Abstract
The recent Parkinson Disease GWAS Consortium meta-analysis and replication study reports association at several previously confirmed risk loci SNCA, MAPT, GAK/DGKQ, and HLA and identified a novel risk locus at RIT2. To further explore functional consequences of these associations, we investigated modification of gene expression in prefrontal cortex brain samples of pathologically confirmed PD cases (N = 26) and controls (N = 24) by 67 associated SNPs in these 5 loci. Association between the eSNPs and expression was evaluated using a 2-degrees of freedom test of both association and difference in association between cases and controls, adjusted for relevant covariates. SNPs at each of the 5 loci were tested for cis-acting effects on all probes within 250 kb of each locus. Trans-effects of the SNPs on the 39,122 probes passing all QC on the microarray were also examined. From the analysis of cis-acting SNP effects, several SNPs in the MAPT region show significant association to multiple nearby probes, including two strongly correlated probes targeting the gene LOC644246 and the duplicated genes LRRC37A and LRRC37A2, and a third uncorrelated probe targeting the gene DCAKD. Significant cis-associations were also observed between SNPs and two probes targeting genes in the HLA region on chromosome 6. Expanding the association study to examine trans effects revealed an additional 23 SNP-probe associations reaching statistical significance (p<2.8×10−8) including SNPs from the SNCA, MAPT and RIT2 regions. These findings provide additional context for the interpretation of PD associated SNPs identified in recent GWAS as well as potential insight into the mechanisms underlying the observed SNP associations.
Highlights
Genome-wide association studies (GWAS) have been successful in implicating multiple risk loci that have provided new insights into the complex genetic etiology of Parkinson disease [1,2,3,4,5,6,7,8,9]
The recent meta-analysis and replication study by the US Parkinson Disease GWAS Consortium [10] further strengthened the evidence for association of five previously reported risk loci near the genes for alpha-synuclein (SNCA), microtubule associated protein tau (MAPT), cyclin G-associated kinase (GAK), betaglucocerebrosidase (GBA), and the major histocompatibility complex locus (HLA) and identified a novel risk locus near the gene Ras-like without CAAX 2 (RIT2)
We examine the association between SNPs observed to be strongly associated to Parkinson disease (PD) risk in the US Parkinson Disease GWAS Consortium [10] and gene expression levels in 26 PD and 24 control cortical brain samples [13]
Summary
Genome-wide association studies (GWAS) have been successful in implicating multiple risk loci that have provided new insights into the complex genetic etiology of Parkinson disease [1,2,3,4,5,6,7,8,9]. The determination of the relationship of PD associated SNPs to gene expression levels, offers the potential to highlight the responsible gene, as well as to provide insight into the possible pathological mechanisms associated with these SNPs. In this study, we examine the association between SNPs observed to be strongly associated to PD risk in the US Parkinson Disease GWAS Consortium [10] and gene expression levels in 26 PD and 24 control cortical brain samples [13]. This study examines SNP-expression relationships in brain tissue, but in samples with the disease, a strategy which may be necessary for the identification of the disease-related eQTLs [14]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.