Genomic approach to investigate air pollution’s causal impact on neurodevelopment and mental health: An extensive-scale 2-sample Mendelian randomization study

Air pollution is a major global public health threat associated with increased morbidity and premature mortality. Growing evidence suggests that air pollution may also adversely affect brain health, contributing to cognitive impairment and mental disorders. However, most existing studies are observational and therefore vulnerable to residual confounding and reverse causation. Mendelian randomization (MR), which uses genetic variants as instrumental variables, offers a framework to strengthen causal inference regarding the neurological effects of air pollution. We conducted a 2-sample MR study using large-scale genome-wide association study data to investigate the causal effects of air pollution on neurodevelopmental and mental health outcomes. Exposures included ambient air pollutants (PM2.5, PM10, PM2.5-10, NO2, and NOx) and workplace-related air pollution, including self-reported "very dusty" workplace exposure, chemical or other fumes, and diesel exhaust. Neurodevelopmental and mental health outcomes comprised 17 genome-wide association studies datasets across 6 domains: cognitive function and intelligence, educational attainment, psychiatric disorders, emotional and behavioral disorders in children and adolescents, attention-deficit/hyperactivity disorder (ADHD), and neuroticism. Genetically proxied higher PM2.5 exposure was associated with lower intelligence and cognitive performance, reduced educational attainment, and increased risks of schizophrenia, depression, panic attacks, and vulnerability during youth. Elevated NOx exposure was associated with poorer cognition, lower educational attainment, and increased risks of anxiety, panic disorder, and attention-deficit/hyperactivity disorder. Higher NO2 levels were associated with an increased risk of schizophrenia and higher neuroticism scores. Workplace-related air pollution exposures were also associated with adverse outcomes. Self-reported "very dusty" workplace exposure was associated with poorer cognitive performance and educational attainment, while chemical fumes and diesel exhaust were linked to reduced academic achievement and increased risks of selected psychiatric outcomes. This MR study provides evidence supporting potential causal relationships between air pollution exposure and a wide range of neurodevelopmental and mental health outcomes, underscoring the importance of reducing air pollution exposure, particularly among vulnerable populations.