Blood DNA Methylation Profiling Identifies Cathepsin Z Dysregulation in Pulmonary Arterial Hypertension

Ulrich, A., Wu, Y., Draisma, H., Wharton, J., Swietlik, E. M., Cebola, I., Vasilaki, E., Balkhiyarova, Z., Jarvelin, M. R., Auvinen, J., Herzig, K. H., Coghlan, J. G., Lordan, J., Church, C., Howard, L. S., Pepke-Zaba, J., Toshner, M., Wort, S. J., Kiely, D. G., Condliffe, R., … Rhodes, C. J. (2024). Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension. Nature communications, 15(1), 330. https://doi.org/10.1038/s41467-023-44683-0

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.