Parkinson's disease-associated genetic variation is linked to quantitative expression of inflammatory genes

Abstract

Genome-wide association studies (GWAS) have linked dozens of single nucleotide polymorphisms (SNPs) with Parkinson's disease (PD) risk. Ascertaining the functional and eventual causal mechanisms underlying these relationships has proven difficult. The majority of risk SNPs, and nearby SNPs in linkage disequilibrium (LD), are found in intergenic or intronic regions and confer risk through allele-dependent expression of multiple unknown target genes. Combining GWAS results with publicly available GTEx data, generated through eQTL (expression quantitative trait loci) identification studies, enables a direct association of SNPs to gene expression levels and aids in narrowing the large population of potential genetic targets for hypothesis-driven experimental cell biology. Separately, overlapping of SNPs with putative enhancer segmentations can strengthen target filtering. We report here the results of analyzing 7,607 PD risk SNPs along with an additional 23,759 high linkage disequilibrium-associated variants paired with eQTL gene expression. We found that enrichment analysis on the set of genes following target filtering pointed to a single large LD block at 6p21 that contained multiple HLA-MHC-II genes. These MHC-II genes remain associated with PD when the genes were filtered for correlation between GWAS significance and eQTL levels, strongly indicating a direct effect on PD etiology.

Fig 1. Study Design.

(A) Euler diagram of 7,607 risk SNPs linked to PD obtained from three sources. Numbers represent the number of variants number in the entire set. (B) Surrogate variants in LD (r² > 0.8) with risk SNPs were added to obtain 31,366 unique SNPs. (C) Flow chart of study design, (detail found in S1–S3 Files). (D) Manhattan plot of associated risk significance for 31,366 SNPS. (E) Manhattan plot of 17,109 SNPs which have an associated significant eQTL measurement in any of 53 tissues from GTEx.

Fig 2. Correlation between GWAS significance and eQTL expression level.

(A) Sample plots of the relationship between GWAS significance and eQTL expression for genes at the HLA, LRRK2, and MAPT loci. (B) Heatmap of positive correlation (green) coefficients for 27 genes at the HLA locus.

Fig 3. UCSC browser view of MHC-II HLA locus.

GWAS p values are from Nalls et. al [3]. A total of 595 PD risk SNPs that overlap dbSUPER defined super-enhancers, show eQTLs, and disrupt a TF binding motif (labeled disrupt eQTL SNPs, S1 File) are shown.