P2RX7, an adaptive immune response gene, is associated with Parkinson's disease risk and age at onset

BACKGROUND: The adaptive immune response has a role in Parkinson's disease (PD). Patients with LRRK2 or GBA1 mutations often exhibit distinct clinical characteristics. OBJECTIVE: To evaluate the involvement of adaptive immune response genes in three PD groups: GBA1-PD, LRRK2-PD, and non-carrier (NC)-PD. METHODS: Differentially expressed genes (DEGs) associated with PD were identified using four datasets. Of them, adaptive immune response genes were evaluated using whole-genome-sequencing of 201 unrelated Ashkenazi-Jewish (AJ) PD patients. Potential pathogenic variants were identified, and P2RX7 variants were assessed in 1200 AJ-PD patients. Burden analysis of rare variants (allele frequencies (AF) < 0.01) on disease risk, and association analyses of common variants (AF ≥ 0.01) with disease risk and age-at-onset (AAO) were conducted. AFs were compared to AJ-non-neuro cases reported in gnomAD. Variants associated with PD were further examined in an independent AJ cohort from AMP-PD. RESULTS: Of the four adaptive immune DEGs identified, CD8B2, P2RX7, IL27RA, and ZC3H12A, three common variants in P2RX7 were statistically significant: Tyr155His was associated with NC-PD (allelic OR = 1.15, p = 0.015) ; Arg276His was associated with LRRK2-PD (allelic OR = 2.10, p = 0.037), while Glu496Ala was associated with earlier AAO in LRRK2-PD (p = 0.014). Burden analysis showed no significant effect on PD-risk. In the AMP-PD cohort, odds ratios of the two risk variants were similar to the primary cohort, but did not reach significance, probably due to small control sample size (n = 263). CONCLUSIONS: Common variants within P2RX7 are likely associated with PD-risk and earlier AAO. These findings further suggest P2RX7's involvement in PD and its potential interplay with LRRK2.