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

GEITP is aware that this project has been a focus of Ge Zhang [Division of Genetics, Cincinnati Children’s Hospital] for >6 years; finally, the results are published and can be shared [see attached]. 😊 More than 15 million pregnancies per year, worldwide, are affected by preterm births (i.e., <37 weeks of gestation); there are no effective ways to prevent preterm births, and premature babies suffer from more neonatal mortality and lifelong morbidities, compared with full-term babies. Genetic factors of mother and fetus explain a large proportion (~30–40%) of the variation in gestational age at delivery (thus, this topic is consistent with the “gene-environment interactions” theme of these GEITP emails). To date, there have been only a few unbiased genome-wide investigations — designed to locate these genes. Recent genome-wide association studies (GWASs) have identified some robust associations. For example, variants in genes including WNT4 (Wnt family member-4), EBF1 (EBF transcription factor-1), AGTR2 (angiotensin II receptor type-2) and KCNAB1 (potassium voltage-gated channel subfamily A regulatory beta subunit-1) have been associated with timing of birth in mothers, and a study with fetal samples discovered a locus near genes that encode pro-inflammatory cytokines associated with gestational duration. Authors hope that better characterization of causal genetic mechanisms could lead to new strategies to treat and prevent preterm births. Authors conducted a genome-wide meta-analysis of gestational duration, and spontaneous preterm birth, in 68,732 and 98,370 European mothers, respectively. The meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel: WNT3A (Wnt family member-3A), RHAG (Rh-associated glycoprotein), KCNN2 (potassium calcium-activated channel subfamily N member-2), COBL (cordon-bleu WH2 repeat protein), GNAQ (G protein subunit alpha q), GC (vitamin D-binding protein), and LINC02824 (long intergenic non-protein coding RNA 2824). The loci mapped to several biologically plausible genes, for example, HAND2 (whose expression was previously shown to decrease during gestation) was associated with gestational duration, and GC was associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. Linkage disequilibrium (LD) score regression found birth-weight measurements as the most strongly correlated traits — highlighting the unique nature of the spontaneous preterm birth phenotype. Tissue expression and co-localization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action. The authors’ findings complement the knowledge (to date) of the genetic factors of preterm birth. 😊 DwN PLoS Genet Oct 2023; 19: e1010982