title: Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility.
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.
authors.affiliation: 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.
authors.forename: Hamdi
authors.initials: H
authors.lastname: Mbarek
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Stacy
authors.initials: S
authors.lastname: Steinberg
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, 4059 Brisbane, Australia; QIMR Berghofer Medical Research Institute, 4029 Brisbane, Australia.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.affiliation: QIMR Berghofer Medical Research Institute, 4029 Brisbane, Australia.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gordon
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Miller
authors.affiliation: QIMR Berghofer Medical Research Institute, 4029 Brisbane, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Allan F
authors.initials: AF
authors.lastname: McRae
authors.affiliation: Department of Biological Psychology, Vrije Universiteit, 1081BT Amsterdam, the Netherlands; EMGO+ Institute for Health and Care Research, 1081BT Amsterdam, the Netherlands.
authors.forename: Jouke Jan
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: Felix R
authors.initials: FR
authors.lastname: Day
authors.affiliation: Department of Biological Psychology, Vrije Universiteit, 1081BT Amsterdam, the Netherlands; EMGO+ Institute for Health and Care Research, 1081BT Amsterdam, the Netherlands.
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.affiliation: Department of Biological Psychology, Vrije Universiteit, 1081BT Amsterdam, the Netherlands; EMGO+ Institute for Health and Care Research, 1081BT Amsterdam, the Netherlands.
authors.forename: Eco J
authors.initials: EJ
authors.lastname: de Geus
authors.affiliation: Avera Institute for Human Genetics, Sioux Falls, SD 57108, USA.
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Davies
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 TBN, UK.
authors.forename: Hilary C
authors.initials: HC
authors.lastname: Martin
authors.affiliation: Department of Psychiatry and EMGO Institute for Health and Care Research, Vrije U Universiteit, Medical Center/GGZ inGeest, 1081HL Amsterdam, the Netherlands.
authors.forename: Brenda W
authors.initials: BW
authors.lastname: Penninx
authors.affiliation: Department of Psychiatry and EMGO Institute for Health and Care Research, Vrije U Universiteit, Medical Center/GGZ inGeest, 1081HL Amsterdam, the Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Jansen
authors.affiliation: QIMR Berghofer Medical Research Institute, 4029 Brisbane, Australia.
authors.forename: Kerrie
authors.initials: K
authors.lastname: McAloney
authors.affiliation: Department of Biological Psychology, Vrije Universiteit, 1081BT Amsterdam, the Netherlands.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Vink
authors.affiliation: 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.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Plomin
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Patrik K
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
authors.affiliation: 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.
authors.forename: R Alan
authors.initials: RA
authors.lastname: Harris
authors.affiliation: 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.
authors.forename: Kjersti
authors.initials: K
authors.lastname: Aagaard
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Ragnar P
authors.initials: RP
authors.lastname: Kristjansson
authors.affiliation: Department of Clinical Biochemistry, Landspitali-The National University Hospital of Iceland, 101 Reykjavik, Iceland.
authors.forename: Isleifur
authors.initials: I
authors.lastname: Olafsson
authors.affiliation: Icelandic Medical Center (Laeknasetrid), Laboratory in Mjodd (RAM), 101 Reykjavik, Iceland.
authors.forename: Gudmundur Ingi
authors.initials: GI
authors.lastname: Eyjolfsson
authors.affiliation: Department of Clinical Biochemistry, Akureyri Hospital, 109 Akureyri, Iceland.
authors.forename: Olof
authors.initials: O
authors.lastname: Sigurdardottir
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Iacono
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Medicine, VU University Medical Center, 1007MB Amsterdam, the Netherlands.
authors.forename: Cornelis B
authors.initials: CB
authors.lastname: Lambalk
authors.affiliation: QIMR Berghofer Medical Research Institute, 4029 Brisbane, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: McGue
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: Ken K
authors.initials: KK
authors.lastname: Ong
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: John R B
authors.initials: JRB
authors.lastname: Perry
authors.affiliation: QIMR Berghofer Medical Research Institute, 4029 Brisbane, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefánsson
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefánsson
authors.affiliation: 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.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
mesh_terms: D001007:Anxiety / Q000235:genetics; D016022:Case-Control Studies; D003863:Depression / Q000235:genetics; D005190:Family; D005260:Female; D005298:Fertility / Q000235:genetics*; D005640:Follicle Stimulating Hormone / Q000097:blood; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009035:Mothers; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000235:genetics*; D011247:Pregnancy; D014429:Twins, Dizygotic / Q000235:genetics*
chemical_list: D005640:Follicle Stimulating Hormone