Publication:
Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset

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dc.contributor.coauthorLim, Kai Shi
dc.contributor.coauthorPeriñan, Maria Teresa
dc.contributor.coauthorChew, Elaine Guo Yan
dc.contributor.coauthorLee, Paul Suhwan
dc.contributor.coauthorAkçimen, Fulya
dc.contributor.coauthorLim, Jia Lun
dc.contributor.coauthorKoretsky, Mathew J.
dc.contributor.coauthorFunayama, Manabu
dc.contributor.coauthorYoshino, Hiroyo
dc.contributor.coauthorHattori, Nobutaka
dc.contributor.coauthorKaiyrzhanov, Rauan
dc.contributor.coauthorHoulden, Henry
dc.contributor.coauthorIsayan, Mariam
dc.contributor.coauthorTay, Yi Wen
dc.contributor.coauthorToh, Tzi Shin
dc.contributor.coauthorLit, Lei-Cheng
dc.contributor.coauthorKhairul Anuar, Anis Nadhirah
dc.contributor.coauthorDing, Hans Xing
dc.contributor.coauthorScreven, Laurel
dc.contributor.coauthorIbrahim, Norlinah Mohamed
dc.contributor.coauthorLin, Chin-Hsien
dc.contributor.coauthorKim, Han-Joon
dc.contributor.coauthorLee, Lee-Young
dc.contributor.coauthorChung, Sun Ju
dc.contributor.coauthorFoo, Jia Nee
dc.contributor.coauthorTan, Eng-King
dc.contributor.coauthorLim, Shen-Yang
dc.contributor.coauthorTan, Ai Huey
dc.contributor.coauthorBandres-Ciga, Sara
dc.contributor.coauthorAhmad-Annuar, Azlina
dc.contributor.coauthorAtadzhanov, Masharip
dc.contributor.coauthorNguyen, Toan
dc.contributor.coauthorNguyen, Duan
dc.contributor.coauthorForoud, Tatiana
dc.contributor.coauthorXie, Tao
dc.contributor.coauthorWalker, Ruth
dc.contributor.coauthorAlcalay, Roy
dc.contributor.coauthorAlbin, Roger
dc.contributor.coauthorShulman, Lisa
dc.contributor.coauthorDean, Marissa
dc.contributor.coauthorRuffrage, Lauren
dc.contributor.coauthorChahine, Lana M.
dc.contributor.coauthorMarek, Kenneth
dc.contributor.coauthorMarkopoulou, Katerina
dc.contributor.coauthorKieburtz, Karl
dc.contributor.coauthorNuytemans, Karen
dc.contributor.coauthorShulman, Joshua
dc.contributor.coauthorInca-Martinez, Miguel
dc.contributor.coauthorJankovic, Joseph
dc.contributor.coauthorLubbe, Steven
dc.contributor.coauthorMencacci, Niccolò E.
dc.contributor.coauthorKeller Sarmiento, Ignacio Juan
dc.contributor.coauthorChen, Honglei
dc.contributor.coauthorBeach, Thomas
dc.contributor.coauthorSerrano, Geidy E.
dc.contributor.coauthorDumanis, Sonya
dc.contributor.coauthorRiley, Ekemini
dc.contributor.coauthorWilliamson, Jared
dc.contributor.coauthorShamim, Ejaz
dc.contributor.coauthorHall, Deborah
dc.contributor.coauthorWegel, Claire
dc.contributor.coauthorPantazis, Caroline B.
dc.contributor.coauthorCruchaga, Carlos
dc.contributor.coauthorJonas, Cabell
dc.contributor.coauthorSobering, Andrew K.
dc.contributor.coauthorSherer, Todd
dc.contributor.coauthorChowdhury, Sohini
dc.contributor.coauthorLouie, Naomi
dc.contributor.coauthorKuhl, Maggie
dc.contributor.coauthorMurphy, Kaileigh
dc.contributor.coauthorSolle, Justin C.
dc.contributor.coauthorComart, Charisse
dc.contributor.coauthorFiske, Brian
dc.contributor.coauthorCasey, Bradford
dc.contributor.coauthorSiddiqi, Bernadette
dc.contributor.coauthorO’Grady, Alyssa
dc.contributor.coauthorMarsili, Luca
dc.contributor.coauthorEspay, Alberto
dc.contributor.coauthorStott, Simon
dc.contributor.coauthorLove, Seth
dc.contributor.coauthorLewis, Patrick A.
dc.contributor.coauthorWilliams, Nigel
dc.contributor.coauthorMok, Kin Y.
dc.contributor.coauthorGrosset, Donald
dc.contributor.coauthorBale, Claire
dc.contributor.coauthorCarroll, Camille
dc.contributor.coauthorObese, Vida
dc.contributor.coauthorJasaitye, Simona
dc.contributor.coauthorWeil, Rimona
dc.contributor.coauthorOkunoye, Olaitan
dc.contributor.coauthorWood, Nicholas
dc.contributor.coauthorHardy, John
dc.contributor.coauthorMorris, Huw
dc.contributor.coauthorStafford, Eleanor J.
dc.contributor.coauthorSchapira, Anthony
dc.contributor.coauthorSchrag, Anette
dc.contributor.coauthorMartínez-Carrasco, Alejandro
dc.contributor.coauthorGenç, Gencer
dc.contributor.coauthorSassi, Samia Ben
dc.contributor.coauthorAmouri, Rim
dc.contributor.coauthorWu, Serena
dc.contributor.coauthorKung, Pin-Jui
dc.contributor.coauthorWu, Yih-Ru
dc.contributor.coauthorWu, Hsiu-Chuan
dc.contributor.coauthorWu, Ruey-Meei
dc.contributor.coauthorKrack, Paul
dc.contributor.coauthorZweier, Christiane
dc.contributor.coauthorEl-Sadig, Sarah
dc.contributor.coauthorPastor, Pau
dc.contributor.coauthorBeyer, Katrin
dc.contributor.coauthorHoenicka, Janet
dc.contributor.coauthorAlvarez, Ignacio
dc.contributor.coauthorCubo, Esther
dc.contributor.coauthorKim, Yun Joong
dc.contributor.coauthorJeon, Beomseok
dc.contributor.coauthorBardien, Soraya
dc.contributor.coauthorCarr, Jonathan
dc.contributor.coauthorAmod, Ferzana
dc.contributor.coauthorUmair, Muhammad
dc.contributor.coauthorMubarak, Bashayer Al
dc.contributor.coauthorIakovenko, Elena
dc.contributor.coauthorVinuela, Angel
dc.contributor.coauthorRosales, Raymond
dc.contributor.coauthorDoquenia, Maria Leila
dc.contributor.coauthorCornejo-Olivas, Mario
dc.contributor.coauthorUr-Rehman, Shoaib
dc.contributor.coauthorTan, Manuela
dc.contributor.coauthorPihlstrøm, Lasse
dc.contributor.coauthorAasly, Jan O.
dc.contributor.coauthorOjo, Oluwadamilola
dc.contributor.coauthorPitcher, Toni L.
dc.contributor.coauthorAnderson, Tim J.
dc.contributor.coauthorOjha, Rajeev
dc.contributor.coauthorTserensodnom, Bayasgalan
dc.contributor.coauthorReayes-Perez, Paula
dc.contributor.coauthorRodriguez-Violante, Mayela
dc.contributor.coauthorMartinez-Ramirez, Daniel
dc.contributor.coauthorMohamed, Wael
dc.contributor.coauthorAzmin, Shahrul
dc.contributor.coauthorAbdul Murad, Nor Azian
dc.contributor.coauthorKrüger, Rejko
dc.contributor.coauthorShambetova, Cholpon
dc.contributor.coauthorKaishibayeva, Gulnaz
dc.contributor.coauthorKarimova, Altynay
dc.contributor.coauthorShiraishi, Tomotaka
dc.contributor.coauthorSchirinzi, Tommaso
dc.contributor.coauthorParnetti, Lucilla
dc.contributor.coauthorAvenali, Micol
dc.contributor.coauthorValente, Enza Maria
dc.contributor.coauthorQuattrone, Andrea
dc.contributor.coauthorSalari, Mehri
dc.contributor.coauthorBorgohain, Rupam
dc.contributor.coauthorRajan, Roopa
dc.contributor.coauthorKukkle, Prashanth Lingappa
dc.contributor.coauthorPal, Pramod
dc.contributor.coauthorDivya, K.P.
dc.contributor.coauthorKishore, Asha
dc.contributor.coauthorZhou, Xiaopu
dc.contributor.coauthorChan, Phillip
dc.contributor.coauthorIp, Nancy
dc.contributor.coauthorCheung, Nelson Yuk-Fai
dc.contributor.coauthorChan, Germaine Hiu-Fai
dc.contributor.coauthorMedina, Alex
dc.contributor.coauthorStamelou, Maria
dc.contributor.coauthorStefanis, Leonidas
dc.contributor.coauthorTarnanas, Ioannis
dc.contributor.coauthorDagklis, Ioannis
dc.contributor.coauthorDardiotis, Efthymios
dc.contributor.coauthorHadjigeorgiou, Georgios
dc.contributor.coauthorXiromerisiou, Georgia
dc.contributor.coauthorAkpalu, Albert
dc.contributor.coauthorGroppa, Sergio
dc.contributor.coauthorFang, Zih-Hua
dc.contributor.coauthorGasser, Thomas
dc.contributor.coauthorSharma, Manu
dc.contributor.coauthorLange, Lara M.
dc.contributor.coauthorHöglinger, Günter
dc.contributor.coauthorHopfner, Franziska
dc.contributor.coauthorMollenhauer, Brit
dc.contributor.coauthorIllarionova, Anastasia
dc.contributor.coauthorLohmann, Katja
dc.contributor.coauthorJunker, Johanna
dc.contributor.coauthorTrinh, Joanne
dc.contributor.coauthorMadoev, Harutyun
dc.contributor.coauthorVollstedt, Eva-Juliane
dc.contributor.coauthorKlein, Christine
dc.contributor.coauthorWestenberger, Ana
dc.contributor.coauthorCorvol, Jean-Christophe
dc.contributor.coauthorBrice, Alexis
dc.contributor.coauthorZewde, Yared Z.
dc.contributor.coauthorKamel, Walaa A.
dc.contributor.coauthorSalama, Mohamed
dc.contributor.coauthorHernandez, Alvaro
dc.contributor.coauthordel Rio, Marlene Jimenez
dc.contributor.coauthorOrozco, Jorge
dc.contributor.coauthorArboleda, Gonzalo
dc.contributor.coauthorLuo, Wei
dc.contributor.coauthorChan, Piu
dc.contributor.coauthorGuo, Jifeng
dc.contributor.coauthorShang, Huifang
dc.contributor.coauthorTang, Beisha
dc.contributor.coauthorBustamante, Maria Leonor
dc.contributor.coauthorMiranda, Marcelo
dc.contributor.coauthorOlguin, Patricio
dc.contributor.coauthorGalleguillos, Benjamin Pizarro
dc.contributor.coauthorMonchi, Oury
dc.contributor.coauthorFon, Ted
dc.contributor.coauthorFon, Edward A.
dc.contributor.coauthorCamargos, Sarah
dc.contributor.coauthorTumas, Vitor
dc.contributor.coauthorRieder, Carlos
dc.contributor.coauthorZimprich, Alexander
dc.contributor.coauthorKoks, Sulev
dc.contributor.coauthorRentería, Miguel E.
dc.contributor.coauthorEllis, Melina
dc.contributor.coauthorKumar, Kishore
dc.contributor.coauthorHunter, Julie
dc.contributor.coauthorShepherd, Claire E.
dc.contributor.coauthorTavadyan, Zaruhi
dc.contributor.coauthorKhachatryan, Samson
dc.contributor.coauthorKauffman, Marcelo
dc.contributor.coauthorGatto, Emilia M.
dc.contributor.coauthorOkubadejo, Njideka
dc.contributor.coauthorRizig, Mie
dc.contributor.coauthorYan, Chew Elaine Guo
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorBaşak, Ayşe Nazlı
dc.contributor.kuauthorÇakmak, Özgür Öztop
dc.contributor.kuauthorErtan, Fatoş Sibel
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2026-07-02T07:28:48Z
dc.date.issued2026
dc.description.abstractCommon 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
dc.description.abstract95% CI: 1.66–5.10
dc.description.abstractp = 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.) © The Author(s) 2026.
dc.description.fulltextNo
dc.description.harvestedfromManual
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.openaccessAll Open Access
dc.description.openaccessGold Open Access
dc.description.openaccessGreen Open Access
dc.description.publisherscopeInternational
dc.description.readpublishN/A
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipWe gratefully acknowledge all the participants for their contributions, without whom this research would not have been possible. Data and code used to prepare this article were obtained from the Global Parkinson's Genetics Program (GP2). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (https://gp2.org). For a complete list of GP2 members, see https://gp2.org. Data used to prepare this article were obtained from the Accelerating Medicines Partnership (R) (AMP (R)) Parkinson's Disease (AMP (R) PD) Knowledge Platform. For up-to-date information on the study, visit https://www.amp-pd.org. ACCELERATING MEDICINES PARTNERSHIP and AMP are registered service marks of the US Department of Health and Human Services. We thank the research participants for consenting to this study. Additionally, data used in this article were obtained from the UK Biobank, the All of Us Research Program, an East Asian whole-exome dataset, and a Japanese whole-exome dataset. This research has been conducted using the UK Biobank Resource under Application Number 33601. The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276. In addition, the All of Us Research Program would not be possible without the partnership of its participants. We have received an exception to the Data and Statistics Dissemination Policy from the All of Us Resource Access Board. The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. The authors declared no potential conflicts of interest for the research, authorship, and/or publication of this article. We thank Paige Jarreau for assistance with the graphical abstract. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services; project number ZO1 AG000535 and ZIA AG000949, as well as the National Institute of Neurological Disorders and Stroke (NINDS) and the National Human Genome Research Institute (NHGRI). This project was also supported by the Global Parkinson's Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (MJFF). For a complete list of GP2 members see https://doi.org/10.5281/zenodo.7904831. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Additional funding was provided by The Michael J. Fox Foundation for Parkinson's Research through grant MJFF-009421/17483. The AMP (R) PD program is a public-private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute of Neurological Disorders and Stroke (NINDS) in partnership with the Aligning Science Across Parkinson's (ASAP) initiative; Celgene Corporation, a subsidiary of Bristol-Myers Squibb Company; GlaxoSmithKline plc (GSK); The Michael J. Fox Foundation for Parkinson's Research; Pfizer Inc.; Sanofi US Services Inc.; and Verily Life Sciences. The Malaysian cohort was supported by funding from the Ministry of Higher Education Malaysia Fundamental Research Grant Scheme (FRGS/1/2020/SKK0/UM/01/2) and the University of Malaya Parkinson's Disease and Movement Disorders Research Program (PV035-2017). The Singapore East Asian work was supported by the Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant (MOH-000207; to E.-K.T), Open Fund Individual Research Grant (MOH-000559; to J.N.F.), as well as the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE-T2EP30220-0005; to J.N.F.) and Tier 3 (MOE-MOET32020-0004; to J.N.F.). The Japan East Asian work was supported by The Japan Society for the Promotion of Science (JSPS) KAKENHI (24K02372 and 23K06958; to F.M. and 24H00068 to H.N.), The Japan Agency for Medical Research and Development (AMED) (25bm1423015h0003; to both F.M. and H.N. while 24ek0109677h0002, JP23dm0207070, and JP23dm0307101 to H.N.), The Japan Science and Technology Agency (JST) Moonshot R&D Program (JPMJMS2024-5 to H.N.) and Promotion and Mutual Aid Corporation for Private Schools of Japan, a subaward from Juntendo University awarded to both F.M. and H.N. The CAT-PD Consortium is supported by the Global Parkinson's Genetics Program (GP2; grant ID MJFF-022153).
dc.description.versionPublished Version
dc.identifier.WoSQuartileQ1
dc.identifier.doi10.1038/s41531-026-01265-3
dc.identifier.eissn2373-8057
dc.identifier.embargoNo
dc.identifier.issue1
dc.identifier.pubmed41629305
dc.identifier.scopus2-s2.0-105032537253
dc.identifier.urihttps:doi.org/10.1038/s41531-026-01265-3
dc.identifier.urihttps://hdl.handle.net/20.500.14288/32960
dc.identifier.volume12
dc.identifier.wos001692632700001
dc.keywordsParkinson's disease (PD)
dc.keywordsLRRK2
dc.keywordsp.A419V
dc.keywordsEast Asian ancestry
dc.keywordsARM domain
dc.languageeng
dc.publisherNature Research
dc.relation.affiliationKoç University
dc.relation.collectionKoç University Institutional Repository
dc.relation.ispartofnpj Parkinson's Disease
dc.relation.openaccessN/A
dc.rightsN/A
dc.rights.uriN/A
dc.subjectNeurology
dc.titleAssociation of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset
dc.typeJournal Article
dspace.entity.typePublication
relation.isOrgUnitOfPublicationd02929e1-2a70-44f0-ae17-7819f587bedd
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relation.isParentOrgUnitOfPublication.latestForDiscovery17f2dc8e-6e54-4fa8-b5e0-d6415123a93e

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