Multi-omic Association Study Identifies DNA Methylation-Mediated Genotype and Smoking Exposure Effects on Lung Function in Children Living in Urban Settings

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10(-9); beta(z) = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10(-5); beta = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure. Author summaryLung function is determined by both genetic and environmental factors. Impairment of lung function can result from harmful environmental exposures in early life, which disproportionally affect children living in low-income, urban communities. However, most genetic association studies of lung function have been performed in adults and without regard for socioeconomic status. Therefore, genetic risk factors discovered to date may not reflect those most relevant to high-risk populations. In this study, we sought to identify genetic variants correlated with lung function in a multiethnic cohort of children living in low-income, urban neighborhoods and analyze how tobacco smoke exposure may influence any genetic effects. We discovered a common genetic variant associated with lower lung function in this population, and we found that the association was mediated by nearby epigenetic changes in DNA methylation, which were in turn correlated with smoking exposure. We then identified a nearby gene, PPP1R13B, which is known to aid in the deactivation of damaged cells, whose expression in airway cells aligned with these genetic and epigenetic effects. This study reveals a potential mechanism through which genetic risk and environmental exposures can affect airway development, perhaps leading to interventions that can help reduce the burden of asthma in socioeconomically disadvantaged children.