Enrichment of risk SNPs in regulatory regions implicate diverse tissues in Parkinson's disease etiology

Abstract

Recent genome-wide association studies (GWAS) of Parkinson's disease (PD) revealed at least 26 risk loci, with associated single nucleotide polymorphisms (SNPs) located in non-coding DNA having unknown functions in risk. In order to explore in which cell types these SNPs (and their correlated surrogates at r(2) ≥ 0.8) could alter cellular function, we assessed their location overlap with histone modification regions that indicate transcription regulation in 77 diverse cell types. We found statistically significant enrichment of risk SNPs at 12 loci in active enhancers or promoters. We investigated 4 risk loci in depth that were most significantly enriched (-logeP > 14) and contained 8 putative enhancers in the different cell types. These enriched loci, along with eQTL associations, were unexpectedly present in non-neuronal cell types. These included lymphocytes, mesendoderm, liver- and fat-cells, indicating that cell types outside the brain are involved in the genetic predisposition to PD. Annotating regulatory risk regions within specific cell types may unravel new putative risk mechanisms and molecular pathways that contribute to PD development.

Figure 1. Tissue specific enrichment at PD GWAS loci.

The relative enrichment of 21 index SNP (x axis) is shown by multiple hypothesis adjusted p-value (negative natural log) for each of the 77 REMC tissues (y axis). The data from Supplemental Table 1 are plotted; color from white to red indicates increasingly significant hits. SNPs and tissues selected for in-depth analysis are highlighted with red type on the axes and with guidelines on the plot. The specific SNP–tissue interactions that appear in subsequent figures are outlined in black.

Figure 2. Functional enrichment at the 4q21 locus.

Segmentation tracks summarize the functional annotations according to the REMC color scheme: orange for EAR (active enhancer), rose for PAR (active promoter), light purple for EPR and PPR (poised enhancers and promoters), grey for SCR (silenced regions), blue-grey for HET (heterochromatic) and green for TRS (transcribed). Wiggle tracks for H3K4me1 and H3K27Ac show the fine-grained epigenomics context in the regions surrounding each locus. The location of SNPs that disrupt transcription factor motifs are indicated with a dotted black line and an expanded view at the bottom. The motif is aligned with the genomic sequence surrounding the SNP, whose position is indicated in red; reference and alternate alleles are indicated in the red bounding box in the sequence below.

Figure 3. Functional enrichment at the 8p22 locus.

(a,b) Two different regions at 8p22. Segmentation tracks summarize the functional annotations according to the REMC color scheme: orange for active enhancer, rose for active promoter, light purple for poised enhancers and promoters, grey for silenced regions, blue-grey for heterochromatin and green for transcribed regions. Wiggle tracks for H3K4me1 and H3K27ac show the fine-grained epigenomics context in the regions surrounding each locus. The location of SNPs that disrupt transcription factor motifs are indicated with a dotted black line and an expanded view at the bottom. The motif is aligned with the genomic sequence surrounding the SNP, whose position is indicated in red; reference and alternate alleles are indicated in the red bounding box in the sequence below.

Figure 4. Functional enrichment at the 12q12 locus.

Segmentation tracks summarize the functional annotations according to the REMC color scheme: orange for active enhancer, rose for active promoter, light purple for poised enhancers and promoters, grey for silenced regions, blue-grey for heterochromatin and green for transcribed regions. Wiggle tracks for H3K4me1 and H3K27ac show the fine-grained epigenomics context in the regions surrounding each locus. The location of SNPs that disrupt transcription factor motifs are indicated with a dotted black line and an expanded view at the bottom. The motif is aligned with the genomic sequence surrounding the SNP, whose position is indicated in red; reference and alternate alleles are indicated in the red bounding box in the sequence below.

Figure 5. Functional enrichment at the 14q24 locus.

Segmentation tracks summarize the functional annotations according to the REMC color scheme: orange for active enhancer, rose for active promoter, light purple for poised enhancers and promoters, grey for silenced regions, blue-grey for heterochromatin and green for transcribed regions. Wiggle tracks for H3K4me1 and H3K27ac show the fine-grained epigenomics context in the regions surrounding each locus. The location of SNPs that disrupt transcription factor motifs are indicated with a dotted black line and an expanded view at the bottom. The motif is aligned with the genomic sequence surrounding the SNP, whose position is indicated in red; reference and alternate alleles are indicated in the red bounding box in the sequence below.

Figure 6. Outline of the novel connections made in this study.