Innate immune genetic variants are associated with Parkinson`s disease

Parkinson`s disease (PD) is a common neurodegenerative disorder with a complex genetic basis. The involvement of inflammation and activation of the innate immune system was demonstrated as part of PD pathology. A different clinical presentation was established in subgroups of PD patients, with either LRRK2 or GBA mutations, and in non-carriers. We aimed to test if genetic variations in innate immune genes are associated with PD status in these subgroups.

Innate immune genes were identified and classified into sub-lists according to their related cellular pathways. Whole-genome-sequencing (WGS) was performed for 201 unrelated Ashkenazi-Jewish (AJ) PD patients including 32 carriers of LRRK2-G2019S (LRRK2-PD), 104 carriers of GBA mutations (GBA-PD), and 65 non-carriers (NC-PD). Gene-based SKAT-O analysis was performed to identify innate immune genes with different burden among PD subgroups, based on innate immune pathways. Candidate variants within significant genes were genotyped in a cohort of 1200 unrelated, consecutively recruited AJ-PD patients (of them 170 with WGS), and analyzed for PD-risk or protection, in the entire cohort and in a stratified manner, compared to AJ-non-neuro cases reported in gnomAD database.

SKAT-O analyses identified a significant different burden of mutation in two genes: PSMB9 (GBA-PD versus NC-PD) and FGR (GBA-PD versus LRRK2-PD) (FDR-p=0.038 and FDR-p=0.037, respectively). Odds ratios of candidate variants within these genes show association with LRRK2-PD-risk (FGR, OR=4.626, CI=1.322-16.189, p=0.016), GBA-PD-risk and NC-PD-risk (PSMB9, OR=2.317, CI=1.178-4.560, p=0.015; OR=2.206, CI=1.258-3.867, p=0.006; respectively).

Our results suggest a genetic involvement of the innate immune system in PD and further support differences between PD subgroups.