Meta-analysis of genome-wide association studies of gestational duration and spontaneous preterm birth identifies new maternal risk loci

BackgroundPreterm birth (<37 weeks of gestation) is a major cause of neonatal death and morbidity. Up to 40% of the variation in timing of birth results from genetic factors, mostly due to the maternal genome.MethodsWe conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,370 European mothers, respectively.ResultsThe meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel. The loci mapped to several biologically plausible genes, for example HAND2 whose expression was previously shown to decrease during gestation, associated with gestational duration, and GC (Vitamin D-binding protein), associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. LD score regression found birth weight measures as the most strongly correlated traits, highlighting the unique nature of spontaneous preterm birth phenotype. Tissue expression and colocalization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action.ConclusionWe report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth.

Automated summary

We conducted a genome-wide meta-analysis on gestational duration and spontaneous preterm birth in European mothers. Our findings identified novel genetic risk loci associated with preterm birth and gestational duration. The data suggests potential regulatory mechanisms for these loci. Further research is needed to fully understand the causal genetic mechanisms and develop strategies for prevention and treatment of preterm birth.