Large-scale genome-wide association studies reveal the genetic causal etiology between air pollutants and autoimmune diseases

Abstract Background Epidemiological evidence links a close correlation between long-term exposure to air pollutants and autoimmune diseases, while the causality remained unknown. Methods Two-sample Mendelian randomization (TSMR) was used to investigate the role of PM10, PM2.5, NO 2 , and NO X (N = 423,796–456,380) in 15 autoimmune diseases (N = 14,890–314,995) using data from large European GWASs including UKB, FINNGEN, IMSGC, and IPSCSG. Multivariable Mendelian randomization (MVMR) was conducted to investigate the direct effect of each air pollutant and the mediating role of common factors, including body mass index (BMI), alcohol consumption, smoking status, and household income. Transcriptome-wide association studies (TWAS), two-step MR, and colocalization analyses were performed to explore underlying mechanisms between air pollution and autoimmune diseases. Results In TSMR, after correction of multiple testing, hypothyroidism was causally associated with higher exposure to NO 2 odds ratio (OR): 1.37, p = 9.08 × 10 –4 and NO X OR: 1.34, p = 2.86 × 10 –3 , ulcerative colitis (UC) was causally associated with higher exposure to NO X OR: 2.24, p = 1.23 × 10 –2 and PM2.5 OR: 2.60, p = 5.96 × 10 –3 , rheumatoid arthritis was causally associated with higher exposure to NO X OR: 1.72, p = 1.50 × 10 –2 , systemic lupus erythematosus was causally associated with higher exposure to NO X OR: 4.92, p = 6.89 × 10 –3 , celiac disease was causally associated with lower exposure to NO X OR: 0.14, p = 6.74 × 10 –4 and PM2.5 OR: 0.17, p = 3.18 × 10 –3 . The risky effects of PM2.5 on UC remained significant in MVMR analyses after adjusting for other air pollutants. MVMR revealed several common mediators between air pollutants and autoimmune diseases. Transcriptional analysis identified specific gene transcripts and pathways interconnecting air pollutants and autoimmune diseases. Two-step MR revealed that POR, HSPA1B, and BRD2 might mediate from air pollutants to autoimmune diseases. POR pQTL (rs59882870, PPH4=1.00) strongly colocalized with autoimmune diseases. Conclusion This research underscores the necessity of rigorous air pollutant surveillance within public health studies to curb the prevalence of autoimmune diseases. Graphical abstract (Built by the Biorender)