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

Scientists studied genetic differences that might increase autism risk in Chinese and European children. They found two specific genetic variants that consistently increased autism risk in both groups - one by about 30% and another by about 23%. These genetic changes appear to work by affecting how a particular gene (SERPINE1) functions in the brain. This research helps us better understand the biological causes of autism.

This fine-mapping study investigated genetic variants associated with autism spectrum disorder (ASD) across Chinese and European populations. Researchers analyzed 158 ASD susceptibility SNPs with brain tissue expression effects, identifying two variants (rs2192932 and rs10487150) that consistently increased ASD risk in both populations. The rs2192932 variant increased ASD risk by 29.5% while rs10487150 increased risk by 22.7%. Both variants appear to influence ASD development by regulating SERPINE1 gene expression in brain tissue.

The study combined genetic data from 1,244 Chinese children and 46,351 European samples, providing cross-population validation of these genetic risk factors and advancing understanding of ASD's molecular genetics.

These genetic variants could potentially contribute to autism risk prediction models and early screening strategies. The identification of SERPINE1 as a regulatory target may inform future therapeutic research, though clinical application requires further validation studies.

Sample sizes not clearly reported for all analyses. Regulatory mechanisms are inferred rather than directly demonstrated. Cross-population validation limited to two ethnic groups. Clinical significance of identified effect sizes unclear.

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.