TY - JOUR
T1 - Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset
AU - the Global Parkinson’s Genetics Program (GP2)
AU - Lim, Kai Shi
AU - Periñan, Maria Teresa
AU - Chew, Elaine Guo Yan
AU - Lee, Paul Suhwan
AU - Akçimen, Fulya
AU - Lim, Jia Lun
AU - Koretsky, Mathew J.
AU - Funayama, Manabu
AU - Yoshino, Hiroyo
AU - Hattori, Nobutaka
AU - Kaiyrzhanov, Rauan
AU - Houlden, Henry
AU - Isayan, Mariam
AU - Tay, Yi Wen
AU - Toh, Tzi Shin
AU - Lit, Lei Cheng
AU - Khairul Anuar, Anis Nadhirah
AU - Ding, Hans Xing
AU - Screven, Laurel
AU - Ibrahim, Norlinah Mohamed
AU - Lin, Chin Hsien
AU - Kim, Han Joon
AU - Lee, Jee Young
AU - Chung, Sun Ju
AU - Foo, Jia Nee
AU - Tan, Eng King
AU - Lim, Shen Yang
AU - Tan, Ai Huey
AU - Bandres-Ciga, Sara
AU - Ahmad-Annuar, Azlina
AU - Atadzhanov, Masharip
AU - Nguyen, Toan
AU - Nguyen, Duan
AU - Foroud, Tatiana
AU - Xie, Tao
AU - Walker, Ruth
AU - Alcalay, Roy
AU - Albin, Roger
AU - Shulman, Lisa
AU - Dean, Marissa
AU - Ruffrage, Lauren
AU - Chahine, Lana M.
AU - Marek, Kenneth
AU - Markopoulou, Katerina
AU - Kieburtz, Karl
AU - Nuytemans, Karen
AU - Shulman, Joshua
AU - Inca-Martinez, Miguel
AU - Jankovic, Joseph
AU - Lubbe, Steven
AU - Mencacci, Niccolò E.
AU - Keller Sarmiento, Ignacio Juan
AU - Chen, Honglei
AU - Beach, Thomas
AU - Serrano, Geidy E.
AU - Dumanis, Sonya
AU - Riley, Ekemini
AU - Williamson, Jared
AU - Shamim, Ejaz
AU - Hall, Deborah
AU - Wegel, Claire
AU - Pantazis, Caroline B.
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 - Marsili, Luca
AU - Espay, Alberto
AU - Stott, Simon
AU - Love, Seth
AU - Lewis, Patrick A.
AU - Williams, Nigel
AU - Mok, Kin Y.
AU - Grosset, Donald
AU - Bale, Claire
AU - Carroll, Camille
AU - Obese, Vida
AU - Jasaitye, Simona
AU - Weil, Rimona
AU - Okunoye, Olaitan
AU - Wood, Nicholas
AU - Hardy, John
AU - Morris, Huw
AU - Stafford, Eleanor J.
AU - Schapira, Anthony
AU - Schrag, Anette
AU - Martínez-Carrasco, Alejandro
AU - Genc, Gencer
AU - Ertan, Sibel
AU - Çakmak, Özgür Öztop
AU - Başak, A. Nazl
AU - Sassi, Samia Ben
AU - Amouri, Rim
AU - Wu, Serena
AU - Kung, Pin Jui
AU - Wu, Yih Ru
AU - Wu, Hsiu Chuan
AU - Wu, Ruey Meei
AU - Krack, Paul
AU - Zweier, Christiane
AU - El-Sadig, Sarah
AU - Pastor, Pau
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 - 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 - Pitcher, Toni L.
AU - Anderson, Tim J.
AU - Ojha, Rajeev
AU - Tserensodnom, Bayasgalan
AU - Reayes-Perez, Paula
AU - Rodriguez-Violante, Mayela
AU - Martinez-Ramirez, Daniel
AU - Mohamed, Wael
AU - Azmin, Shahrul
AU - Abdul Murad, Nor Azian
AU - Krüger, Rejko
AU - Shambetova, Cholpon
AU - Kaishibayeva, Gulnaz
AU - Karimova, Altynay
AU - Shiraishi, Tomotaka
AU - Schirinzi, Tommaso
AU - Parnetti, Lucilla
AU - Avenali, Micol
AU - Valente, Enza Maria
AU - Quattrone, Andrea
AU - Salari, Mehri
AU - Borgohain, Rupam
AU - Rajan, Roopa
AU - Kukkle, Prashanth Lingappa
AU - Pal, Pramod
AU - Divya, K. P.
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 - Dardiotis, Efthymios
AU - Hadjigeorgiou, Georgios
AU - Xiromerisiou, Georgia
AU - Akpalu, Albert
AU - Groppa, Sergio
AU - Fang, Zih Hua
AU - Gasser, Thomas
AU - Sharma, Manu
AU - Lange, Lara M.
AU - Höglinger, Günter
AU - Hopfner, Franziska
AU - Mollenhauer, Brit
AU - Illarionova, Anastasia
AU - Lohmann, Katja
AU - Junker, Johanna
AU - Trinh, Joanne
AU - Madoev, Harutyun
AU - Vollstedt, Eva Juliane
AU - Klein, Christine
AU - Westenberger, Ana
AU - Corvol, Jean Christophe
AU - Brice, Alexis
AU - Zewde, Yared Z.
AU - Kamel, Walaa A.
AU - Salama, Mohamed
AU - Hernandez, Alvaro
AU - del Rio, Marlene Jimenez
AU - Orozco, Jorge
AU - Arboleda, Gonzalo
AU - Luo, Wei
N1 - Publisher Copyright:
© The Author(s) 2026.
PY - 2026/12
Y1 - 2026/12
N2 - Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling. (Figure presented.)
AB - Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling. (Figure presented.)
UR - https://www.scopus.com/pages/publications/105032537253
U2 - 10.1038/s41531-026-01265-3
DO - 10.1038/s41531-026-01265-3
M3 - Article
C2 - 41629305
AN - SCOPUS:105032537253
SN - 2373-8057
VL - 12
JO - npj Parkinson's Disease
JF - npj Parkinson's Disease
IS - 1
M1 - 51
ER -