Associations of air pollution and genetic risk and their interaction with risk of Alzheimer's disease: identification of risk loci and potential biological pathways

BACKGROUND: Air pollution is associated with Alzheimer's disease (AD), and the susceptibility of AD from air pollution may be affected by genetic characteristics, but the underlying mechanisms remain unknown. METHODS: Data from the UK Biobank, in conjunction with PLINK2, was utilized to conduct a genome-wide analysis of a gene-air pollution (PM2.5, PM₁₀, NO₂, and NOx) interaction in AD. Functional annotation, positional gene mapping, expression Quantitative Trait Loci (eQTL) analysis, 3D chromatin interactions mapping (ciMap), and gene expression analysis were conducted using FUMA. Potential biological pathways was analyzed by Metascape. RESULTS: A total of 322,958 participants were included in the study. Genome-wide gene-air pollution interaction analysis (GWIA) identified 38, 36, 66, and 101 genomic risk loci that interacted with PM2.5, PM₁₀, NO₂ and NOx (p < 5 × 10⁻⁸). The functional annotation positional gene mapping, eQTL, ciMap mapping, and quantitative gene prioritization prioritized 26, 25, 46 and 70 prioritized genes for PM2.5, PM₁₀, NO₂ and NOx, including PTCH1, UNC80, TUBGCP3, RUNX2, RCAN2, SUPT3H, DNPH1, TTBK1, and RSPH9, and we found significantly high expression of NOx-related prioritized genes in the heart atrial appendage, the modulation of smoothened signaling was associated with PM2.5 and PM₁₀, hemopoiesis was associated with nitrogen oxides, and learning or memory processes may be involved in the interaction between PM2.5, NO₂, NOx, and genes, affecting Alzheimer's disease. CONCLUSIONS: We prioritized genetic risk loci that interact with air pollutants in AD and revealed that learning or memory are crucial pathways through which these pollutants interact with genes PDE1B, SRF, ZNF385A, and TTBK1.