetics, Oxford OX3 TBN, UK.
11
Department of Psychiatry and EMGO Institute for Health and Care Research, Vrije U Universiteit, Medical Center/GGZ inGeest, 1081HL Amsterdam, the Netherlands.
12
Department of Biological Psychology, Vrije Universiteit, 1081BT Amsterdam, the Netherlands.
13
Institute for Molecular Medicine Finland FIMM, University of Helsinki; Department of Public Health, University of Helsinki; National Institute for Health and Welfare, 00014 Helsinki, Finland.
14
Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, UK.
15
Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK.
16
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 171 77 Stockholm, Sweden.
17
Institute of Medical Biology, Laboratory of Human Genetics and Embryology, A(∗)STAR, 138648 Singapore, Singapore; Amsterdam Reproduction & Development, Academic Medical Centre, Reproductive Biology Laboratory (Q3-119), Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Department of Obstetrics, Gynecology and Reproductive Medicine, VU University Medical Center, 1007MB Amsterdam, the Netherlands.
18
Division of Maternal-Fetal Medicine, Departments of Obstetrics and Gynecology, Molecular and Human Genetics, and Molecular and Cell Biology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
19
Department of Clinical Biochemistry, Landspitali-The National University Hospital of Iceland, 101 Reykjavik, Iceland.
20
Icelandic Medical Center (Laeknasetrid), Laboratory in Mjodd (RAM), 101 Reykjavik, Iceland.
21
Department of Clinical Biochemistry, Akureyri Hospital, 109 Akureyri, Iceland.
22
Department of Obstetrics, Gynecology and Reproductive Medicine, VU University Medical Center, 1007MB Amsterdam, the Netherlands.
23
Department of Biological Psychology, Vrije Universiteit, 1081BT Amsterdam, the Netherlands; EMGO+ Institute for Health and Care Research, 1081BT Amsterdam, the Netherlands. Electronic address: di.boomsma@vu.nl.

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.

Comment in

PMID:
27132594
PMCID:
PMC4863559
DOI:
10.1016/j.ajhg.2016.03.008
[Indexed for MEDLINE]
Free PMC Article

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