The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population

the Global Parkinson’s Genetics Program (GP2)

doi:10.1038/s41531-025-00896-2

The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population

the Global Parkinson’s Genetics Program (GP2)

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

Abstract

LRRK2-PD represents the most common form of autosomal dominant Parkinson’s disease. We identified the LRRK2 p.L1795F variant in three families and six additional unrelated cases using genetic data from over 50,000 individuals. Carriers with available genotyping data shared a common haplotype. The clinical presentation resembles other LRRK2-PD forms. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, we provide evidence that LRRK2 p.L1795F is pathogenic.

Original language	English
Article number	58
Journal	npj Parkinson's Disease
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41531-025-00896-2
State	Published - Dec 2025

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10.1038/s41531-025-00896-2

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@article{e8a2f52b725b49358bfdef99e550e496,

title = "The LRRK2 p.L1795F variant causes Parkinson{\textquoteright}s disease in the European population",

abstract = "LRRK2-PD represents the most common form of autosomal dominant Parkinson{\textquoteright}s disease. We identified the LRRK2 p.L1795F variant in three families and six additional unrelated cases using genetic data from over 50,000 individuals. Carriers with available genotyping data shared a common haplotype. The clinical presentation resembles other LRRK2-PD forms. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, we provide evidence that LRRK2 p.L1795F is pathogenic.",

author = "{the Global Parkinson{\textquoteright}s Genetics Program (GP2)} and Lange, {Lara M.} and Kristin Levine and Fox, {Susan H.} and Connie Marras and Nazish Ahmed and Nicole Kuznetsov and Dan Vitale and Hirotaka Iwaki and Katja Lohmann and Luca Marsili and Espay, {Alberto J.} and Peter Bauer and Christian Beetz and Jessica Martin and Factor, {Stewart A.} and Higginbotham, {Lenora A.} and Honglei Chen and Hampton Leonard and Nalls, {Mike A.} and Mencacci, {Niccolo E.} and Morris, {Huw R.} and Singleton, {Andrew B.} and Christine Klein and Cornelis Blauwendraat and Fang, {Zih Hua} and Masharip Atadzhanov and Toan Nguyen and Duan Nguyen and Mathew Koretsky and Makarious, {Mary B.} and Faraz Faghri and Thomas Beach and Tao Xie and Sonya Dumanis and Ruth Walker and Roy Alcalay and Roger Albin and Steven Lubbe and Puckelwartz, {Megan J.} and Matthew Farrer and Marissa Dean and Lisa Shulman and Lauren Ruffrage and Chahine, {Lana M.} and Kenneth Marek and Katerina Markopoulou and Karl Kieburtz and Karen Nuytemans and Galvelis, {Kamalini Ghosh} and Joshua Shulman and Joseph Jankovic and Jared Williamson and Miguel Inca-Martinez and Mata, {Ignacio F.} and Serrano, {Geidy E.} and Ekemini Riley and Ejaz Shiamim and Yeajin Song and Kim, {Jonggeol Jeff} and Dena Hernandez and Deborah Hall and Tatiana Foroud and Claire Wegel and Laura Ibanez and Carlos Cruchaga and Cabell Jonas and Sobering, {Andrew K.} and Todd Sherer and Sohini Chowdhury and Naomi Louie and Maggie Kuhl and Kaileigh Murphy and Solle, {Justin C.} and Charisse Comart and Brian Fiske and Bradford Casey and Bernadette Siddiqi and Alyssa O{\textquoteright}Grady and Sarmiento, {Ignacio Juan Keller} and Sara Bandres-Ciga and Laurel Screven and Kate Andersh and Pantazis, {Caroline B.} and Simon Stott and Seth Love and Lewis, {Patrick Alfryn} and Nigel Williams and Donald Grosset and Claire Bale and Camille Carroll and Vida Obese and Simona Jasaityte and Rimona Weil and Rauan Kaiyrzhanov and Olaitan Okunoye and Nicholas Wood and Mie Rizig and Mok, {Kin Ying} and John Hardy and Henry Houlden and Stafford, {Eleanor J.} and Anthony Schapira and Anette Schrag and Alejandro Mart{\'i}nez-Carrasco and Sumit Dey and Alastair Noyce and Gencer Genc and Sibel Ertan and {\c C}akmak, {{\"O}zg{\"u}r {\"O}ztop} and Ba{\c s}ak, {A. Nazlı} and {Ben Sassi}, Samia and Rim Amouri and Yihru Wu and Wu, {Ruey Meei} and Wu, {Hsiu Chuan} and Kung, {Pin Jui} and Lin, {Chin Hsien} and Gerd Tinkhauser and Paul Krack and Christiane Zweier and Kajsa Brolin and Sarah El-Sadig and Pau Pastor and Peri{\~n}an, {Maria Teresa} and Katrin Beyer and Janet Hoenicka and Ignacio Alvarez and Esther Cubo and Kim, {Yun Joong} and Beomseok Jeon and Soraya Bardien and Jonathan Carr and Ferzana Amod and Foo, {Jia Nee} and Tan, {Eng King} and Muhammad Umair and Mubarak, {Bashayer Al} and Elena Iakovenko and Angel Vinuela and Raymond Rosales and Doquenia, {Maria Leila} and Mario Cornejo-Olivas and Shoaib Ur-Rehman and Manuela Tan and Lasse Pihlstr{\o}m and Aasly, {Jan O.} and Oluwadamilola Ojo and Njideka Okubadejo and Arinola Sanyaolu and Pitcher, {Toni L.} and Anderson, {Tim J.} and Rajeev Ojha and Bayasgalan Tserensodnom and Paula Reyes-P{\'e}rez and Mayela Rodriguez-Violante and Daniel Martinez-Ramirez and Wael Mohamed and Shahrul Azmin and Murad, {Nor Azian Abdul} and Norlinah, {Mohamed Ibrahim} and Tay, {Yi Wen} and Lim, {Shen Yang} and Azlina Ahmad-Annuar and Tan, {Ai Huey} and Rejko Kr{\"u}ger and Cholpon Shambetova and Gulnaz Kaishibayeva and Altynay Karimova and Tomotaka Shiraishi and Nobutaka Hattori and Manabu Funayama and Tommaso Schirinzi and Lucilla Parnetti and Grazia Annesi and Micol Avenali and Valente, {Enza Maria} and Monica Gagliardi and Andrea Quattrone and Mehri Salari and Rupam Borgohain and Roopa Rajan and Kukkle, {Prashanth Lingappa} and Pramod Pal and Divya KP and Asha Kishore and Xiaopu Zhou and Phillip Chan and Nancy Ip and Cheung, {Nelson Yuk Fai} and Chan, {Germaine Hiu Fai} and Alex Medina and Maria Stamelou and Leonidas Stefanis and Ioannis Tarnanas and Ioannis Dagklis and Efthymios Dadiotis and Georgios Hadjigorgiou and Georgia Xiromerisiou and Albert Akpalu and Sergiu Groppa",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41531-025-00896-2",

language = "English",

volume = "11",

journal = "npj Parkinson's Disease",

issn = "2373-8057",

number = "1",

}

TY - JOUR

T1 - The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population

AU - the Global Parkinson’s Genetics Program (GP2)

AU - Lange, Lara M.

AU - Levine, Kristin

AU - Fox, Susan H.

AU - Marras, Connie

AU - Ahmed, Nazish

AU - Kuznetsov, Nicole

AU - Vitale, Dan

AU - Iwaki, Hirotaka

AU - Lohmann, Katja

AU - Marsili, Luca

AU - Espay, Alberto J.

AU - Bauer, Peter

AU - Beetz, Christian

AU - Martin, Jessica

AU - Factor, Stewart A.

AU - Higginbotham, Lenora A.

AU - Chen, Honglei

AU - Leonard, Hampton

AU - Nalls, Mike A.

AU - Mencacci, Niccolo E.

AU - Morris, Huw R.

AU - Singleton, Andrew B.

AU - Klein, Christine

AU - Blauwendraat, Cornelis

AU - Fang, Zih Hua

AU - Atadzhanov, Masharip

AU - Nguyen, Toan

AU - Nguyen, Duan

AU - Koretsky, Mathew

AU - Makarious, Mary B.

AU - Faghri, Faraz

AU - Beach, Thomas

AU - Xie, Tao

AU - Dumanis, Sonya

AU - Walker, Ruth

AU - Alcalay, Roy

AU - Albin, Roger

AU - Lubbe, Steven

AU - Puckelwartz, Megan J.

AU - Farrer, Matthew

AU - Dean, Marissa

AU - Shulman, Lisa

AU - Ruffrage, Lauren

AU - Chahine, Lana M.

AU - Marek, Kenneth

AU - Markopoulou, Katerina

AU - Kieburtz, Karl

AU - Nuytemans, Karen

AU - Galvelis, Kamalini Ghosh

AU - Shulman, Joshua

AU - Jankovic, Joseph

AU - Williamson, Jared

AU - Inca-Martinez, Miguel

AU - Mata, Ignacio F.

AU - Serrano, Geidy E.

AU - Riley, Ekemini

AU - Shiamim, Ejaz

AU - Song, Yeajin

AU - Kim, Jonggeol Jeff

AU - Hernandez, Dena

AU - Hall, Deborah

AU - Foroud, Tatiana

AU - Wegel, Claire

AU - Ibanez, Laura

AU - Cruchaga, Carlos

AU - Jonas, Cabell

AU - Sobering, Andrew K.

AU - Sherer, Todd

AU - Chowdhury, Sohini

AU - Louie, Naomi

AU - Kuhl, Maggie

AU - Murphy, Kaileigh

AU - Solle, Justin C.

AU - Comart, Charisse

AU - Fiske, Brian

AU - Casey, Bradford

AU - Siddiqi, Bernadette

AU - O’Grady, Alyssa

AU - Sarmiento, Ignacio Juan Keller

AU - Bandres-Ciga, Sara

AU - Screven, Laurel

AU - Andersh, Kate

AU - Pantazis, Caroline B.

AU - Stott, Simon

AU - Love, Seth

AU - Lewis, Patrick Alfryn

AU - Williams, Nigel

AU - Grosset, Donald

AU - Bale, Claire

AU - Carroll, Camille

AU - Obese, Vida

AU - Jasaityte, Simona

AU - Weil, Rimona

AU - Kaiyrzhanov, Rauan

AU - Okunoye, Olaitan

AU - Wood, Nicholas

AU - Rizig, Mie

AU - Mok, Kin Ying

AU - Hardy, John

AU - Houlden, Henry

AU - Stafford, Eleanor J.

AU - Schapira, Anthony

AU - Schrag, Anette

AU - Martínez-Carrasco, Alejandro

AU - Dey, Sumit

AU - Noyce, Alastair

AU - Genc, Gencer

AU - Ertan, Sibel

AU - Çakmak, Özgür Öztop

AU - Başak, A. Nazlı

AU - Ben Sassi, Samia

AU - Amouri, Rim

AU - Wu, Yihru

AU - Wu, Ruey Meei

AU - Wu, Hsiu Chuan

AU - Kung, Pin Jui

AU - Lin, Chin Hsien

AU - Tinkhauser, Gerd

AU - Krack, Paul

AU - Zweier, Christiane

AU - Brolin, Kajsa

AU - El-Sadig, Sarah

AU - Pastor, Pau

AU - Periñan, Maria Teresa

AU - Beyer, Katrin

AU - Hoenicka, Janet

AU - Alvarez, Ignacio

AU - Cubo, Esther

AU - Kim, Yun Joong

AU - Jeon, Beomseok

AU - Bardien, Soraya

AU - Carr, Jonathan

AU - Amod, Ferzana

AU - Foo, Jia Nee

AU - Tan, Eng King

AU - Umair, Muhammad

AU - Mubarak, Bashayer Al

AU - Iakovenko, Elena

AU - Vinuela, Angel

AU - Rosales, Raymond

AU - Doquenia, Maria Leila

AU - Cornejo-Olivas, Mario

AU - Ur-Rehman, Shoaib

AU - Tan, Manuela

AU - Pihlstrøm, Lasse

AU - Aasly, Jan O.

AU - Ojo, Oluwadamilola

AU - Okubadejo, Njideka

AU - Sanyaolu, Arinola

AU - Pitcher, Toni L.

AU - Anderson, Tim J.

AU - Ojha, Rajeev

AU - Tserensodnom, Bayasgalan

AU - Reyes-Pérez, Paula

AU - Rodriguez-Violante, Mayela

AU - Martinez-Ramirez, Daniel

AU - Mohamed, Wael

AU - Azmin, Shahrul

AU - Murad, Nor Azian Abdul

AU - Norlinah, Mohamed Ibrahim

AU - Tay, Yi Wen

AU - Lim, Shen Yang

AU - Ahmad-Annuar, Azlina

AU - Tan, Ai Huey

AU - Krüger, Rejko

AU - Shambetova, Cholpon

AU - Kaishibayeva, Gulnaz

AU - Karimova, Altynay

AU - Shiraishi, Tomotaka

AU - Hattori, Nobutaka

AU - Funayama, Manabu

AU - Schirinzi, Tommaso

AU - Parnetti, Lucilla

AU - Annesi, Grazia

AU - Avenali, Micol

AU - Valente, Enza Maria

AU - Gagliardi, Monica

AU - Quattrone, Andrea

AU - Salari, Mehri

AU - Borgohain, Rupam

AU - Rajan, Roopa

AU - Kukkle, Prashanth Lingappa

AU - Pal, Pramod

AU - KP, Divya

AU - Kishore, Asha

AU - Zhou, Xiaopu

AU - Chan, Phillip

AU - Ip, Nancy

AU - Cheung, Nelson Yuk Fai

AU - Chan, Germaine Hiu Fai

AU - Medina, Alex

AU - Stamelou, Maria

AU - Stefanis, Leonidas

AU - Tarnanas, Ioannis

AU - Dagklis, Ioannis

AU - Dadiotis, Efthymios

AU - Hadjigorgiou, Georgios

AU - Xiromerisiou, Georgia

AU - Akpalu, Albert

AU - Groppa, Sergiu

PY - 2025/12

Y1 - 2025/12

N2 - LRRK2-PD represents the most common form of autosomal dominant Parkinson’s disease. We identified the LRRK2 p.L1795F variant in three families and six additional unrelated cases using genetic data from over 50,000 individuals. Carriers with available genotyping data shared a common haplotype. The clinical presentation resembles other LRRK2-PD forms. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, we provide evidence that LRRK2 p.L1795F is pathogenic.

AB - LRRK2-PD represents the most common form of autosomal dominant Parkinson’s disease. We identified the LRRK2 p.L1795F variant in three families and six additional unrelated cases using genetic data from over 50,000 individuals. Carriers with available genotyping data shared a common haplotype. The clinical presentation resembles other LRRK2-PD forms. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, we provide evidence that LRRK2 p.L1795F is pathogenic.

UR - http://www.scopus.com/inward/record.url?scp=105001136183&partnerID=8YFLogxK

U2 - 10.1038/s41531-025-00896-2

DO - 10.1038/s41531-025-00896-2

M3 - Article

C2 - 40133296

AN - SCOPUS:105001136183

SN - 2373-8057

VL - 11

JO - npj Parkinson's Disease

JF - npj Parkinson's Disease

IS - 1

M1 - 58

ER -

The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population

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