Parity modifies the effect of genetic variants associated with gestational duration and birth weight

Gestational duration and birth weight are linked to both short- and long-term adverse health outcomes in mothers and their offspring. Previous genome-wide association studies on these pregnancy outcomes have been successful but have overlooked the number of a mother's previous pregnancies. In this study, we explored if parity (the number of children a mother has previously delivered) modifies the maternal or foetal genetic effect of gestational duration and birth weight (gene × parity interactions) using data from the Norwegian Mother, Father, and Child Cohort Study in up to 58,528 mothers and their offspring. Potential genetic effect differences were investigated by: (1) performing parity-stratified genome-wide association studies, (2) testing SNP × parity interactions, (3) testing the interaction between a polygenic prediction of the traits and parity, and (4) assessing the genetic correlation within each outcome across parity. For both phenotypes, we identified shared and distinct loci for each outcome in terms both of genetic region and number in the parity-stratified genome-wide association studies, and the genetic correlation by parity deviated from one for all outcomes. The strongest evidence of genetic modification effect by parity was found for gestational duration in the maternal genome where genetic effects were stronger in the first pregnancy compared to later pregnancies. For instance, the polygenic prediction of the maternal genome on gestational duration had a significant interaction with parity (p-value interaction = 5 × 10^-5). The results for birth weight were more uncertain, suggesting that the identified gene × parity interactions is largely limited to gestational duration. In conclusion, our study reveals that parity modifies the genetic effects on gestational duration and highlights the relevance of considering parity in genetic studies on pregnancy outcomes.