SCIENTIFIC LITERATURE · MED

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

Parlar SC, Senkevich K, Yu E, Ruskey JA, Ahmad J, Asayesh F, Spiegelman D, Waters C, Monchi O, Dauvilliers Y, Dupré N, Greenbaum L, Hassin-Baer S, Miliukhina I, Timofeeva A, Emelyanov A, Pchelina S, Alcalay RN, Fon EA, Trempe JF, Gan-Or Z.

NPJ Parkinsons Dis · 2025-04-29

DOI: 10.1038/s41531-025-00934-zPMID: 40301370

Open accessbrief-report; Journal ArticleOriginal source ↗

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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: PFDR = 1.61 × 10-22, Non-synonymous: PFDR = 1.54 × 10-23, CADD > 20: PFDR = 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.

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