Time-varying effects are common in genetic control of gestational duration.
Julius JuodakisKarin YtterbergChristopher FlatleyPol Sole NavaisBo JacobssonPublished in: Human molecular genetics (2023)
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 foetal 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.
Keyphrases
- preterm birth
- gestational age
- birth weight
- genome wide
- genome wide association
- low birth weight
- weight gain
- dna methylation
- case control
- mental health
- copy number
- public health
- pregnancy outcomes
- healthcare
- pregnant women
- electronic health record
- body mass index
- gene expression
- risk factors
- big data
- data analysis
- machine learning
- free survival
- transcription factor
- genetic diversity
- climate change