A Protective Super‐Enhancer Variant Regulating <scp> <i>SLC7A7</i> </scp> Modulates Autism Spectrum Disorder Risk: A Cross‐Population Study

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental condition with a rising global prevalence. However, the functional role of super-enhancers, the key genomic regulatory elements, remains largely uncharacterized in ASD. This study aims to identify functional single-nucleotide polymorphisms (SNPs) within super-enhancers that regulate ASD-associated genes and to validate their contribution to ASD risk. We integrated 1394 ASD susceptibility genes with 1315 differentially expressed genes and 2954 super-enhancers from the cerebral cortex. SNPs located in these regions were prioritized through expression quantitative trait locus (eQTL) analysis (p < 1 × 10^-4) and functional prediction tools. The identified candidate SNPs were first assessed in a Chinese case-control study (622 cases and 622 controls) and subsequently validated in a European population using the iPSYCH-PGC dataset (18,381 cases and 27,969 controls). The regulatory effect of a key SNP was further investigated using a dual-luciferase reporter assay. We screened 20 super-enhancers regulating 15 differentially expressed ASD susceptibility genes. From these regions, 11 functional SNPs for population-based validation were identified. Among these, the rs1951568 G>A variant, located within the super-enhancer regulating SLC7A7, demonstrated a significant association with reduced ASD risk in the Chinese population (OR = 0.783, 95% CI: 0.604-0.957, p = 0.017). The protective association was further replicated in the European population (A allele vs. G allele, OR = 0.963, 95% CI: 0.935-0.992, p = 0.012). The eQTL analysis linked the rs1951568-A allele to reduced SLC7A7 expression. Functional characterization confirmed the variant's regulatory activity and predicted that the A allele enhanced binding motifs for the transcriptional repressors TBX5 and ZEB1. Our findings identify rs1951568-A as a novel protective variant for ASD within a SLC7A7 super-enhancer. This allele likely confers protection by modulating SLC7A7 expression, potentially through enhanced repressor binding, highlighting the importance of super-enhancer variants in ASD etiology.