Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Dongbing Lai; Babak Alipanahi; Pierre Fontanillas; Tae-Hwi Schwantes-An; Jan Aasly; Roy N Alcalay; Gary W Beecham; Daniela Berg; Susan Bressman; Alexis Brice; Kathrin Brockman; Lorraine Clark; Mark Cookson; Sayantan Das; Vivianna Van Deerlin; Jordan Follett; Matthew J Farrer; Joanne Trinh; Thomas Gasser; Stefano Goldwurm; Emil Gustavsson; Christine Klein; Anthony E Lang; J William Langston; Jeanne Latourelle; Timothy Lynch; Karen Marder; Connie Marras; Eden R Martin; Cory Y McLean; Helen Mejia-Santana; Eric Molho; Richard H Myers; Karen Nuytemans; Laurie Ozelius; Haydeh Payami; Deborah Raymond; Ekaterina Rogaeva; Michael P Rogers; Owen A Ross; Ali Samii; Rachel Saunders-Pullman; Birgitt Schüle; Claudia Schulte; William K Scott; Caroline Tanner; Eduardo Tolosa; James E Tomkins; Dolores Vilas; John Q Trojanowski; Ryan Uitti; Jeffery M Vance; Naomi P Visanji; Zbigniew K Wszolek; Cyrus P Zabetian; Anat Mirelman; Nir Giladi; Avi Orr Urtreger; Paul Cannon; Brian Fiske; Tatiana Foroud; 23andMe Research Team

doi:10.1002/ana.26094

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Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

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Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Dongbing Lai, Babak Alipanahi, Pierre Fontanillas, Tae-Hwi Schwantes-An, Jan Aasly, Roy N Alcalay, Gary W Beecham, Daniela Berg, Susan Bressman, Alexis Brice, …

Annals of neurology, Vol.90(1), pp.76-88

2021-05-02

DOI: https://doi.org/10.1002/ana.26094

PMID: 33938021

Abstract

The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.67 Parkinson's Disease
Web Of Science research areas: Clinical Neurology; Neurosciences
ESI research areas: Neuroscience & Behavior

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Title: Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease
Creators: Dongbing Lai - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
Babak Alipanahi - Google LLC, Palo Alto, CA
Pierre Fontanillas - 23andMe, Inc., Sunnyvale, CA
Tae-Hwi Schwantes-An - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
Jan Aasly - Department of Neurology, St. Olavs Hospital, Trondheim, Norway
Roy N Alcalay - Department of Neurology, Columbia University, New York, NY
Gary W Beecham - John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL
Daniela Berg - Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Susan Bressman - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY
Alexis Brice - Sorbonne Université, Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, Inserm, CNRS, University Hospital Pitié-Salpêtrière, Paris, France
Kathrin Brockman - German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Lorraine Clark - Department of Pathology and Cell Biology, Columbia University, New York, NY
Mark Cookson - Laboratory of Neurogenetics, National Institute of Aging, National Institute of Health, Bethesda, MD
Sayantan Das - 23andMe, Inc., Sunnyvale, CA
Vivianna Van Deerlin - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Jordan Follett - Laboratory of Neurogenetics and Neuroscience, Fixel Institute for Neurological Diseases, McKnight Brain Institute, L5-101D, UF Clinical and Translational Science Institute, University of Florida, Gainesville, FL
Matthew J Farrer - Laboratory of Neurogenetics and Neuroscience, Fixel Institute for Neurological Diseases, McKnight Brain Institute, L5-101D, UF Clinical and Translational Science Institute, University of Florida, Gainesville, FL
Joanne Trinh - Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
Thomas Gasser - German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Stefano Goldwurm - Parkinson Institute, ASST "G.Pini-CTO, Milan, Italy
Emil Gustavsson - Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada
Christine Klein - Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
Anthony E Lang - The Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Canada
J William Langston - Departments of Neurology, Neuroscience, and Pathology, Stanford University School of Medicine, Stanford, CA
Jeanne Latourelle - GNS Healthcare, Cambridge, MA
Timothy Lynch - Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
Karen Marder - Department of Neurology and Psychiatry, Taub Institute and Sergievsky Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY
Connie Marras - The Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Canada
Eden R Martin - John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL
Cory Y McLean - Google LLC, Cambridge, MA
Helen Mejia-Santana - Gertrude H. Sergievsky Center, Columbia University, New York, NY
Eric Molho - Department of Neurology, Albany Medical College, Albany, NY
Richard H Myers - Department of Neurology, Boston University, Boston, MA
Karen Nuytemans - John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL
Laurie Ozelius - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY
Haydeh Payami - Department of Neurology, University of Alabama at Birmingham, Birmingham, AL
Deborah Raymond - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY
Ekaterina Rogaeva - Tanz Centre for Research in Neurodegenerative Diseases and Department of Neurology, University of Toronto, Toronto, Canada
Michael P Rogers - Department of General Surgery, University of South Florida Morsani College of Medicine, Tampa, FL
Owen A Ross - School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
Ali Samii - VA Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA
Rachel Saunders-Pullman - Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY
Birgitt Schüle - Department of Pathology, Stanford University School of Medicine, Stanford, CA
Claudia Schulte - German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
William K Scott - John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL
Caroline Tanner - University of California, San Francisco Veterans Affairs Health Care System, San Francisco, CA
Eduardo Tolosa - Parkinson Disease and Movement Disorders Unit, Hospital Clínic Universitari, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
James E Tomkins - School of Pharmacy, University of Reading, Reading, UK
Dolores Vilas - Parkinson Disease and Movement Disorders Unit, Hospital Clínic Universitari, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
John Q Trojanowski - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Ryan Uitti - Department of Neurology, Mayo Clinic, Jacksonville, FL
Jeffery M Vance - John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL
Naomi P Visanji - The Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Canada
Zbigniew K Wszolek - Department of Neurology, Mayo Clinic, Jacksonville, FL
Cyrus P Zabetian - VA Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA
Anat Mirelman - Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
Nir Giladi - Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
Avi Orr Urtreger - Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
Paul Cannon - 23andMe, Inc., Sunnyvale, CA
Brian Fiske - The Michael J. Fox Foundation for Parkinson's Research, New York, NY
Tatiana Foroud - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
23andMe Research Team
Publication Details: Annals of neurology, Vol.90(1), pp.76-88
Grant note: The Canadian Consortium on Neurodegeneration in Aging the 2019 Biomarkers Across Neurodegenerative Diseases Grant Program Else Kroener Fresenius Foundation The Canadian Institutes of Health Research 7984.02 / The Michael J. Fox Foundation for Parkinson's Research Grants P50 NS039764 / NINDS NIH HHS The Albertson Parkinson's Research Foundation NS071674 / NINDS NIH HHS R01 NS065070 / NINDS NIH HHS The Brookdale Foundation U54-NS110435 / NINDS NIH HHS HHSN268201200008I / NHLBI NIH HHS The Haworth Family Professorship in Neurodegenerative Diseases fund P50 NS072187 / NINDS NIH HHS The Mangurian Foundation Lewy Body Dementia Program at Mayo Clinic and Mayo Clinic Center for Individualized Medicine U54-NS100693 / NINDS NIH HHS 7984.01 / The Michael J. Fox Foundation for Parkinson's Research Grants R01-NS078086 / NINDS NIH HHS The Functional Genomics of LBD Program FOR2488 / Deutsche Forschungsgemeinschaft (DFG) NS036630 / National Institutes of Health (NIH) 18063 / BAND3 (Michael J Fox Foundation, Alzheimer's Association, Alzheimer's Research UK and Weston Brain Institute) The Sol Goldman Charitable Trust R01NS096740 / National Institutes of Health (NIH) The Parkinson's Foundation 7984 / The Michael J. Fox Foundation for Parkinson's Research Grants K02NS080915 / National Institutes of Health (NIH) UL1TR001873 / National Institutes of Health (NIH) NS053488 / National Institutes of Health (NIH) 5I01CX001702 / The Department of Veterans Affairs 8981 / The Michael J. Fox Foundation for Parkinson's Research Grants AG062418 / National Institutes of Health (NIH) UL1 TR000040 / NCATS NIH HHS The Riley Chair in Parkinson's Disease W81XWH-17-1-0249 / DOD AG010124 / National Institutes of Health (NIH) P50 NS062684 / NINDS NIH HHS The Little Family Foundation
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 33938021
Record Identifier: 991031596996202976