Allele-specific expression of Parkinson’s disease susceptibility genes in human brain

Abstract

Genome-wide association studies have identifed genetic variation in genomic loci associated with susceptibility to Parkinson’s disease (PD), the most common neurodegenerative movement disorder worldwide. We used allelic expression profling of genes located within PD-associated loci to identify cis-regulatory variation afecting gene expression. DNA and RNA were extracted from post-mortem superior frontal gyrus tissue and whole blood samples from PD patients and controls. The relative allelic expression of transcribed SNPs in 12 GWAS risk genes was analysed by real-time qPCR. Allele-specifc expression was identifed for 9 out of 12 genes tested (GBA, TMEM175, RAB7L1, NUCKS1, MCCC1, BCKDK, ZNF646, LZTS3, and WDHD1) in brain tissue samples. Three genes (GPNMB, STK39 and SIPA1L2) did not show signifcant allele-specifc efects. Allele-specifc efects were confrmed in whole blood for three genes (BCKDK, LZTS3 and MCCC1), whereas two genes (RAB7L1 and NUCKS1) showed brain-specifc allelic expression. Our study supports the hypothesis that changes to the cis-regulation of gene expression is a major mechanism behind a large proportion of genetic associations in PD. Interestingly, allele-specifc expression was also observed for coding variants believed to be causal variants (GBA and TMEM175), indicating that splicing and other regulatory mechanisms may be involved in disease development.