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. 2025 Jul;42(7):2231-2245.
doi: 10.1007/s10815-025-03515-4. Epub 2025 May 27.

Polygenic scores for dizygotic twinning: insights into the genetic architecture of female fertility

Nikki Hubers  1   2   3 , Christian M Page  4   5 , René Pool  6   7 , Hamdi Mbarek  6   8   9 , Nils Lambalk  8 , Velja Mijatovic  8 , Lannie Ligthart  6 , Jenny van Dongen  6   8   7 , Siri Håberg  10 , Elizabeth C Corfield  11 , Jeffrey J Beck  12 , Erik A Ehli  12 , Nicholas G Martin  13 , Gonneke Willemsen  6   8   14 , Jennifer R Harris  4 , Jouke-Jan Hottenga  9 , Dorret I Boomsma  8   15   7
Affiliations

Polygenic scores for dizygotic twinning: insights into the genetic architecture of female fertility

Nikki Hubers et al. J Assist Reprod Genet. 2025 Jul.

Abstract

Purpose: Natural dizygotic twinning (DZT) results from hyper-ovulation and is an indicator of female fertility. However, some traits linked to DZ twinning are also associated with infertility. We examined the relationship between DZT and female (in)fertility using recent GWAS findings.

Methods: We investigated the genetic architecture of DZT and compared polygenic scores (PGS) for DZT between mothers of naturally conceived DZ twin pregnancies and mothers who required fertility treatments (MAR) in the Netherlands Twin Register (NTR) and the Norwegian Mother, Father, and Child Cohort Study (MoBa). We also calculated genetic correlations between DZT and seven fertility related traits.

Results: DZT has a low polygenicity, with only 0.20% of SNPs estimated to have a nonzero effect. The DZT PGS explains 1.6% of variance in DZT liability, and we observe an odds ratio of 2.29 between the first and the tenth PGS deciles. The DZT PGS distinguishes between mothers of naturally conceived pregnancies and mothers who received MAR and is associated with a shorter time to pregnancy in mothers of singletons. The lowest PGSs were observed for mothers who received hormonal ovulation induction, indicating maternal fertility issues. DZT showed genetic correlations with anovulatory infertility (rg = - 0.698) and PCOS (rg = - 0.278), and endometriosis (rg = 0.279).

Conclusions: Female fertility appears to exists on a genetic spectrum, with anovulation/infertility at one end and DZT at the other. Results suggest that the DZT PGS can be of added value to evaluate female fertility and be incorporated in clinical practice in the future.

Keywords: Dizygotic twinning; Female fertility; Medically assisted reproduction (MAR); Polygenic scores (PGS).

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Conflict of interest statement

Declarations. Ethics approval: The study protocol was reviewed by the medical ethics review committee of the University Medical Centre of Amsterdam (IRB) (Numbers 2003/161 and 548 6565). The establishment of MoBa and initial data collection were based on a license from the Norwegian Data Protection Agency and approval from The Regional Committees for Medical and Health Research Ethics. The MoBa cohort is currently regulated by the Norwegian Health Registry Act. This study was approved by the Regional Committees for Medical and Health Research Ethics of South East Norway (#2017/1362). All participants provided written informed consent. Conflict of interest: The authors declare no competing interests. Web resources: GENESIS: https://github.com/yandorazhang/GENESIS SBayesS: https://cnsgenomics.com/software/gctb/ GWAS Catalog: DZT: 27132594. Endometriosis: 36914876.

Figures

Fig. 1
Fig. 1
The variance explained on the liability scale by the polygenic score (PGS) for dizygotic (DZT) twinning in 1635 cases and 2797 controls for each fraction of top SNPs from the 2024 DZT GWAS included in the PGS
Fig. 2
Fig. 2
Odds ratios for dizygotic twinning (DZT) in the 7178 Netherlands Twin Register (NTR) participants by PGS decile. Odds ratios and 95% confidence intervals were estimated with logistic regression for both A being of mother of a naturally conceived DZ twin and B being a mother of a DZ twin who conceived after medically assisted reproduction (MAR) treatments. The reported odds ratios are relative to the fifth decile. The points represent odds ratios, and the bars represent the lower and upper 95% CI of the odds ratios
Fig. 3
Fig. 3
The mean PGS for dizygotic (DZ) twinning in mothers of naturally conceived DZ, controls, and monozygotic (MZ) twins from the A and C Netherlands twin register (NTR) and B and D the Norwegian Mother, Children, and Father (MoBa) cohort study
Fig. 4
Fig. 4
The mean PGS for dizygotic (DZ) twinning in mothers of naturally conceived DZ twins and mothers from DZ twins that received medically assisted reproduction (MAR) treatments from A the Netherlands Twin Register (NTR) and B the Norwegian Mother, Children, and Father Cohort Study (MoBa)
Fig. 5
Fig. 5
The mean PGS of the DZ medically assisted reproduction (MAR) group of the NTR is further split between ovulation induction (OI) and IVF and ICSI
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