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P3‐127: Sex‐specific Alternative Splicing Regulation of Alzheimer's Risk Variants in Clu

Year: 2019
Type: article
Abstract: Clusterin (CLU) is one of GWAS identified Alzheimer's disease (AD) risk genes associated with AD pathology and several variants in CLU have shown to be associated with AD risk. Previous studies suggest that expression of CLU is regulated by alternative splicing. Here, we analyzed changes in alternative splicing to identify the effect of AD risk variants in CLU on alternative splicing. We used RNA-Seq and GWAS data from the AMP-AD study and conducted an integrative analysis to identify alternative splicing events in CLU and AD risk SNPs affecting alternative splicing events. RNA-Seq data were generated from 3 temporal lobe brain regions of cognitively normal controls (CN) and AD: temporal cortex (TCX, 78 CN and 81 AD), superior temporal gyrus (ST, 101 CN and 60 AD) and parahippocampal gyrus (PH, 93 CN and 64 AD). We mapped RNA-Seq data to hg19 reference and estimated percent spliced in index (PSI), a ratio between reads including or excluding exon. We performed an association analysis between PSI values and AD risk SNPs. Among 7 AD risk SNPs in CLU, rs7982 was located in 5 exon with intron retention (IR). As shown in the Figure 1, Our analysis showed that decreased IR rates of 5 exon in CLU were observed in AD compared to CN in the temporal cortex (p=0.04) and only in female, AD was significantly associated with decreased IR rates (p=0.01). rs7982 (A/G) was significantly associated with IR rates of 5 exon in CLU in the temporal cortex (p=0.03), where individuals with minor alleles (G) of rs7982 have decreased retention levels, leading to a loss of the cleavage site. In addition, only in female, minor allele (G) of rs7982 was significantly associated with decreased IR rates (p=0.001).
DOI: 10.1016/j.jalz.2019.06.3155
Language: English
Open Access status: bronze
OpenAlex ID: W2980320688
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