Deciphering mechanisms leading to preterm birth through post-GWAS integration of multi-omics data

Preterm birth (birth before 37 weeks) is a major cause of neonatal mortality and is linked to various health adversities in childhood and adult life. This study investigates the genetic factors contributing to spontaneous preterm birth (sPTB) in an Indian cohort. We conducted genome-wide association study of sPTB in GARBH-Ini cohort and identified 40 significantly associated SNPs, of which rs57480735 crossed genome-wide significance (<i>p</i> = 2.3 × 10^-8). Haplotypes containing the risk allele at rs57480735 were significantly associated with sPTB. Transethnic replication study identified 212 SNPs that were associated with sPTB in both Indian and European cohorts. Integration of genotype, DNA methylation, gene expression, and clinical data revealed that transethnic variants majorly alter the methylation and/or expression of inflammatory genes, whereas the population-specific variants affect genes involved in placental bed formation. Finally, we identified a combination of 66 SNPs using machine learning that predicted sPTB (area under the curve [AUC]: 0.78) and can be further used for risk stratification.