Abstract
Natural dizygotic twinning (DZT) results from hyper-ovulation and is often considered an indicator of female fertility. Paradoxically, DZT is associated with factors linked to sub-fertility, such as advanced maternal age. We investigated the association between DZT and female fertility by comparing polygenic scores (PGS) for DZT in mothers of twins and singletons who conceived naturally versus those who conceived after medically assisted reproduction (MAR). We also estimated genetic correlations between DZT and other fertility-related traits.
Using GENESIS and SbayesS, we found that DZT is not highly polygenic, with about 0.20% of SNPs showing a nonzero effect and 17 SNPs contributing to 17.2% of the total predicted SNP heritability of 7.2%. We calculated PGSs for 4,381 twin mothers and 2,797 fathers of twins in the Netherlands Twin Register (NTR) and 1,299 twin mothers versus 64,810 singleton mothers in the Norwegian Mother, Father, and Child Cohort Study (MoBa). The PGS for DZT captured 1.60% of the variance in DZT liability. PGSs were higher in mothers of naturally conceived twins compared to those with MAR-conceived twins, especially for mothers who used hormonal ovulation induction and higher PGSs were associated with a shorted time to pregnancy. High genetic correlations were observed between DZT and anovulatory infertility (rg = -0.698, p = 5.099x10-5), PCOS (rg = -0.278, p = 0.035), and endometriosis (rg = 0.279, p = 0.003).
These findings suggest that the PGS for DZT is a valuable, under-recognized marker of female fertility, meriting further exploration within fertility research to improve reproductive health insights.
Competing Interest Statement
Erik A. Ehli and Jeffery J. Beck were employed by the Avera Institute for Human Genetics (Sioux Falls, SD, USA). The remaining authors declare no conflicts of interest.
Funding Statement
We warmly thank all participant of the NTR and MoBa and all previous employees who contributed to the data collection and preparation.NH is supported by the Royal Netherlands Academy of Science Professor Award (PAH/6635)to DIB. JvD is supported by Netherlands Organization for Scientific Research (NWO) Large Scale infrastructures, X-omics (184.034.019). The NTR is supported by multiple grants from the NWO and Medical Research (ZonMW): NTR Repository (NWO 480-15-001/674); CID Gravitation Program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO 0240-001-003). Genetic influences on stability and change in psychopathology from childhood to young adulthood (ZonMw 912-10-020); Twin family database for behavior genomics studies (NWO 480-04-004); Twin research focusing on behavior (NWO 400-05-717); the European Science Council (ERC) Genetics of Mental Illness (ERC Advanced, 230374); Developmental trajectories of psychopathology (NIMH 1RC2 MH089995).This work was partly funded by the Research Council of Norway (320656) and through its Centres of Excellence funding scheme (262700; CMP, SEH and JRH). We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (223273), South East Norway Versjon 7.0 3 Health Authorities and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities. The Norwegian Mother, Father, and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families who take part in this ongoing cohort study.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
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).This study was approved by the Regional Committees for Medical and Health Research Ethics of South East Norway (#2017/1362).
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Data and code availability
The data of the NTR may be requested through the NTR data access committee (https://tweelingenregister.vu.nl/information_for_researchers/working-with-ntr-data). Data from the MoBa and the MBRN used in this study are managed by the national health register holders in Norway (Norwegian Institute of public health) and can be made available to researchers, provided approval from the Regional Committees for Medical and Health Research Ethics (REC), compliance with the EU General Data Protection Regulation (GDPR) and approval from the data owners. The consent given by the participants does allow storage of data on an individual level in repositories or journals. Researchers who want access to data sets for replication should apply through www.helsedata.no. Access to data sets requires approval from The Regional Committee for Medical and Health Research Ethics in Norway and an agreement with MoBa. All code can be mase available from the corresponding author on request.