Introduction: DNA methylation (DNAm) has shown promise as a biological marker of gestational age (GA). Here, we aimed to characterize how plasma circulating miRNAs, another epigenetic mechanism regulating gene expression, associate with GA at birth, and to construct a miRNA-based GA clock (miRClock-GA). Methods: We leveraged 2083 umbilical cord plasma-derived circulating miRNAs from Generation R (N=1695). First, we performed linear regressions to identify miRNome-wide significant miRNAs associated with GA. Second, we applied elastic net regression to construct miRClock-GA. These steps were validated in Gen3G (N=213). Finally, we computed age acceleration (miRClock-AA) and evaluated association of miRClock-GA and miRClock-AA with child developmental outcomes up to 17 years of age, including comparisons with DNAmClocks. Findings: We identified 123 miRNAs associated with GA, with miR-150-5p showing the strongest positive association (B=0.244, SE=0.036, P=2.3e-11) and miR-373-3p the strongest negative association (B=-0.255, SE=0.065, P=8.6e-5). MiRClock-GA correlated consistently with GA in Generation R train (r_range=0.62-0.72) and test sets (r_range=0.45-0.52) and in the independent validation cohort (r_Gen3G=0.33). Correlations between miRClock-GA and DNAmClocks were weak to moderate (r()_range=0.28-0.42). MiRClock-AA explained significant variance in birthweight and childhood BMI beyond clinical GA. Conclusions: This study reveals widespread associations between circulating miRNAs and GA, supports miRClock-GA as a consistent, well-performing biological marker of GA, with miRClock-AA predicting birthweight and childhood BMI beyond GA itself. Our findings provide a broader perspective on the potential utility of miRNAs as early markers of development. Funding: E.U. Horizon Europe Research and Innovation Programme (FAMILY,No.101057529); European Research Council (TEMPO,No.101039672). Full funding in Acknowledgements.
Finke, T., Kuilman, M. M., White, F., Felix, J., Prijatelj, V., Schuurmans, I. K., Tiemeier, H., van Haren, N., Bouchard, L., Jacques, P.-E., Hivert, M.-F., Ghanbari, M., Neumann, A., Cecil, C. A. M.
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