Interaction between XRN2 mutation and gut microbiota on the risks of autism spectrum disorder

Background: The intestinal dysbiosis can be observed in patients with autism spectrum disorder (ASD), partly explained by the alteration in gut microbiota composition. Our study aims to screen ASD causal variants and explore the potential interaction between variants and gut microbiota.Methods: We conducted the expression quantitative trait loci (eQTL) analysis to identify variations that regulated the expression of the ASD risk gene XRN2, and then validated genetic susceptibility to ASD risk in the case-control study among 627 ASD children and 606 healthy controls. The fecal samples were analyzed by 16S rRNA sequencing. Logistic regression model analysis was conducted to examine the interaction.Results: We identified that rs2295412 was a cis-eQTL of XRN2 in brain tissues (P < 0.0005), And individuals with rs2295412 TC genotypes had decreased ASD risks compared to the TT genotype (OR = 0.42, 95(%) CI: 0.19-0.94, P = 0.036). And rs2295412 genotypes and the abundance of f__Monoglobaceae showed the interaction on the ASD risks (P-mul = 0.049). Compared to the children with a higher abundance of f__Monoglobaceae and rs2295412 CT+CC genotype, the children with a lower abundance and TT genotype might have higher ASD risks.Conclusions: These findings suggested the potential interaction between genetic variation and gut microbiota on ASD risks, which enhanced the understanding of pathogenic mechanisms and the underlying etiology of ASD, and provided clues for future investigations.