Genetic variant rs11136000 upregulates clusterin expression and reduces Alzheimer's disease risk

Clusterin (CLU) is an extracellular chaperone involved in reducing amyloid beta (Aβ) toxicity and aggregation. Although previous genome-wide association studies (GWAS) have reported a potential protective effect of CLU on Alzheimer's disease (AD) patients, how intron-located rs11136000 (CLU) affects AD risk by regulating CLU expression remains unknown. In this study, we integrated multiple omics data to construct the regulated pathway of rs11136000-CLU-AD. In step 1, we investigated the effects of variant rs11136000 on AD risk with different genders and diagnostic methods using GWAS summary statistics for AD from International Genomics of Alzheimer's Project (IGAP) and UK Biobank. In step 2, we assessed the regulation of rs11136000 on CLU expression in AD brain samples from Mayo clinic and controls from Genotype-Tissue Expression (GTEx). In step 3, we investigated the differential gene/protein expression of CLU in AD and controls from four large cohorts. The results showed that rs11136000 T allele reduced AD risk in either clinically diagnosed or proxy AD patients. By using expression quantitative trait loci (eQTL) analysis, rs11136000 variant downregulated CLU expression in 13 normal brain tissues, but upregulated CLU expression in cerebellum and temporal cortex of AD samples. Importantly, CLU was significantly differentially expressed in temporal cortex, dorsolateral prefrontal cortex and anterior prefrontal cortex of AD patients compared with normal controls. Together, rs11136000 may reduce AD risk by regulating CLU expression, which may provide important information about the biological mechanism of rs9848497 in AD progress.