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Abstract
Genome-wide association studies have identified genetic variation in genomic loci associated with susceptibility to Parkinson’s disease (PD), the most common neurodegenerative movement disorder worldwide. We used allelic expression profiling of genes located within PD-associated loci to identify cis-regulatory variation affecting 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-specific expression was identified 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 significant allele-specific effects. Allele-specific effects were confirmed in whole blood for three genes (BCKDK, LZTS3 and MCCC1), whereas two genes (RAB7L1 and NUCKS1) showed brain-specific 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-specific 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.
Highlights
Genome-wide association studies have identified genetic variation in genomic loci associated with susceptibility to Parkinson’s disease (PD), the most common neurodegenerative movement disorder worldwide
The genome-wide association studies (GWAS) era, where thousands of genetic associations have been identified without a known causal mechanism, has created an enormous potential for understanding and treating human disease
In PD, previous studies have found a non-random distribution of risk single nucleotide polymorphisms (SNPs) overlapping with tissue-specific putative regulatory elements[27]
Summary
Genome-wide association studies have identified genetic variation in genomic loci associated with susceptibility to Parkinson’s disease (PD), the most common neurodegenerative movement disorder worldwide. We used allelic expression profiling of genes located within PD-associated loci to identify cis-regulatory variation affecting gene expression. Allele-specific expression was 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. Follow-up analyses of GWAS susceptibility loci aim to establish causal mechanisms underlying the identified associated genetic variants. This is not a straight-forward task since the identified loci normally span numerous genes as a result of the complicated local linkage disequilibrium (LD) structure of many human chromosomal loci. Allele-specific expression is detected, it indicates the presence of cis-regulatory variation in high LD with the transcribed marker used to differentiate between a lleles[18]
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