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

Sitki Cem Parlar; Konstantin Senkevich; Eric Yu; Jennifer A. Ruskey; Jamil Ahmad; Farnaz Asayesh; Dan Spiegelman; Cheryl Waters; Oury Monchi; Yves Dauvilliers; Nicolas Dupré; Lior Greenbaum; Sharon Hassin-Baer; Irina Miliukhina; Alla Timofeeva; Anton Emelyanov; Sofya Pchelina; Roy N. Alcalay; Edward A. Fon; Jean-François Trempe; Ziv Gan-Or

doi:10.1038/s41531-025-00934-z

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

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

Sitki Cem Parlar, Konstantin Senkevich, Eric Yu, Jennifer A. Ruskey, Jamil Ahmad, Farnaz Asayesh, Dan Spiegelman, Cheryl Waters, Oury Monchi, Yves Dauvilliers, …

NPJ Parkinson's Disease, Vol.11(1), pp.102-7

29/04/2025

DOI: https://doi.org/10.1038/s41531-025-00934-z

PMID: 40301370

Résumé

Brief Communication

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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Titre: LRRK2 rare-variant per-domain genetic burden in Parkinson’s Disease: association confined to the kinase domain
Créateurs - sans rôle: Sitki Cem Parlar - Montréal, QC Canada Montréal, QC Canada Montréal, QC Canada
Konstantin Senkevich - Montréal, QC Canada Montréal, QC Canada Montreal, QC Canada
Eric Yu - Montréal, QC Canada Montréal, QC Canada
Jennifer A. Ruskey - Montréal, QC Canada Montréal, QC Canada
Jamil Ahmad - Montréal, QC Canada Montréal, QC Canada
Farnaz Asayesh - Montréal, QC Canada Montréal, QC Canada
Dan Spiegelman - Montréal, QC Canada
Cheryl Waters - New York, NY USA
Oury Monchi - Montréal, QC Canada Calgary, AB Canada Calgary, AB Canada
Yves Dauvilliers - Montpellier, France
Nicolas Dupré - Quebec City, QC Canada Québec, QC Canada
Lior Greenbaum - Ramat Gan, Israel Ramat Gan, Israel Tel Aviv-Yafo, Israel
Sharon Hassin-Baer - Tel Aviv-Yafo, Israel Tel Aviv, Israel
Irina Miliukhina - Saint Petersburg, Russia
Alla Timofeeva - Saint Petersburg, Russia
Anton Emelyanov - Saint Petersburg, Russia
Sofya Pchelina - Saint Petersburg, Russia
Roy N. Alcalay - New York, NY USA Tel Aviv-Yafo, Israel
Edward A. Fon - Montréal, QC Canada Montréal, QC Canada Montreal, QC Canada
Jean-François Trempe - Montréal, QC Canada
Ziv Gan-Or - Montréal, QC Canada Montréal, QC Canada Montréal, QC Canada
Détails de publication: NPJ Parkinson's Disease, Vol.11(1), pp.102-7
Éditeur: Nature Publishing Group UK
Identifiants: 99140083909311
Unité académique: Institut des Neurosciences de Montpellier - INM
Langue: English
Type de ressource: Journal article