LRRK2 rare-variant per-domain genetic burden in Parkinson’s Disease: association confined to the kinase domain
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<sup>FDR</sup> = 1.61 × 10<sup>-22</sup>, Non-synonymous: P<sup>FDR</sup> = 1.54 × 10<sup>-23</sup>, CADD > 20: P<sup>FDR</sup> = 3.09 × 10<sup>-24</sup>). 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.
Authors
- Konstantin Senkevich (ORCID: https://orcid.org/0000-0003-3407-5716)
- Farnaz Asayesh
- Cheryl Waters (ORCID: https://orcid.org/0000-0002-1908-8773)
- Jean‐François Trempe (ORCID: https://orcid.org/0000-0002-6543-3371)
- Edward A. Fon (ORCID: https://orcid.org/0000-0002-5520-6239)
- Jennifer A. Ruskey (ORCID: https://orcid.org/0000-0002-6392-5014)
- Oury Monchi (ORCID: https://orcid.org/0000-0003-2148-5409)
- Sharon Hassin‐Baer (ORCID: https://orcid.org/0000-0001-7657-0171)
- Dan Spiegelman (ORCID: https://orcid.org/0000-0001-6450-3238)
- Sitki Cem Parlar (ORCID: https://orcid.org/0009-0003-9026-114X)
- Irina Miliukhina (ORCID: https://orcid.org/0000-0002-6433-542X)
- Lior Greenbaum (ORCID: https://orcid.org/0000-0001-6176-0941)
- Eric Yu (ORCID: https://orcid.org/0000-0003-3525-4564)
- Nicolas Dupré (ORCID: https://orcid.org/0000-0001-7270-6115)
- Yves A Dauvilliers (ORCID: https://orcid.org/0000-0003-0683-6506)
- Ziv Gan‐Or (ORCID: https://orcid.org/0000-0003-0332-234X)
- Jamil Ahmad (ORCID: https://orcid.org/0000-0003-4594-2723)
- Alla Timofeeva (ORCID: https://orcid.org/0000-0003-1661-7753)
- Anton Emelyanov (ORCID: https://orcid.org/0000-0002-3249-7889)
- Roy N. Alcalay
- Sofya Pchelina
Institutions
- Montreal Neurological Institute and Hospital (CA)
- Tel Aviv University (IL)
- University of Calgary (CA)
- Université de Montpellier (FR)
- Columbia University Irving Medical Center (US)
- First Pavlov State Medical University of St. Petersburg (RU)
- Tel Aviv Sourasky Medical Center (IL)
- Sheba Medical Center (IL)
- McGill University Health Centre (CA)
- Institute of the Human Brain (RU)
- McGill Genome Centre (CA)
- Academic College of Tel Aviv-Yafo (IL)
- Ontario Brain Institute (CA)
- Université Laval (CA)
- Hotchkiss Brain Institute (CA)
- McGill University (CA)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1038/s41531-025-00934-z
- Citations
- 2
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.78
Funders
- U.S. Department of Health and Human Services
- Bristol-Myers Squibb
- Pfizer
- GlaxoSmithKline
- Sanofi
- Celgene
- McGill University
- Verily Life Sciences
- Canada First Research Excellence Fund
- Alliance de recherche numérique du Canada
- National Institutes of Health
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé
- National Institute of Neurological Disorders and Stroke
- Accelerated Innovation Research Initiative Turning Top Science and Ideas into High-Impact Values