Evaluation of Parkinson disease risk variants as expression-QTLs

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.

Figure 1. HLA region probes and SNPs involved in significant cis eSNP relationships.

Two probes in the HLA region on chromosme 6 showing significant association with PD risk SNPs are shown on the alternative sequence haplotype chr6_ssto_hap7. Six PD risk SNPs (shown in green) showed significant association to A_24_P326084 located in HLA-DQA1, while four SNPs (shown in red) had significant association to A_24P852756, located in HLA-DQA2.

Figure 2. MAPT region probes and SNPs involved in significant cis eSNP relationships.

Three probes in the MAPT region on chromosme 17 showing significant association with PD risk SNPs are displayed. Significant SNP associations with A_24_P110521 located in the duplicated genes LRRC37A and LRRC37A2 are shown in blue, while SNPs associated with A_24_P221327 located in LOC644246 are shown in green and SNPs associated with A_24_P58331 (in DCAKD) are shown in red.