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

Abstract

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 98,371 European mothers, respectively.ResultsWe detected 19 associated loci of which seven were novel. The loci mapped to several biologically plausible genes, includingHAND2whose expression was previously shown to decrease during gestation, associated with gestational duration, andGCencoding 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.

Capture-recapture for -omics data meta-analysis

“…Two large maternal GWASs of pregnancy duration have been conducted recently [38,39]. Both studies analysed the samples in two statistical models: case-control tests with preterm delivery as the outcome, and regression models of continuous gestational duration.…”

“…In Solé-Navais et al [38], 23 genes were reported for GA, and 7 for PTD, of which all but 1 were also reported for GA. The Pasanen et al [39] study reported 15 genes for GA and 4 for PTD (of these 2 unique to PTD). Some samples were used in both studies, and the top hits were largely shared, but 14 of the genes were still unique to [38] and 7 unique to [39].…”

“…The Pasanen et al [39] study reported 15 genes for GA and 4 for PTD (of these 2 unique to PTD). Some samples were used in both studies, and the top hits were largely shared, but 14 of the genes were still unique to [38] and 7 unique to [39].…”

“…Deviations from the expected duration of 40 weeks, in particular preterm birth (birth <37 weeks), have major consequences to neonatal survival and health[36]. Several genome-wide association studies of pregnancy duration have been conducted[37][38][39], as well as many proteomic, transcriptomic and candidate-gene studies attempting to identify any relevant biomarkers. Still, a large fraction of the variability in this trait remains unexplained.…”