PROJECT SUMMARY/ABSTRACT The goal of the proposed research is to discover genetic and epigenetic factors that underlie lung function decline in middle-aged to older adults, including factors that interact with omega-3 fatty acids (ω3 FAs), which attenuate lung function decline. We will identify genetic variants and epigenetic (DNA methylation, DNAm) biomarkers associated with lung function decline, map genetic variants underlying DNAm differences, and extend the genetic and epigenetic associations to clinically defined chronic obstructive pulmonary disease (COPD). Results will add knowledge of the pathophysiology that precedes COPD. Accelerated decline in lung function, as measured by pulmonary function tests (PFTs), often precedes a diagnosis of COPD─the 4th leading cause of death in the United States. The decline in PFTs over time is influenced by environment (e.g., cigarette smoking is harmful, and ω3 FAs are beneficial) and by genetics (average heritability of 38%). Genome-wide association studies (GWAS) of PFTs measured at a single time point (reflecting both lung development until early adulthood and decline thereafter) have identified 270+ genetic loci from amassing large sample sizes. Yet, evidence that these loci influence PFT decline in adults is limited, and definitive associations have eluded the few smaller-scale GWAS of PFT decline. Gene-environment interactions are likely key to the etiology of PFT decline. We will model interactions of ω3 FAs concentrations in blood (“[ω3 FAs]”) to find genetic variants and blood-based DNAm biomarkers associated with PFT decline and test whether the associations reflect risk factors for COPD, as follows: Specific Aim 1: Conduct GWAS and genome-wide joint meta-analyses of variant and variant × [ω3 FAs] interaction for PFT decline. Specific Aim 2: Identify DNAm biomarkers for PFT decline and map cis-methylation quantitative trait loci (cis-meQTLs), accounting for [ω3 FAs] interaction. Specific Aim 3: Extend associations for PFT decline to COPD, accounting for [ω3 FAs] interaction. Aims 1─2 will be carried out across general population cohorts: Cohorts for Heart and Aging Research in Genomic Epidemiology, SpiroMeta, and UK Biobank (total N=60,586). Aim 3 will leverage the COPDGene cohort of clinically defined COPD cases and controls. Our integration of GWAS, DNAm, and [ω3 FAs] and extension to COPD will greatly improve the likelihood of meaningful discovery by identifying factors with high biological and clinical relevance. PFT decline-associated genetic variants and DNAm biomarkers, including ones that interact with [ω3 FAs] to attenuate decline, may provide specific targets for developing intervention strategies, such as tailored dietary guidance or new druggable targets, to prevent or delay onset of COPD in people with steeper PFT decline due to genetic risk or environmental insults (e.g., smoking).