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[Preprint]. 2025 Mar 5:2024.12.02.24318308.
doi: 10.1101/2024.12.02.24318308.

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

Polygenic Scores for Dizygotic Twinning: Insights into the Genetic Architecture of Female Fertility

Nikki Hubers et al. medRxiv. .

Update in

Abstract

Natural dizygotic twinning (DZT) results from hyper-ovulation and is considered an indicator of female fertility. DZT has low polygenicity, with only 0.20% of SNPs estimated to have a nonzero effect. A polygenic score (PGS) for DZT explains 1.6% of variance in DZT liability and we observe an odds ratio of 2.29 between the 1st and the 10th PGS decile. The PGS is higher in mothers of naturally conceived twins compared to mothers who received fertility (MAR) treatments in both the Netherlands and Norway. The largest differences were observed for mothers who received hormonal ovulation induction, indicating maternal fertility issues. A higher PGS was also linked to shorter time to pregnancy. DZT showed significant negative genetic correlations with anovulatory infertility (rg = -0.698) and PCOS (rg = -0.278), and a positive genetic correlation with endometriosis (rg = 0.279). These findings suggest DZT PGS is an important, yet under-recognized fertility marker.

Keywords: Dizygotic Twinning; Female Fertility; Medically Assisted reproduction (MAR); Polygenic Scores (PGS).

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Conflict of interest statement

Declaration of interest The authors declare no conflicts of interest.

Figures

Figure 1:
Figure 1:
The variance explained on the liability scale by the polygenic score (PGS) for dizygotic (DZT) twinning in 1,635 cases and 2,797 controls for each fraction of top SNPs from the 2024 DZT GWAS included in the PGS.
Figure 2:
Figure 2:
Odds ratios for dizygotic twinning (DZT) in the 7,178 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). 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.
Figure 3:
Figure 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. MAR = Medically assisted reproduction.
Figure 4:
Figure 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).
Figure 5:
Figure 5:
The mean PGS of the DZ MAR group of the NTR is further split between ovulation induction (OI) and remaining MAR treatments.
See this image and copyright information in PMC

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