Meta-analysis of gestational duration and spontaneous preterm birth identifies new maternal risk loci

Background Preterm 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. Methods We conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,371 European mothers, respectively. Results We detected 19 associated loci of which seven were novel. The loci mapped to several biologically plausible genes, including HAND2 whose expression was previously shown to decrease during gestation, associated with gestational duration, and GC encoding 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. Conclusion We 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.