Evaluation of Parkinson disease risk variants as expression-QTLs

• Published in: PloS one 2012-10, Vol.7 (10), p.e46199-e46199
• Main Authors: Latourelle, Jeanne C, Dumitriu, Alexandra, Hadzi, Tiffany C, Beach, Thomas G, Myers, Richard H
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Alzheimers disease; Bioinformatics; Biology; Brain; Chromosome 6; Chromosomes; Consortia; DNA methylation; DNA microarrays; Gene duplication; Gene expression; Genes; Genetic Predisposition to Disease; Genetic research; Genomes; Genomics; Health risks; Humans; Kinases; Loci; Medicine; Meta-analysis; Movement disorders; Neurodegenerative diseases; Neurology; Neuropathology; Oligonucleotide Array Sequence Analysis; Parkinson disease; Parkinson Disease - genetics; Parkinson's disease; Parkinsons disease; Polymorphism, Single Nucleotide; Prefrontal cortex; Probes; Quantitative Trait Loci; Risk; Risk factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Statistical analysis; Statistical methods; Studies
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0046199

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