m⁶A Modification Genetic Variants Associated with Autism Spectrum Disorder Risks

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with increasing prevalence and high heritability. As a key epigenetic mechanism in brain development and function, the specific mechanisms of N⁶-methyladenosine (m⁶A) modification in ASD remain unknown. This study conducted bioinformatics analysis of m⁶A-QTL data from Yoruba lymphoblastoid cell lines and the RMVar database to identify m⁶A-QTL SNPs and modification genes associated with ASD. A two-stage population validation includes 1244 Chinese children with ASD and controls, followed by replication in a large European cohort consisting of 18,382 cases and 27,969 controls. The potential functions of candidate variants and target genes were examined through functional annotations. There were 2830 SNPs associated with the m⁶A modification levels of target genes. We further identified 91 m⁶A-QTL-associated ASD candidate SNPs in Chinese samples and validated 8 variants in the European cohort (P < 0.05), including three high-confidence variants: rs10242048 (P _combined = 8.06 × 10^-3), rs2304447 (P _combined = 5.01 × 10^-3), and rs4074309 (P _combined = 1.59 × 10^-2). Functional annotations revealed that rs4074309 might potentially regulate m⁶A levels of STAT6 and modulate LRP1 expression in brain tissues, binding the transcription factor THAP1. Both STAT6 and LRP1 are implicated in crucial neurodevelopmental pathways, such as the JAK-STAT signaling and the tau-protein kinase regulation, respectively. Our study suggests that genetic variants in m⁶A modification genes may contribute to ASD susceptibility. The findings highlight the importance of m⁶A modification in neurodevelopmental disorders and provide insights into the epigenetic mechanisms involved in ASD.