Integration of gene expression and DNA methylation identifies epigenetically controlled modules related to PM2.5 exposure

Air pollution has been associated with adverse health effects across the life-course. Although underlying mechanisms are unclear, several studies suggested pollutant-induced changes in transcriptomic profiles. In this meta-analysis of transcriptome-wide association studies of 656 children and adolescents from three European cohorts participating in the MeDALL Consortium, we found two differentially expressed transcript clusters (FDR p < 0.05) associated with exposure to particulate matter < 2.5 mu m in diameter (PM2.5) at birth, one of them mapping to the MIR1296 gene. Further, by integrating gene expression with DNA methylation using Functional Epigenetic Modules algorithms, we identified 9 and 6 modules in relation to PM2.5 exposure at birth and at current address, respectively (including NR1I2, MAPK6, TAF8 and SCARA3). In conclusion, PM2.5 exposure at birth was linked to differential gene expression in children and adolescents. Importantly, we identified several significant interactome hotspots of gene modules of relevance for complex diseases in relation to PM2.5 exposure. The research leading to these results has received funding from the European Community's Seventh Framework Program under grant agreement numbers: 211,250 (ESCAPE), and 261,357 (MeDALL), and the European Research Council (grant agreement number 757919, TRIBAL). NL was recipient of ANR-15-IDEX-02 grant. BAMSE: BAMSE was supported by The Swedish Research Council, The Swedish Heart-Lung Foundation, Region Stockholm, the Strategic Research Programme (SFO) in Epidemiology at Karolinska Institutet, The Swedish Research Council Formas and the Swedish Environment Protection Agency, the Swedish Asthma and Allergy Research Foundation, the Cancer and Allergy Foundation. O. Gruzieva is supported by the Swedish Research Council for Health, Working life and Welfare (FORTE 2017-01146). GINIplus: The GINIplus study was mainly supported for the first 3 years of the Federal Ministry for Education, Science, Research and Technology (interventional arm) and Helmholtz Zentrum Munich (former GSF) (observational arm). The 4 year, 6 year, 10 year and 15 year follow-up examinations of the GINIplus study were covered from the respective budgets of the 5 study centres (Helmholtz Zentrum Munich (former GSF), Research Institute at Marien-Hospital Wesel, LMU Munich, TU Munich and from 6 years onwards also from IUF -Leibniz Research-Institute for Environmental Medicine at the University of Dusseldorf) and a grant from the Federal Ministry for Environment (IUF Dusseldorf, FKZ 20462296). Further, the 15-year follow-up examination of the GINIplus study was supported by the Commission of the European Communities, the 7th Framework Program: MeDALL project, and as well by the companies Mead Johnson and Nestle. INMA: INMA project was mainly supported by the Commission of the European Community, the 7th Framework Program: MeDALL project and by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI04/1436; PI06/0867; PI08/1151; and PI18/01142 incl. FEDER funds), and Generalitat de Catalunya-CIRIT 1999SGR 00241, Department of Health of the Basque Government (2005111093), Provincial Government of Gipuzkoa (DFG06/002), and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain)