Aasly JO

Abdul Murad NA

Ahmad-Annuar A

Akpalu A

Albin R

Alcalay R

Alvarado CX

Alvarez I

Amod F

Amouri R

Anderson TJ

Arboleda G

Atadzhanov M

Avenali M

Awad PS

Azmin S

Bale C

Bandres-Ciga S

Bardien S

Beach T

Beyer K

Blauwendraat C

Borgohain R

Brice A

Brolin K

Bustamante ML

Cadavid AN

Cakmak OO

Camargos S

Carr J

Carroll C

Casey B

Chahine LM

Chan GH-F

Chan P

Chana P

Chen H

Cheung NY-F

Chowdhury S

Comart C

Cornejo-Olivas M

Corvol J-C

Cruchaga C

Cubo E

Dadiotis E

Dagklis I

Dean M

Del Rio MJ

Dey S

Divya KP

Doquenia ML

Dumanis S

El-Sadig S

Ellis M

Ertan S

Espay A

Faghri F

Fang Z-H

Fiske B

Fon EA

Fon T

Foo JN

Foroud T

Funayama M

Galleguillos BP

Gasser T

Gatto EM

Genc G

Groppa S

Grosset D

Guo J

Hadjigorgiou G

Hall D

Hardy J

Hattori N

Hernandez A

Hernandez D

Hernandez-Medrano AJ

Hoenicka J

Hoglinger G

Hopfner F

Houlden H

Hunter J

Iakovenko E

Ibrahim NM

Illarionova A

Inca-Martinez M

Ip N

Iwaki H

Jankovic J

Jasaityte S

Jeon B

Jonas C

Junker J

Kaishibayeva G

Kaiyrzhanov R

Kamel WA

Karimova A

Kauffman M

English

Lazaro-Figueroa A

Ramirez-Pineda DB

Makarious M

Perinan MT

Khachatryan S

Tavadyan Z

Shepherd CE

Kumar K

Renteria ME

Koks S

Zimprich A

Schumacher-Schuh AF

Rieder C

Tumas V

Monchi O

Miranda M

Olguin P

Tang B

Shang H

Luo W

Orozco J

Salama M

Zewde YZ

Westenberger A

Mollenhauer B

Klein C

Vollstedt E-J

Madoev H

Trinh J

Lohmann K

Lange LM

Sharma M

Xiromerisiou G

Tarnanas I

Stefanis L

Stamelou M

Medina A

Zhou X

Kishore A

Pal P

Kukkle PL

Rajan R

Salari M

Quattrone A

Valente EM

Parnetti L

Schirinzi T

Shiraishi T

Shambetova C

Kruger R

Tan AH

Norlinah MI

Newcastle University E-Prints

L E T T E R : N E W O B S E R V A T I O NIs SH3GL2 p.G276V the CausalFunctional Variant UnderlyingParkinson’s Disease Riskat this Locus?We read with great interest the article by Bademosiand colleagues,1 where they investigated the role of SH3GL2p.G276V on neuron dysfunction in Parkinson’s disease (PD).The SH3GL2 gene encodes the endophilin-A1 (EndoA1)protein, crucial for synaptic vesicle endocytosis and blood–brain barrier permeability regulation.1 Two SH3GL2 inde-pendent signals have been identified to potentially increase PDrisk in the latest European genome-wide association studies(GWAS) meta-analysis: rs13294100 and rs10756907.2Exome sequencing on a German cohort suggested thep.G276V variant as an independent PD risk factor.Bademosi et al1 recently demonstrated that p.G276Vimpairs Ca2+ influx-induced synaptic autophagy withoutdestabilizing EndoA1. The authors found that the humanp.G276V protein was stable but showed a significantdecrease in the number of autophagosomes compared withcontrol neurons.To clarify the association between SH3GL2 and PD, we lev-eraged whole-genome sequencing (WGS) data from the Accel-erating Medicines Partnership-Parkinson’s Disease (AMP-PD;https://amp-pd.org/) release 3.0, consisting of 3,105 cases and3,670 controls from European descent, and large-scalegenotyping imputed data from the Global Parkinson’s GeneticsProgram (GP2; https://gp2.org/) release 5.0, consisting of 12,728cases and 10,533 controls from 10 different ancestries. Qualitycontrol analyses are described elsewhere (https://github.com/vitale199/GenoTools/). Variants were annotated usingANNOVAR, and Fisher’s exact test was applied using PLINK1.9. Summary statistics from the latest PD risk GWAS meta-analyses were assessed.2-5 We leveraged data from the omicSynthdata resource looking at quantitative trait loci (QTL). Gene-based burden analyses were performed by using RVTESTS.We identified 14,590 SH3GL2 variants in AMP-PD(Supplementary Table S1). Likewise, 30,719 variants wereidentified in GP2 (Supplementary Table S1). The p.G276V var-iant was found in Europeans in both AMP-PD (one case, twocontrols) and GP2 (three cases, one control); however, no asso-ciation was found with PD risk (AMP-PD: P = 0.394, oddsratio [OR] = 1.296; GP2: P = 0.869, OR = 1.034) (Table 1).This variant was also identified in GP2 in three African Ameri-can (AAC) controls and one Ashkenazi Jew (AJ) PD patient.No linkage disequilibrium (LD) was observed between p.G276V and the European GWAS lead single nucleotide poly-morphisms (SNPs). Conditional analyses suggested that thesevariants were most likely independent signals. No significantassociation between SH3GL2 common genetic variation andPD risk was identified in the Latino nor Asian populations.4,5The analysis of a multi-ancestry population3 identified theintronic variant rs910316833 as the most significant SNP(Supplementary Fig. S1).The QTL analysis revealed six potential functional impactsfor SH3GL2 (top SNPs: rs2145659, rs3758217, rs10756899,and rs2383044). Finally, no cumulative effect of multiplegenetic variants within SH3GL2 on PD risk was found afterconducting rare variant burden meta-analyses.Using the largest case–control genetic cohorts publicly avail-able to date in the PD field, the p.G276V variant was found inboth AMP-PD and GP2 in Europeans; however, this variantwas not associated with PD risk and consequently does notcausally explain the PD GWAS significant association at theSH3GL2 locus.Acknowledgments: This work was carried out with the support andguidance of the “GP2 Trainee Network” that is part of the GlobalParkinson’s Genetics Program and funded by the Aligning Science AcrossParkinson’s (ASAP) initiative. Data used in the preparation of this articlewere obtained from Global Parkinson’s Genetics Program (GP2). For acomplete list of GP2 members, see https://gp2.org. Data used in thepreparation of this article were obtained from the Accelerating MedicinesPartnership® (AMP®) Parkinson’s Disease (AMP® PD) Knowledge Plat-form. For up-to-date information on the study, visit https://www.amp-pd.org. ACCELERATING MEDICINES PARTNERSHIP and AMP are- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -© 2024 The Author(s). Movement Disorders published by Wiley Periodi-cals LLC on behalf of International Parkinson and Movement DisorderSociety.This is an open access article under the terms of the CreativeCommons Attribution-NonCommercial-NoDerivs License, which permitsuse and distribution in any medium, provided the original work is prop-erly cited, the use is non-commercial and no modifications or adapta-tions are made.*Correspondence to: Dr. Maria Teresa Periñan, Unidad de Trastornosdel Movimiento, Servicio de Neurología y Neurofisiología Clínica,Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen delRocío, Consejo Superior de Investigaciones Científicas (CSIC),Universidad de Sevilla, 41013, Seville, Spain; E-mail:t.perinantocino@qmul.ac.ukAlejandra Lazaro-Figueroa, Ana Jimena Hernandez-Medrano, andDiana Berenice Ramírez-Pineda contributed equally to this study.Relevant conflicts of interest/financial disclosures: The authorsreport no competing interests.Funding agencies: This research was supported in part by the Intra-mural Research Program of the National Institutes of Health (NIH),National Institute on Aging, NIH, Department of Health and Human Ser-vices; project number ZO1 AG000535 and ZIA AG000949, as well asthe National Institute of Neurological Disorders and Stroke (NINDS) andthe National Human Genome Research Institute. Data used in the prep-aration of this article were obtained from Global Parkinson’s GeneticsProgram (GP2; https://gp2.org). GP2 is funded by the Aligning ScienceAcross Parkinson’s (ASAP) initiative and implemented by The MichaelJ. Fox Foundation for Parkinson’s Research. Additional funding wasprovided by The Michael J. Fox Foundation for Parkinson’s Researchthrough grant MJFF-009421/17483. The Accelerating Medicines Part-nership Parkinson’s Disease program is a public-private partnershipmanaged by the Foundation for the National Institutes of Health andfunded by the NINDS in partnership with the ASAP initiative; CelgeneCorporation, a subsidiary of Bristol-Myers Squibb Company;GlaxoSmithKline plc; The Michael J. Fox Foundation for Parkinson’sResearch; Pfizer; Sanofi US Services; and Verily Life Sciences.Received: 7 December 2023; Revised: 22 December 2023; Accepted:2 January 2024Published online 12 August 2024 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.29719Movement Disorders, Vol. 39, No. 11, 2024 2117registered service marks of the United States Department of Health andHuman Services.Data Availability StatementAll GP2 data is hosted in collaboration with the AMP PD, andis available via application on the website (https://amp-pd.org/register-for-amp-pd; https://doi.org/10.5281/zenodo.7904832).Genotyping imputation, quality control, ancestry prediction, andprocessing was performed using GenoTools v1.0, publicly avail-able on GitHub (https://github.com/GP2code/GenoTools). Allscripts for analyses are publicly available on GitHub (https://github.com/GP2-TNC-WG/GP2_TRAINEES-SH3GL2/; ZenodoDOI: https://doi.org/10.5281/zenodo.10257319).Alejandra Lazaro-Figueroa, BSc,1Ana Jimena Hernandez-Medrano, MSc,2Diana Berenice Ramírez-Pineda, BSc,3Andrés Navarro Cadavid, PhD,4 Mary Makarious, BSc,5Jia Nee Foo, PhD,6 Chelsea X. Alvarado, MSc,7,8Sara Bandres-Ciga, PhD,7Maria Teresa Periñan, PhD,9,10* andthe Global Parkinson’s Genetics Program (GP2)1Laboratorio de Neurogenomica Cognitiva, Unidad deInvestigacion en Psicobiología y Neurociencias, Coordinacion dePsicobiología y Neurociencias, Facultad de Psicología, UniversidadNacional Autonoma de México (UNAM), Mexico City, Mexico,2Laboratorio Clínico de Enfermedades Neurodegenerativas,Instituto Nacional de Neurología y Neurocirugía Manuel VelascoSuarez, Mexico City, Mexico, 3Laboratorio de RegulacionGenomica y Bioinformatica, del Laboratorio Internacional deInvestigacion sobre el Genoma Humano, Universidad NacionalAutonoma de México (UNAM), Campus Juriquilla, Queretaro,Mexico, 4Lab i2t/CENIT, Universidad Icesi, Cali, Colombia,5Laboratory of Neurogenetics, National Institute on Aging,Bethesda, Maryland, USA, 6Lee Kong Chian School of Medicine,Nanyang Technological University, Singapore, Singapore, 7Centerfor Alzheimer’s and Related Dementias (CARD), National Instituteon Aging and National Institute of Neurological Disorders andStroke, National Institutes of Health, Bethesda, Maryland, USA,8Data Tecnica International LLC, Washington DC, USA, 9Unidad deTrastornos del Movimiento, Servicio de Neurología y NeurofisiologíaClínica, Instituto de Biomedicina de Sevilla, Hospital UniversitarioVirgen del Rocío, Consejo Superior de Investigaciones Científicas(CSIC), Universidad de Sevilla, Seville, Spain, and 10Centre forPreventive Neurology, Wolfson Institute of Population Health,Queen Mary University of London, London,United KingdomReferences1. Bademosi AT, Decet M, Kuenen S, et al. EndophilinA-dependent cou-pling between activity-induced calcium influx and synaptic autophagyis disrupted by a Parkinson-risk mutation. Neuron 2023;111:1402–1422.e13.2. Nalls MA, Blauwendraat C, Vallerga CL, et al. Identification of novelrisk loci, causal insights, and heritable risk for Parkinson’s disease: ameta-analysis of genome-wide association studies. Lancet Neurol2019;18:1091–1102.3. Kim JJ, Vitale D, Otani DV, et al. Multi-ancestry genome-wide meta-analysis in Parkinson’s disease. Nat Genet 2024;56:27–36. https://doi.org/10.1038/s41588-023-01584-84. Loesch DP, Horimoto ARVR, Heilbron K, et al. Characterizing thegenetic architecture of Parkinson’s disease in Latinos. Ann Neurol2021;90:353–365.5. Foo JN, Chew EGY, Chung SJ, et al. Identification of risk loci forParkinson disease in Asians and comparison of risk between Asiansand Europeans: a genome-wide association study. JAMA Neurol2020;77:746–754.Global Parkinson’s GeneticsProgram (GP2) CollaboratorsEmilia M. Gatto, Marcelo Kauffman, Samson Khachatryan,Zaruhi Tavadyan, Claire E. Shepherd, Julie Hunter, KishoreKumar, Melina Ellis, Miguel E. Rentería, Sulev Koks, Alexan-der Zimprich, Artur F. Schumacher-Schuh, Carlos Rieder,TABLE 1 SH3GL2 p.Gly276Val variant identified in the AMP-PD and GP2 datasetsLocationa Variant A1 A2 Cohort F (Cases) F (Controls) OR (95% CI) P-value9: 17793465 p.Gly276Val rs150543523 T G AMP PD 0.003275 0.002528 1.296 0.3944GP2 AAC 0 0.001455 NA 0.3589GP2 AFR 0 0 NA NAGP2 AJ 0.000676 0 NA 0.4701GP2 AMR 0 0 NA NAGP2 CAS 0 0 NA NAGP2 EUR 0.003955 0.003828 1.034 (0.69780–1.531) 0.8693GP2 SAS 0 0 NA NAGP2 MDE 0 0 NA NAGP2 FIN 0 0 NA NAaChromosomal location is given according to GRCh38/hg38.Abbreviations: A1, effect allele; A2, reference allele; AAC, African American; AFR, African; AJ, Ashkenazi Jew; AMP-PD, Accelerating Medicines Partnership–Parkinson Dis-ease; AMR, Admixed American/Latin American; CAS, Central Asian; EUR, European; F, allele frequency (A1); FIN, Finnish; GP2, Global Parkinson’s Genetics Program;MDE, Middle Eastern; NA, not applicable; OR (95% CI), odds ratio with 95% confidence intervals; SAS, South Asian.2118 Movement Disorders, Vol. 39, No. 11, 2024L Á Z A R O - F I G U E R O A E T A L 15318257, 2024, 11, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29719 by Test, Wiley Online Library on [11/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicensePaula Saffie Awad, Vitor Tumas, Sarah Camargos, Edward A.Fon, Oury Monchi, Ted Fon, Benjamin Pizarro Galleguillos,Marcelo Miranda, Maria Leonor Bustamante, PatricioOlguin, Pedro Chana, Beisha Tang, Huifang Shang, JifengGuo, Piu Chan, Wei Luo, Gonzalo Arboleda, Jorge Orozco,Marlene Jimenez del Rio, Alvaro Hernandez, Mohamed Sal-ama, Walaa A. Kamel, Yared Z. Zewde, Alexis Brice, Jean-Christophe Corvol, Ana Westenberger, Anastasia Illarionova,Brit Mollenhauer, Christine Klein, Eva-Juliane Vollstedt,Franziska Hopfner, Günter Höglinger, Harutyun Madoev,Joanne Trinh, Johanna Junker, Katja Lohmann, Lara M.Lange, Manu Sharma, Sergio Groppa, Thomas Gasser, Zih-Hua Fang, Albert Akpalu, Georgia Xiromerisiou, GeorgiosHadjigorgiou, Ioannis Dagklis, Ioannis Tarnanas, LeonidasStefanis, Maria Stamelou, Efthymios Dadiotis, Alex Medina,Germaine Hiu-Fai Chan, Nancy Ip, Nelson Yuk-Fai Cheung,Phillip Chan, Xiaopu Zhou, Asha Kishore, KP Divya, PramodPal, Prashanth Lingappa Kukkle, Roopa Rajan, RupamBorgohain, Mehri Salari, Andrea Quattrone, Enza Maria Val-ente, Lucilla Parnetti, Micol Avenali, Tommaso Schirinzi,Manabu Funayama, Nobutaka Hattori, Tomotaka Shiraishi,Altynay Karimova, Gulnaz Kaishibayeva, CholponShambetova, Rejko Krüger, Ai Huey Tan, Azlina Ahmad-Annuar, Mohamed Ibrahim Norlinah, Nor Azian AbdulMurad, Norlinah Mohamed Ibrahim, Shahrul Azmin, Shen-Yang Lim, Wael Mohamed, Yi Wen Tay, Daniel Martinez-Ramirez, Mayela Rodriguez-Violante, Paula Reyes-Pérez,Bayasgalan Tserensodnom, Rajeev Ojha, Tim J. Anderson,Toni L. Pitcher, Arinola Sanyaolu, Njideka Okubadejo,Oluwadamilola Ojo, Jan O. Aasly, Lasse Pihlstrøm, ManuelaTan, Shoaib Ur-Rehman, Mario Cornejo-Olivas, Maria LeilaDoquenia, Raymond Rosales, Angel Vinuela, ElenaIakovenko, Bashayer Al Mubarak, Muhammad Umair, Eng-King Tan, Jia Nee Foo, Ferzana Amod, Jonathan Carr,Soraya Bardien, Beomseok Jeon, Yun Joong Kim, EstherCubo, Ignacio Alvarez, Janet Hoenicka, Katrin Beyer, MariaTeresa Periñan, Pau Pastor, Sarah El-Sadig, Kajsa Brolin,Christiane Zweier, Krack Paul, Chin-Hsien Lin, Hsiu-ChuanWu, Pin-Jui Kung, Ruey-Meei Wu, Serena Wu, Yihru Wu,Rim Amouri, Samia Ben Sassi, A. Nazlı Başak, Gencer Genc,Özgür Öztop Çakmak, Sibel Ertan, Alastair Noyce, AlejandroMartínez-Carrasco, Anette Schrag, Anthony Schapira,Camille Carroll, Claire Bale, Donald Grosset, Eleanor J. Staf-ford, Henry Houlden, Huw R. Morris, John Hardy, Kin YingMok, Mie Rizig, Nicholas Wood, Nigel Williams, OlaitanOkunoye, Patrick Alfryn Lewis, Rauan Kaiyrzhanov, RimonaWeil, Seth Love, Simon Stott, Simona Jasaityte, Sumit Dey,Vida Obese, Alberto Espay, Alyssa O’Grady, Andrew B Sin-gleton, Andrew K. Sobering, Bernadette Siddiqi, BradfordCasey, Brian Fiske, Cabell Jonas, Carlos Cruchaga, CarolineB. Pantazis, Charisse Comart, Claire Wegel, CornelisBlauwendraat, Dan Vitale, Deborah Hall, Dena Hernandez,Ejaz Shiamim, Ekemini Riley, Faraz Faghri, Geidy E. Serrano,Hampton Leonard, Hirotaka Iwaki, Honglei Chen, Ignacio F.Mata, Ignacio Juan Keller Sarmiento, Jared Williamson,Jonggeol Jeff Kim, Joseph Jankovic, Joshua Shulman, JustinC. Solle, Kaileigh Murphy, Karen Nuytemans, Karl Kieburtz,Katerina Markopoulou, Kenneth Marek, Kristin S. Levine,Lana M. Chahine, Laurel Screven, Lauren Ruffrage, LisaShulman, Luca Marsili, Maggie Kuhl, Marissa Dean, Mary B.Makarious, Mathew Koretsky, Miguel Inca-Martinez,Mike A. Nalls, Naomi Louie, Niccolò Emanuele Mencacci,Roger Albin, Roy Alcalay, Ruth Walker, Sara Bandres-Ciga,Sohini Chowdhury, Sonya Dumanis, Steven Lubbe, Tao Xie,Tatiana Foroud, Thomas Beach, Todd Sherer, Yeajin Song,Duan Nguyen, Toan Nguyen, and Masharip AtadzhanovSupporting DataAdditional Supporting Information may be found in theonline version of this article at the publisher’s web-site.Computerized Cognitive TrainingIncreases Gray Matter Volumesin Huntington’s Disease:A Pilot StudyComputerized cognitive training (CCT) aims to improvecognition through practice on tasks that invoke targeted cog-nitive domains. CCT improvements to cognition and graymatter structure have been found in healthy older adults andclinical populations.1,2 However, its effects in Huntington’sdisease (HD) have not been thoroughly examined.3We conducted a pilot randomized controlled trial to examinethe effects of CCT in pre-manifest and early-stage HD. Partici-pants were randomized to either multidomain CCT (two1-hour sessions weekly) or lifestyle education (monthly newslet-ters) over 3 months. A sub-sample of participants (n = 6 CCT,n = 10 lifestyle education) completed structural magnetic reso-nance imaging and cognitive assessments at baseline and followup. We predicted increased or preserved gray matter volumes in- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -© 2024 The Author(s). Movement Disorders published by Wiley Periodi-cals LLC on behalf of International Parkinson and Movement DisorderSociety.This is an open access article under the terms of the CreativeCommons Attribution-NonCommercial-NoDerivs License, which permitsuse and distribution in any medium, provided the original work is prop-erly cited, the use is non-commercial and no modifications or adapta-tions are made.*Correspondence to: Prof. Nellie Georgiou-Karistianis, Turner Institutefor Brain and Mental Health, 18 Innovation Walk, Monash University,Clayton VIC 3800, Australia; E-mail: nellie.georgiou-karistianis@monash.eduRelevant conflict of interest/financial disclosure: The authors declarethat there are no conflicts of interest relevant to this work. K.H. &M.N.S. are supported by an Australian Government Research TrainingProgram (RTP) Scholarship. S.D.J. is supported by an AustralianNational Health and Medical Research Council (NHMRC) Fellowship(APP1174164).Funding agencies: This study was funded by Monash University(PAG19-0576) and Huntington’s Victoria (2022 Peter WalshScholarship).Received: 20 June 2024; Revised: 19 July 2024; Accepted: 24July 2024Published online 9 August 2024 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.29972Movement Disorders, Vol. 39, No. 11, 2024 2119L E T T E R S : N E W O B S E R V A T I O N 15318257, 2024, 11, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29719 by Test, Wiley Online Library on [11/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Is SH3GL2 p.G276V the Causal Functional Variant Underlying Parkinson\u27s Disease Risk at this Locus?

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Is SH3GL2 p.G276V the Causal Functional Variant Underlying Parkinson\u27s Disease Risk at this Locus?

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