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

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 TrempeZiv Gan-Or^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	102
Journal	npj Parkinson's Disease
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41531-025-00934-z
State	Published - Dec 2025

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Parlar, S. C., Senkevich, K., Yu, E., Ruskey, J. A., 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, R. N., Fon, E. A., ... Gan-Or, Z. (2025). LRRK2 rare-variant per-domain genetic burden in Parkinson’s Disease: association confined to the kinase domain. npj Parkinson's Disease, 11(1), Article 102. https://doi.org/10.1038/s41531-025-00934-z

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title = "LRRK2 rare-variant per-domain genetic burden in Parkinson{\textquoteright}s Disease: association confined to the kinase domain",

abstract = "LRRK2 variants are key genetic risk factors for Parkinson{\textquoteright}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.",

author = "Parlar, {Sitki Cem} and Konstantin Senkevich and Eric Yu and Ruskey, {Jennifer A.} and Jamil Ahmad and Farnaz Asayesh and Dan Spiegelman and Cheryl Waters and Oury Monchi and Yves Dauvilliers and Nicolas Dupr{\'e} and Lior Greenbaum and Sharon Hassin-Baer and Irina Miliukhina and Alla Timofeeva and Anton Emelyanov and Sofya Pchelina and Alcalay, {Roy N.} and Fon, {Edward A.} and Trempe, {Jean Fran{\c c}ois} and Ziv Gan-Or",

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year = "2025",

month = dec,

doi = "10.1038/s41531-025-00934-z",

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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 2025, 'LRRK2 rare-variant per-domain genetic burden in Parkinson’s Disease: association confined to the kinase domain', npj Parkinson's Disease, vol. 11, no. 1, 102. https://doi.org/10.1038/s41531-025-00934-z

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T1 - LRRK2 rare-variant per-domain genetic burden in Parkinson’s Disease

T2 - association confined to the kinase domain

AU - Parlar, Sitki Cem

AU - Senkevich, Konstantin

AU - Yu, Eric

AU - Ruskey, Jennifer A.

AU - Ahmad, Jamil

AU - Asayesh, Farnaz

AU - Spiegelman, Dan

AU - Waters, Cheryl

AU - Monchi, Oury

AU - Dauvilliers, Yves

AU - Dupré, Nicolas

AU - Greenbaum, Lior

AU - Hassin-Baer, Sharon

AU - Miliukhina, Irina

AU - Timofeeva, Alla

AU - Emelyanov, Anton

AU - Pchelina, Sofya

AU - Alcalay, Roy N.

AU - Fon, Edward A.

AU - Trempe, Jean François

AU - Gan-Or, Ziv

PY - 2025/12

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AB - 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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ER -

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

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