Abstract

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 98,370 European mothers, respectively.

Results: The 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.

Conclusions: 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.

Author summary Annually, more than 15 million pregnancies are affected by preterm births all over the world. There are no effective ways to prevent preterm birth, and premature babies suffer from neonatal mortality and lifelong morbidities. Genetic factors of mother and fetus explain a large proportion, approximately 30–40%, of the of the variation in gestational age at delivery. To date, there have been just a few unbiased genome-wide investigations set out to locate these genes. Better characterization of the causal genetic mechanisms could suggest new strategies to treat and prevent preterm birth. In the current study, we aimed to identify maternal genetic factors that contribute to the timing of birth by meta-analyzing genome-wide association studies from European populations. We detected 17 independent loci that were associated with gestational duration and/or the risk of preterm birth. Ten of the loci replicated associations from previous studies, and seven were novel. The replicated associations provide strong evidence for the importance of these loci in the timing of birth, although the exact genes and causal variants and pathways still require further functional analysis. The seven novel associations provide further intriguing candidates that may account for the risk of preterm birth. Bioinformatics analysis proposed the associated loci have regulatory functions predominantly in immune cell types and reproductive tissues. The analysis further highlighted the unique nature or preterm birth as a phenotype, since the only traits with strong correlations were birth weight measures that are closely linked to the studied phenotypes. Our findings complement the knowledge of the genetic factors of preterm birth.