LRRK2 rare-variant per-domain genetic burden in Parkinson's Disease: association confined to the kinase domain.

ABSTRACT: LRRK2 variants are key genetic risk factors for Parkinson's Disease (PD). We conducted a per-domain rare coding variant burden analysis, including 8,888 PD cases and 69,412 controls. In meta-analysis, the Kinase domain was strongly associated with PD (Exonic: P^FDR = 1.61 × 10^-22, Non-synonymous: P^FDR = 1.54 × 10^-23, CADD > 20: P^FDR = 3.09 × 10^-24). Excluding the p.G2019S variant nullified this effect. Nominal associations were found in the ANK and Roc-COR domains, with potentially protective variants, p.R793M and p.Q1353K.

SUBMITTER: Parlar SC 

PROVIDER: S-EPMC12041573 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature