Multi-omics reveals cross-tissue regulatory mechanisms of autism risk loci via gut microbiota-immunity-brain axis

Autism Spectrum Disorder (ASD) involves a multi-system interaction mechanism among genetics, immunity, and gut microbiota, yet its regulatory network remains undefined. This study conducted a meta-analysis on Genome-Wide Association Study data from four independent ASD cohorts to identify potential genetic loci. By integrating Polygenic Priority Score, brain region, and brain cell eQTL enrichment analyses, and combining summary-data-based Mendelian Randomisation (SMR) analyses of brain cis-eQTL and mQTL, bidirectional Mendelian Randomisation analyses of 473 gut microbiota, and SMR analysis of blood eQTL, SNPs such as rs2735307 and rs989134 with significant multi-dimensional associations were identified. These loci exert cross-tissue regulatory effects by participating in gut microbiota regulation, involving immune pathways such as T cell receptor signal activation and neutrophil extracellular trap formation, as well as cis-regulating neurodevelopmental genes (HMGN1 and H3C9P), or synergistically influencing epigenetic methylation modifications to regulate the expression of BRWD1 and ABT1. The cross-scale evidence chain constructed in this study provides a theoretical foundation for precision medicine research in ASD, holding promise to advance the development of innovative therapeutic strategies.