Objective: To identify rare variants that may contribute to Parkinson’s disease (PD) risk in individuals whose polygenic background does not adequately explain their disease status.

Background: Monogenic, high-penetrance forms account for only 5–10% of PD cases, and most genetic risk reflects many variants of small effect. Genome-wide association studies (GWAS) have identified over 100 common risk loci, supporting a polygenic architecture for sporadic PD. Polygenic risk scores (PRS), which aggregate the effect weight of these variants into an individual-level metric, can thus be used to stratify relative risk in populations. However, these signals explain only a fraction of overall heritability. The remaining unexplained heritability may reflect contributions from rare variants. Individuals whose disease status is discordant with their polygenic burden may therefore be enriched for additional genetic contributors not captured by common-variant analyses.

Method: Using PRSice-2, we stratified two cohorts by PRS quartiles into four subgroups: top-case vs top-control (TT), top-case vs bottom-control (TB), bottom-case vs top-control (BT) and bottom-case vs bottom-control (BB). We performed a genome-wide exploratory rare-variant burden analysis (variants with minor allele frequency <1%) in the AMP-PD cohort (1,931 cases; 3,062 controls), followed by replication of the top ten signals per subgroup in the UKBB cohort (3,384 cases; 338,955 controls; Application 45551). Rare variant burden analysis was conducted using SKAT-O and results were meta-analyzed using MetaSKAT.

Results: In the exploratory analysis, OTOP1 from the TB (P_CADD=6.28E-08) and BB (P_CADD=1.37E-08) subgroups surpassed the exome-wide significance threshold (2.50E-06). Top hits from the TT and BT subgroups included BRINP1 (P_exonic=8.02E-05) and SLC6A18 (P_CADD=1.13E-05), respectively. In the replication cohort, ZSWIM4 (P_exonic=2.76E-04, P_FDR=9.94E-03) from the BT subgroup was the sole association to survive false discovery rate correction. Meta-analysis further strengthened this signal (P_exonic=1.79E-06, P_FDR=6.09E-05).

Conclusion: We identified a novel association for rare exonic variants of ZSWIM4 and PD risk. The enrichment of this signal in low-PRS cases compared to high-PRS controls suggests that it may contribute to unexplained PD heritability, highlighting the value of PRS-stratification for detecting genetic contributors missed by standard population-wide GWAS.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rare-variant-analysis-in-parkinsons-disease-patients-stratified-by-polygenic-risk/