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

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.