TMEM175, SCARB2 and CTSB associations with Parkinson’s disease risk across populations

Genome-wide association study of Parkinson's disease (PD) identified common variants associated with lysosomal mechanism, including TMEM175, SCARB2, and CTSB. We investigated the association between common and rare variants across populations using cohorts from the Global Parkinson's Genetics Program (GP2) (33,733 cases and 18,703 controls from ten ancestries). In the European cohort, we confirmed significant associations with PD risk for all known genetic risk variants across the three genes and TMEM175 p. Met393Thr as an independent genome-wide significant signal. Additionally, a novel independent signal, SCARB2 rs11547135, was detected. The burden analysis linked PD to SCARB2 in African American, Ashkenazi Jewish and East Asian cohorts. Single variants-based tests identified rare missense variants in SCARB2 in several populations. Our study reinforces the association of lysosomal genetic variants with PD risk, revealing genetic heterogeneity across populations.

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Publication Details

Journal
npj Parkinson s Disease
Published
2025-12-02
DOI
https://doi.org/10.1038/s41531-025-01180-z
Citations
2
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
2.78

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article

TMEM175, SCARB2 and CTSB associations with Parkinson’s disease risk across populations

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2 citations
npj Parkinson s Disease
Parkinson's Disease Mechanisms and Treatments
2.78
article

TMEM175, SCARB2 and CTSB associations with Parkinson’s disease risk across populations

Mario Cornejo‐Olivas, Patrick A. Lewis, Gonzálo Arboleda, Jorge Orozco, Alvaro Gonzalo Hernandez, Vítor Tumas, Roger L. Albin, Joshua M Shulman, Andrea Quattrone, Jean‐Christophe Corvol, Germaine Hiu-Fai Chan, Cabell Jonas, Anastasia Illarionova, Katja Lohmann, Ignacio Álvarez, Joanne Trinh, Claire E. Shepherd, Honglei Chen, Serena Wu, J Solle, Paul Krack, Prashanth Lingappa Kukkle, Christiane Zweier, Johanna Junker, Steven Lubbe, Nobutaka Hattori, Zaruhi Tavadyan, Georgia Xiromerisiou, Sarah Camargos, Seth Love, Rauan Kaiyrzhanov, Miguel E. Rentería, Manabu Funayama, Sergiu Groppa, Franziska Hopfner, Lucilla Parnetti, Walaa A. Kamel, Shahrul Azmin, Gulnaz Kaishibayeva, Janet Hoenicka, John Hardy, Efthimios Dardiotis, Xiaopu Zhou, Zih‐Hua Fang, Ana Westenberger, Ruey‐Meei Wu, Olaitan Okunoye, Mayela Rodríguez‐Violante, Alexis Brice, Alexander Zimprich, Phillip Chan, Masharip Atadzhanov, Karl Kieburtz, M. Leonor Bustamante, Roopa Rajan, Katerina Markopoulou, Edward A. Fon, Alex Medina, Hampton L. Leonard, Chin‐Hsien Lin, Bradford Casey, Marlene Jiménez-Del-Río, Jonathan Ambrose Carr, Oury Monchi, Roy N. Alcalay, Claire Wegel, Marcelo Kauffman, Christine Klein, Nancy Y. Ip, Lauren Ruffrage, Manu Sharma, Carlos C Cruchaga, Mohamed Salama, Alberto J. Espay, Ignacio Fernandez Mata, Tim Anderson, Jan Olav Aasly, Sara Bandrés‐Ciga, Ejaz A. Shamim, Lisa Shulman, Paula Reyes‐Pérez, Raymond L. Rosales, Norlinah Mohamed Ibrahim, Pedro Chaná, Sulev Kõks, Ángel Viñuela, Manuela Tan, Andrew K. Sobering, Patricio Olguı́n, Lara M. Lange, Niccolò E. Mencacci, Eng‐King Tan, Karen Nuytemans, Piu Chan, Sonya B. Dumanis, Geidy E. Serrano, Shen‐Yang Lim, Ferzana Amod, Luca Marsili, Oluwadamilola O. Ojo, Soraya Bardien, Tommaso Schirinzi, Alejandro Martínez-Carrasco, Samson Khachatryan, Jared Williamson, Yun Joong Kim, Anthony H.V. Schapira, Donald G. Grosset, Cholpon Shambetova, Nor Azian Abdul Murad, Ekemini Riley, Lasse Pihlstrøm, Daniel Martínez-Ramírez, María Stamelou, Yih‐Ru Wu, Eleanor J. Stafford, Marissa Dean, Yi Wen Tay, Carlos Roberto de Mello Rieder, Nicholas William Wood, Altynay Karimova, Toni L. Pitcher, Kalikavil Puthanveedu Divya, Bayasgalan Tserensodnom, Thomas Gasser, Enza Maria Valente, Albert Akpalu, Ai Huey Tan, Günter U. Höglinger, Ioannis Tarnanas, Tomotaka Shiraishi, Nelson Yuk-Fai Cheung, Bashayer Al Mubarak, Rim Amouri, Yared Z. Zewde, Bernadette Siddiqi, Claudia Schulte, Ignacio Juan Keller Sarmiento, Anette E. Schrag, Thomas G. Beach, Cornelis Blauwendraat, Mie Rizig, Tao Xie, Ioannis Dagklis, Jifeng Guo, Simon Stott, Sarah El-Sadig, Melina Ellis, Pramod Kumar Pal, Rimona Sharon Weil, Kishore R. Kumar, Rajeev Ojha, Deborah J. Hall, Sohini Chowdhury, Samia Ben Sassi, Njideka Okubadejo, Huw R. Morris, Henry Houlden, Brian P. Fiske, Nigel Williams, Wei Luo, Miguel Inca‐Martinez, Caroline B. Pantazis, Gençer Genç, Kin Y. Mok, Joseph Jankovic, Beisha Tang, Harutyun Madoev, Özgür Öztop Çakmak, Vida Obese, Е. А. Яковенко, Todd Sherer, Pin‐Jui Kung, Azlina Ahmad‐Annuar, Hirotaka Iwaki, Kenneth Marek, Emilia Mabel Gatto, Micol Avenali, Maggie Kuhl, Benjamin Pizarro Galleguillos, Charisse Comart, Naomi Louie, Shoaib Ur-Rehman, Simona Jasaitye, Ted Fon, Muhammad Umair, Wen-Hua Sun, Hsiu-Chuan Wu, Huifang Shang, Yeajin Song, Kaileigh Murphy, Marcelo Miranda, Julie Hunter, Camille Carroll, Esther Cubo, Andrew Singleton, Mike A. Nalls, Lana M. Chahine, Leonidas Stefanis, Sibel Ertan, Ruth Walker, Georgios M. Hadjigeorgiou, Tatiana Foroud, Katrin Beyer, Claire Bale, Maria Leila Doquenia, A. Nazl Başak, Rupam Borgohain, Duan Nguyen, Alyssa O’Grady, Beomseok Jeon, Toan Nguyen, Eva-Juliane Vollstedt, Rejko Krüger, Asha Kishore
article en
2 citations

Abstract

Genome-wide association study of Parkinson's disease (PD) identified common variants associated with lysosomal mechanism, including TMEM175, SCARB2, and CTSB. We investigated the association between common and rare variants across populations using cohorts from the Global Parkinson's Genetics Program (GP2) (33,733 cases and 18,703 controls from ten ancestries). In the European cohort, we confirmed significant associations with PD risk for all known genetic risk variants across the three genes and TMEM175 p. Met393Thr as an independent genome-wide significant signal. Additionally, a novel independent signal, SCARB2 rs11547135, was detected. The burden analysis linked PD to SCARB2 in African American, Ashkenazi Jewish and East Asian cohorts. Single variants-based tests identified rare missense variants in SCARB2 in several populations. Our study reinforces the association of lysosomal genetic variants with PD risk, revealing genetic heterogeneity across populations.

npj Parkinson s DiseaseVol. 11(1)
Universidade Federal de Minas Gerais (BR), Northwestern University (US), Beni-Suef University (EG), Jikei University School of Medicine (JP), University of Rome Tor Vergata (IT), University of Bern (CH), University of London (GB), Kyrgyz State Medical Academy (KG), University of Maryland, Baltimore (US), Oslo University Hospital (NO), Rush University Medical Center (US), National Institutes of Health (US), Universidade Federal do Rio Grande do Sul (BR), Alion Science and Technology (United States) (US), Beth Israel Deaconess Medical Center (US), Cleveland Clinic (US), Royal Veterinary College (GB), NorthShore University HealthSystem (US), Kaiser Permanente (US), Koç University (TR), Garvan Institute of Medical Research (AU), University of Ghana (GH), Central South University (CN), Nizam's Institute of Medical Sciences (IN), University of Miami (US), University of Thessaly (GR), University of Khartoum (SD), Tribhuvan University (NP), University of Georgia (US), Queen Mary University of London (GB), National Taiwan University (TW), University of Pittsburgh (US), Chang Gung University (TW), Murdoch University (AU), Universidade de São Paulo (BR), Baylor College of Medicine (US), Capital Medical University (CN), University of Luxembourg (LU), Ionian University (GR), University of Lagos (NG), University of Puerto Rico System (PR), Hong Kong University of Science and Technology (HK), Washington University in St. Louis (US), Norwegian University of Science and Technology (NO), Fundación Chile (CL), Aristotle University of Thessaloniki (GR), QIMR Berghofer Medical Research Institute (AU), Sichuan University (CN), University of Pavia (IT), Stellenbosch University (ZA), University of Perugia (IT), University of Michigan (US), Columbia University Irving Medical Center (US), Severance Hospital (KR), Concord Repatriation General Hospital (AU), Sree Chitra Thirunal Institute for Medical Sciences and Technology (IN), King Faisal Specialist Hospital & Research Centre (SA), University Hospital of Bern (CH), German Center for Neurodegenerative Diseases (DE), University Kebangsaan Malaysia Medical Centre (MY), Michael J. Fox Foundation (US), Seoul National University Hospital (KR), LMU Klinikum (DE), Universidad de Costa Rica (CR), University of Alabama at Birmingham (US), University of Zambia (ZM), University of Malaya (MY), Juntendo University (JP), Medizinische Hochschule Hannover (DE), Universidad de Antioquia (CO), University of Bristol (GB), Universidad Nacional de Colombia (CO), Magna Graecia University (IT), University of Illinois Chicago (US), Sorbonne Université (FR), University of Chicago (US), Data Tecnica International (United States) (US), Augusta University Health (US), West China Hospital of Sichuan University (CN), Mongolian National University of Medical Sciences (MN), Biomedical Research Foundation of the Academy of Athens (GR), Taoyuan Chang Gung Memorial Hospital (TW), Hue University (VN), King Abdullah International Medical Research Center (SA), University Hospital Mútua de Terrassa (ES), Hospital de Clínicas de Porto Alegre (BR), Fundación Valle del Lili (CO), Parkinson's UK (GB), Hospital Ramos Mejía (AR), Institute for Neurodegenerative Disorders (US), Hospital Universitario de Burgos (ES), James J. Peters VA Medical Center (US), Universitätsmedizin Göttingen (DE), Indiana University Bloomington (US), Universidad Metropolitana de Honduras (HN), Hygeia Hospital (GR), Mútua Terrassa (ES), National Neuroscience Institute (SG), Colorado Permanente Medical Group (US), National Taiwan University Hospital (TW), Institute on Aging (US), National Institute on Aging (US), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Hertie Institute for Clinical Brain Research (DE), Hospital de Niños de la Santísima Trinidad (AR), Juntendo University Hospital (JP), Banner Sun Health Research Institute (US), Instituto Nacional de Neurología y Neurocirugía (MX), Texas Children's Hospital (US), Aster Medcity (IN), National Hospital for Neurology and Neurosurgery (GB), Anzac Research Institute (AU), Hospital Universitari Germans Trias i Pujol (ES), University of Science and Technology Bannu (PK), Şişli Etfal Eğitim ve Araştırma Hastanesi (TR), National Institute of Neurology Mongi-Ben Hamida (TN), Research Center of Neurology (RU), Xiangya Hospital Central South University (CN), Cure Parkinson's Trust (GB), Manipal Hospital (IN), Queen Elizabeth Hospital (CN), Instituto Nacional de Ciencias Neurológicas, Institut de Recerca Sant Joan de Déu, Indiana University School of Medicine, University College London (GB), Addis Ababa University (ET), McGill University (CA), Indiana University – Purdue University Indianapolis (US), Shahid Beheshti University of Medical Sciences (IR), University of Cincinnati (US), All India Institute of Medical Sciences (IN), University of Chile (CL), National Institute of Mental Health and Neurosciences (IN), Zhejiang University (CN), Medical University of Vienna (AT), University of Glasgow (GB), Cardiff University (GB), University of Otago (NZ), American University in Cairo (EG), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Neuroscience Research Australia (AU), Michigan State University (US), National University of Malaysia (MY), Centro de Estudios Científicos (CL), Universidad Nacional Autónoma de México (MX), University of Plymouth (GB), University of Lübeck (DE), University of KwaZulu-Natal (ZA), Tecnológico de Monterrey (MX), National Taipei University (TW)
Michael J. Fox Foundation for Parkinson's Research, China Scholarship Council, Institut National Du Cancer
Openalex Percentile: Top 8%
Parkinson's Disease Mechanisms and Treatments
2.78
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