Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis

Abstract

Objective: Understanding how different parts of the immune system contribute to pathogenesis in Parkinson's disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson's disease stratified by immune and brain cell types.

Methods: We used summary statistics from the most recent meta-analysis of genomewide association studies in Parkinson's disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types, as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus.

Results: We found significant enrichment of Parkinson's disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these 2 cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting P2RY12, a key microglial gene and target for the antithrombotic agent clopidogrel, as the likely driver of a significant Parkinson's disease association signal on chromosome 3.

Interpretation: Our results provide further support for the importance of immune mechanisms in Parkinson's disease pathogenesis, highlight microglial dysregulation as a contributing etiological factor, and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson's disease. ANN NEUROL 2021;89:942-951.

FIGURE 1:

Stratified LD score regression at tissue level. Results from s-LDSC applied to 5 major tissue groups using either specifically expressed genes or open chromatin regions as identified by ATAC-seq to partition heritability. The dashed line represents a nominal significance threshold of 1-sided p < 0.05. ATAC-seq = Assay for Transposase-Accessible Chromatin sequencing; GTEx = Genotype-Tissue Expression; LD = linkage disequilibrium; s-LDSC = stratified linkage disequilibrium score regression. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 2:

Stratified LD score regression in immune and brain cells. Results from s-LDSC applied to immune and brain cells using open chromatin regions as identified by ATAC-seq to partition the genome. The dashed line represents a Bonferroni-corrected significance threshold of 1-sided p < 0.00625. ATAC-seq = Assay for Transposase-Accessible Chromatin sequencing; LD = linkage disequilibrium; s-LDSC = stratified linkage disequilibrium score regression. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 3:

Pairwise Jaccard statistics for brain and immune cell ATAC-seq peaks. The plot shows Jaccard statistics for the pairwise intersection of ATAC-seq peaks for investigated immune and brain cell types (left) and the total size of open chromatin regions for each cell type (right). Microglia show more overlap with immune cells than other brain cells, and highest overlap with monocytes. ATAC-seq = Assay for Transposase-Accessible Chromatin sequencing.

FIGURE 4:

Venn diagram of genomic positions within ATAC-seq peaks of microglia and monocytes. Venn diagram showing the proportion of overlapping versus unique open chromatin as assessed by ATAC- seq in monocytes and microglia. ATAC-seq = Assay for Transposase-Accessible Chromatin sequencing. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 5:

Overview of the P2RY12 locus. The top panel shows a regional Manhattan plot of the MED12L/P2RY12 locus in PD based on summary statistics from the most recent meta-analysis of PD GWAS. Below, the region containing significant SNPs is expanded to show the location of SNPs belonging to the 95% credible set in relation to brain cell specific results from ATAC-seq and Chromatin immunoprecipitation (ChIP)-seq of H3K27ac, a histone modification marking active enhancers. Credible set variants that colocalize with ATAC-seq peaks within a microglia-specific enhancer region are highlighted with yellow lines. ATAC-seq = Assay for Transposase-Accessible Chromatin sequencing; GWAS = genomewide association studies; PD = Parkinson’s disease; SNPs = single-nucleotide polymorphisms.