DNA Methylation and Resting Brain Function Mediate the Association between Childhood Urbanicity and Better Speed of Processing

Urbanicity has been suggested to affect cognition, but the underlying mechanism remains unknown. We examined whether epigenetic modification (DNA methylation, DNAm), and brain white matter fiber integrity (fractional anisotropy, FA) or local spontaneous brain function activity (regional homogeneity, ReHo) play roles in the association between childhood urbanicity and cognition based on 497 healthy Chinese adults. We found significant correlation between childhood urbanicity and better cognitive performance. Multiset canonical correlation analysis (mCCA) identified an intercorrelated DNAm-FA-ReHo triplet, which showed significant pairwise correlations (DNAm-FA: Bonferroni-adjusted P, P(bon) = 4.99E−03, rho = 0.216; DNAm-ReHo: P(bon) = 4.08E−03, rho = 0.239; ReHo-FA: P(bon) = 1.68E−06, rho = 0.328). Causal mediation analysis revealed that 1) ReHo mediated 10.86% childhood urbanicity effects on the speed of processing and 2) childhood urbanicity alters ReHo through DNA methylation in the cadherin and Wnt signaling pathways (mediated effect: 48.55%). The mediation effect of increased ReHo in the superior temporal gyrus underlying urbanicity impact on a better speed of processing was further validated in an independent cohort. Our work suggests a mediation role for ReHo, particularly increased brain activity in the superior temporal gyrus, in the urbanicity-associated speed of processing.