Regulatory roles of rs2192932 and rs10487150 in autism spectrum disorder: insights from fine-mapping and cross-population validation.

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with increasing global prevalence. GWAS have identified many ASD risk loci, but most are in non-coding regions, and the genetic value of nearby loci remains underexplored. We aim to conduct a fine-mapping analysis of ASD-associated SNPs and validate the signals across ethnic groups, focusing on their regulatory effects on gene expression. Variants within ±500 kb of known ASD loci were selected. Functional annotations were performed using RegulomeDB and CADD. ASD susceptibility genes were obtained from AutDB and SFARI, and screened for validation using 11 high-quality GEO datasets. eQTL analysis was conducted using GTEx database. For Chinese children, a case-control study design was adopted. Biological samples and demographic information were collected from 1244 children between 2010-2024. Extracted DNA was used for ASAMD chip. For European children, GWAS data from 46351 samples were obtained from iPSYCH-PGC-ASD project. 158 ASD susceptibility SNPs with cis-eQTL signals in brain tissue were identified. Notably, rs2192932 and rs10487150 showed consistent associations with ASD in both populations. In additive model, a G to A change at rs2192932 increased ASD risk by 29.5% (OR = 1.295, 95% CI: 1.046-1.605, P = 0.018), while an A to C change at rs10487150 increased risk by 22.7% (OR = 1.227, 95% CI: 1.008-1.495, P = 0.042). Additionally, rs2192932 and rs10487150 may influence ASD onset by regulating SERPINE1 expression. These findings offer new insights into the molecular genetics of ASD and support the potential of genetic markers for risk prediction and early screening.