P-519 Polygenic scores for DZ twinning in mothers of naturally and ART conceived twins and singletons
Authors: Hubers N , Page C , Pool R , Ligthart L , Mbarek H , Hottenga J  J , Lambalk N , Håberg S , Ehli E , Willemsen G , Harris J , Van Dongen J , Boomsma D ,   I. Twinning Genetics Consortium
Published: July 2024

Abstract

Study question
Does the polygenetic score (PGS) of dizygotic (DZ) twinning differ among mothers of naturally conceived DZ twins and mothers of ART twins, or singleton mothers?

Summary answer
Mothers of naturally conceived DZ twins have the highest PGS for DZ twinning, while mothers who received hormonal induction of ovulation have the lowest PGS.

What is known already
Natural DZ twinning results from a double ovulation and has a genetic component. Endocrinology studies in mothers of DZ twins observed higher levels of follicle-stimulating hormone (FSH). FSHB and SMAD3 were the first loci identified as significant in genome-wide association studies (GWAS) of having DZ twins. The GWAS also showed a genetic correlation with anovulatory infertility and a PGS that explained ∼1.5% of the phenotypic variance when comparing mothers of naturally conceived DZ twins to controls. As DZ twinning has been proposed to be a measure of female fertility, we hypothesise that a low PGS could indicate infertility.

Study design, size, duration
We compare the DZ twinning PGS in mothers of naturally conceived DZ twins with other mothers in the Netherlands twin register (NTR) and the Norwegian Mother, Father and Child Cohort Study (MoBa). We tested if the PGS is lower in infertility groups (ART use). We included 1,677 cases, 2,828 other twin mothers and 2,686 controls from the NTR and 396 cases, 1,285 twin mothers and 74,613 singleton mothers from MoBa.

Participants/materials, setting, methods
We calculated PGSs of DZ twinning for all participants employing LDPred0.9 based on the summary statistics from the 2024 GWAS (Mbarek et al., 2024). Differences between groups were assessed by logistic regression, with corrections for relatedness, maternal age, maternal age at first birth, BMI, height, parity and technical covariates.

Main results and the role of chance
Mothers of naturally conceived DZ twins differed in age, body composition, parity and smoking behaviour compared to the other groups. The PGSs were higher in mothers of naturally conceived DZ twins (N = 1,677) compared to all other twin mothers, including mothers of naturally conceived MZ twins (N = 2,165) and mothers who conceived MZ (N = 64) or DZ twins through ART (N = 559) and compared to controls (N = 2,686; p &lt; 0.01). For ART mothers whose fertility treatment involved hormones without IVF (N = 257), the PGS was significantly lower than for the other three groups (DZ-IVF and MZ mothers). In MoBA, we replicate our findings of the higher PGSs for mothers who naturally conceived their DZ twin pregnancy (N = 705) compared to mothers of naturally conceived MZ twins (N = 313) and mothers who conceived their DZ twins through ATR (N = 328) (p &lt; 0.05). However, we do not observe differences between the mothers of naturally conceived DZ twins and the mothers of ART MZ twins in MoBa. We are currently adding analysis comparing the mothers of naturally conceived DZ with mothers who naturally or through ART conceived singletons.

Limitations, reasons for caution
In interpreting our results we should consider that the MZ ART groups are relatively small. Also, we did not have information on the reasons for ART use so we could not distinguish between maternal, paternal or couple fertility issues.

Wider implications of the findings
Mothers of naturally conceived DZ twins are genetically different from other mothers. Genetic influences found for DZ twinning mainly affect multiple ovulation, rather than other characteristics required for a twin pregnancy. The DZ twinning PGS may be associated with infertility.

Trial registration number
not applicable