Genome-wide gene-air pollution interaction analysis on asthma in adolescents: a meta-analysis of 5 European birth cohorts

<bold>Background and aim:</bold> Existing gene-environment interaction (GxE) studies on asthma may miss genetic variants involved in the interaction, as they select variants relevant to the main effects of asthma only. This study aims to (1) identify genome-wide genetic variants related in interaction with air pollutants to asthma and (2) investigate the role of genetic susceptibility in air pollution-associated asthma in adolescents. <bold>Methods:</bold> We included 4,454 adolescents (15–17 years) enrolled in 5 European birth cohorts (BAMSE, GINI/LISA, NFBC1986, PIAMA) with available data on asthma status, genetics, and chronic exposures to particulate matter and nitrogen dioxide. To identify relevant genetic variants, a genome-wide gene-by-air-pollutant-interaction study was performed in BAMSE. Based on the derived single nucleotide polymorphisms (SNPs) and the respective weight estimates, we constructed cohort-specific external-weighted polygenic risk scores (PRS) and conducted PRSxE analysis in the remaining cohorts. Random effects meta-analysis was performed. <bold>Results:</bold> Asthma was present in 7.7 % of individuals. Per each air pollutant, 100 SNPs with the lowest p‑value were identified as no SNP reached genome-wide significance. Cohort-specific adjusted odds ratios (OR) and meta-ORs were consistently close to one. Results remained stable in sensitivity analyses. <bold>Conclusions:</bold> This study applies a new method to construct GxE-based, external-weighted PRS and investigates GxE effects on asthma in adolescents on the largest sample to date. While preliminary results did not provide evidence for GxE effects on asthma, we will extend the discovery dataset with additional cohorts (e.g. ALSPAC).