Stratification by a polygenic risk score of common variation aids in Alzheimer's disease rare variant discovery

This is the authors' abstract. We don't add key points for this paper.

INTRODUCTION: We utilized an Alzheimer's disease (AD) polygenic risk score (PRS) to discover associations with novel rare variants (RVs). METHODS: PRSs for European ancestry (EA) participants of the Alzheimer's Disease Sequencing Project were calculated using summary statistics from a large genome-wide association study. Participants were classified into high (n = 5738) and low (n = 5324) PRS groups based on the median PRS and on the lower and upper 35% of the PRS distribution. RESULTS: Risk variants were disproportionately enriched in the low-PRS group, while protective ones were disproportionately enriched in the high-PRS group. Genome-wide significant (GWS) associations for increased AD risk were identified with RVs spanning a 3.5-Mb region on chromosome 14. GWS protective variants in ALDH9A1, BICC1, and PAN3 were identified in the upper 35% PRS group. CONCLUSION: Our findings provide unique opportunities to study RVs whose effects are opposite to the risk conferred by the genetic background.