Time-varying effects are common in genetic control of gestational duration

Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent-gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31 000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy 'clock'. We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new fetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm, periods and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant and should help design further experimental studies.

Automated summary

Preterm birth is a global burden to neonatal health, influenced by genetics. This study investigates the timing and clinical importance of genes associated with gestational duration or preterm birth using genotyping data from the Norwegian Mother, Father and Child cohort. The research identifies several known maternal associations and a new fetal variant and demonstrates that the interpretation of results is complicated by dichotomization. Flexible survival models reveal that many known loci have time-varying effects, especially in early pregnancy, and suggest the involvement of major histocompatibility complex genes in very preterm births. These findings highlight the clinical relevance of gestational duration loci and inform future experimental studies.