Ytterberg Karin, Sundelin Hedvig, Juodakis Julius, Vaudel Marc, Corfield Elizabeth C, Andreassen Ole A, Magnus Per, Havdahl Alexandra, Nilsson Staffan, Njolstad Pål R, Johansson Stefan, Jacobsson Bo, Solé-Navais Pol
Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway.
medRxiv. 2025 Jun 17:2025.06.17.25329777. doi: 10.1101/2025.06.17.25329777.
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). 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.
妊娠期长短和出生体重与母亲及其后代的短期和长期不良健康结局均有关联。以往针对这些妊娠结局的全基因组关联研究取得了成功，但却忽略了母亲既往怀孕的次数。在本研究中，我们利用挪威母亲、父亲和儿童队列研究中多达58528名母亲及其后代的数据，探究了产次（母亲既往生育孩子的数量）是否会改变妊娠期长短和出生体重的母体或胎儿遗传效应（基因×产次相互作用）。通过以下方式研究潜在的遗传效应差异：（1）进行按产次分层的全基因组关联研究；（2）检验单核苷酸多态性（SNP）×产次相互作用；（3）检验性状的多基因预测与产次之间的相互作用；（4）评估各结局在不同产次间的遗传相关性。对于这两种表型，我们在按产次分层的全基因组关联研究中，从遗传区域和数量方面确定了每个结局的共享和独特位点，并且所有结局按产次的遗传相关性均偏离了1。在母体基因组中，对于妊娠期长短，发现了产次对遗传修饰效应的最有力证据，即首次怀孕时的遗传效应比后续怀孕时更强。例如，母体基因组对妊娠期长短的多基因预测与产次存在显著相互作用（相互作用p值 = 5×10）。出生体重的结果更不确定，这表明所确定的基因×产次相互作用在很大程度上仅限于妊娠期长短。总之，我们的研究表明产次会改变对妊娠期长短的遗传效应，并突出了在妊娠结局的遗传研究中考虑产次的相关性。
