Inhibitory neuron links the causal relationship from air pollution to psychiatric disorders: a large multi-omics analysis

Psychiatric disorders are severe health challenges that exert a heavy public burden. Air pollution has been widely reported as related to psychiatric disorder risk, but their casual association and pathological mechanism remained unclear. Herein, we systematically investigated the large genome-wide association studies (6 cohorts with 1,357,645 samples), single-cell RNA (26 samples with 157,488 cells), and bulk-RNAseq (1595 samples) datasets to reveal the genetic causality and biological link between four air pollutants and nine psychiatric disorders. As a result, we identified ten positive genetic correlations between air pollution and psychiatric disorders. Besides, PM2.5 and NO₂ presented significant causal effects on schizophrenia risk which was robust with adjustment of potential confounders. Besides, transcriptome-wide association studies identified the shared genes between PM2.5/NO2 and schizophrenia. We then discovered a schizophrenia-derived inhibitory neuron subtype with highly expressed shared genes and abnormal synaptic and metabolic pathways by scRNA analyses and confirmed their abnormal level and correlations with the shared genes in schizophrenia patients in a large RNA-seq cohort. Comprehensively, we discovered robust genetic causality between PM2.5, NO₂, and schizophrenia and identified an abnormal inhibitory neuron subtype that links schizophrenia pathology and PM2.5/NO2 exposure. These discoveries highlight the schizophrenia risk under air pollutants exposure and provide novel mechanical insights into schizophrenia pathology, contributing to pollutant-related schizophrenia risk control and therapeutic strategies development.

Graphical Abstract