SNPs in cytochromes P450 catalyzing cholesterol degradation in brain are associated with Parkinson's disease

Abstract

Besides being an essential structural component of plasma membranes and the precursor of many functional compounds and signaling molecules, cholesterol was also proposed to play a role in the etiology and/or manifestation of Parkinson's disease (PD). However, so far systematic investigations on the role of cholesterol and its metabolites present in the brain for the etiology of PD are missing. Here, we investigate for the first time the association of PD with SNPs in the genes of four cytochromes P450 (P450), CYP46A1, CYP39A1, CYP27A1 and CYP7B1, which are critical for the degradation of cholesterol in the brain. Analyzing 1,349 individuals from the PPMI data base, we found 24 SNPs in these four genes, which are significantly over- or under-represented in patients suffering from idiopathic PD (IPD). Studying each of the 362 IPD patients individually, we found that most patients (45%) showed only one associated SNP in one of the four P450 genes, while 31% displayed two associated SNPs and 18% three associated SNPs. The occurrence of some associated SNPs is in the same order of magnitude as SNPs in the GBA (beta-glucocerebrosidase) and thus might reflect a genetic predisposition for PD. As all 24 SNPs were located in introns and 3' untranslated regions, we evaluated the prospective regulatory impact of the surrounding genomic regions by using transcriptome and epigenome data from the Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD). FOUNDIN-PD provides gene expression, open chromatin and DNA methylation data in a cohort of 89 induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons derived from people in the PPMI study. Indeed, two of the 24 SNPs, one in CYP7B1 (rs118111353) and the other one in CYP27A1 (rs74446825), were localized within a region of open chromatin in differentiated neurons. Interestingly, all iPSC lines with open chromatin in rs118111353 showed the reference allele. As all four P450, CYP46A1, CYP39A1, CYP27A1 and CYP7B1, are expressed in dopaminergic neurons, we discuss further functional studies to connect SNPs in regulatory regions with gene expression levels. Finally, potential possibilities for personalized therapeutic treatment of patients with SNPs in the four investigated P450 are discussed.

Keywords: CYP27A1; CYP39A1; CYP46A1; CYP7B1; Parkinson's disease; cholesterol; cytochromes P450.

FIGURE 1

Cholesterol degradation.

FIGURE 2

Distribution of reference and alternative alleles for 24 SNPs associated with IPD in CYP7B1, CYP39A1, CYP27A1 and CYP46A1. Binary heatmaps clustered hierarchically color-coding the allele for all IPD and HC samples (columns) and all 24 SNPs (rows). OR and P450 gene were color-coded and indicated per column and row.

FIGURE 3

RPKM (Reads Per Kilobase per Million mapped reads) of CYP7B1, CYP46A1, CYP39A1 and CYP27A1 based on bulk RNA-seq data of iPSC-derived neurons at day 65. Values are based on individual samples from FOUNDIN-PD bulk RNA-seq data sets and shown for healthy controls as well as PD patients (genetic cohort, PD, prodromal). The expression of CYP3A7 is shown as control.

FIGURE 4

Median coverage of CYP7B1, CYP46A1, CYP39A1 and CYP27A1 based on single cell RNA-seq data of iPSC-derived neurons at day 65. Values compare expression levels in individual cell types and are based on values from the FOUNDIN-PD explorer (https://www.foundinpd.org/#Foundinpd). The expression of α-synuclein (SNCA) is shown as control.