Integrating multi-omics data to reveal the effect of genetic variant rs6430538 on Alzheimer's disease risk

Growing evidence highlights a potential genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD); however, the role of the PD risk variant rs6430538 in AD remains unclear. In Stage 1, we investigated the risk associated with the rs6430538 C allele in seven large-scale AD genome-wide association study (GWAS) cohorts. In Stage 2, we performed expression quantitative trait loci (eQTL) analysis to calculate the cis-regulated effect of rs6430538 on in both AD and neuropathologically normal samples. Stage 3 involved evaluating the differential expression of in 4 brain tissues from AD cases and controls. Finally, in Stage 4, we conducted a transcriptome-wide association study (TWAS) to identify any association between expression and AD. The results showed that genetic variant rs6430538 C allele might increase the risk of AD. eQTL analysis revealed that rs6430538 up-regulated expression in AD brain tissue, but down-regulated its expression in normal samples. Interestingly, showed differential expression in entorhinal cortex (EC) and temporal cortex (TCX). Furthermore, the TWAS analysis indicated strong associations between and AD in various tissues. In summary, our findings suggest that rs6430538 may influence AD by regulating expression. These discoveries may open up new opportunities for therapeutic strategies targeting AD.