Basic Science and Pathogenesis

Pathway-specific polygenic risk scores (pathway-PRS) are a recently developed tool to measure genetic susceptibility to complex diseases along specific biological pathways. Positional strategies annotating risk variants to pathways may not capture genetic susceptibility in non-coding regions. Risk variant localization to non-coding regions is characteristic of many complex diseases, including Alzheimer's Disease (AD). We evaluated the impact of three annotation strategies on AD pathway-PRS performance in the UK Biobank (UKB).

We performed pathway enrichment analysis on Kunkle et al (Nat Genet 2019) summary statistics. Pathways meeting an adjusted p-value threshold were clustered based on overlapping gene content. Variants were annotated to pathway-cluster genes based on variant position within 35kb upstream to 10kb downstream of gene boundaries ("S-1"); S-1 adding chromatin interaction and expression quantitative trait loci (eQTL)-based annotations on prioritized variants ("S-2"); and variant position within gene exon or promoter regions along with genome-wide chromatin interaction and eQTL-based annotations ("S-3"). Variants annotated to pathway-cluster genes were included in pathway-PRS following clumping and thresholding, with tuning in an independent UKB training set (true/proxy cases=33,370; controls=229,486) and validation in a UKB testing set (true/proxy cases=8,309; controls=57,516).

We identified 20 pathway-clusters representing 37 Gene Ontology (GO) pathways meeting adjusted p≤0.25. S-2 annotated 0.5% more and S-3 56% fewer variants to pathway-cluster genes compared to S-1. There was little change in odds-ratios (OR) and incremental R² (Inc.R²) between S-1 and S-2. Larger differences were observed between S-3 and S-1, with both increases and decreases in OR and Inc.R² (Figures 1 & 2). The pathway-PRS with the largest OR under S-1 and S-2 (OR=1.071, p = 4.5×10^-09) contained four pathways related to regulation of amide metabolism (GO: 0034249), amyloid-beta formation (GO: 1902430), and amyloid precursor catabolism (GO: 1902991 and GO: 1902992). The pathway-PRS with the largest OR under S-3 (OR=1.073, p = 2.7×10^-09) contained four protein and cellular localization pathways (GO:0060341, GO:2000009, GO:0070201, and GO:0032880) (Figure 2).

The inclusion of regulatory variants in AD pathway-PRS lead to the prioritization of protein and cellular localization pathways over amyloid pathways. Additional strategies for pathway-PRS construction, such as incorporating functional annotations as priors, will be tested in future work.