Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease
Dongbing Lai
(1)
,
Babak Alipanahi
(2, 3)
,
Pierre Fontanillas
(2)
,
Tae‐hwi Schwantes‐an
(1)
,
Jan Aasly
(4)
,
Roy N Alcalay
(5)
,
Gary W Beecham
(6, 7, 8)
,
Daniela Berg
(9, 10, 11)
,
Susan Bressman
(12)
,
Alexis Brice
(13, 14)
,
Kathrin Brockman
(10, 11, 15)
,
Lorraine Clark
(5)
,
Mark Cookson
(16)
,
Sayantan Das
(2)
,
Vivianna van Deerlin
(17)
,
Jordan Follett
(18, 19)
,
Matthew J Farrer
(18, 19)
,
Joanne Trinh
(20)
,
Thomas Gasser
(10, 11, 15)
,
Stefano Goldwurm
(21)
,
Emil Gustavsson
(22)
,
Christine Klein
(20)
,
Anthony E Lang
(23)
,
J William Langston
(24)
,
Jeanne Latourelle
,
Timothy Lynch
(25, 26, 27)
,
Karen Marder
(28)
,
Connie Marras
(23)
,
Eden R Martin
(6, 7, 8)
,
Cory Y Mclean
(2, 3)
,
Helen Mejia‐santana
(5)
,
Eric Molho
(29)
,
Richard H Myers
(30)
,
Karen Nuytemans
(6, 7, 8)
,
Laurie Ozelius
(12)
,
Haydeh Payami
(31)
,
Deborah Raymond
(12)
,
Ekaterina Rogaeva
(32)
,
Michael P Rogers
(33)
,
Owen A Ross
(34, 25)
,
Ali Samii
(35)
,
Rachel Saunders‐pullman
(12)
,
Birgitt Schüle
(11, 10, 15)
,
Claudia Schulte
(11, 10, 15)
,
William K Scott
(6, 7, 8)
,
Caroline Tanner
(36, 37)
,
Eduardo Tolosa
(38, 39, 40, 41)
,
James E Tomkins
(42)
,
Dolores Vilas
(38, 39, 40, 41)
,
John Q Trojanowski
(17)
,
Ryan Uitti
(34)
,
Jeffery M Vance
(6, 7, 8)
,
Naomi P Visanji
(23)
,
Zbigniew K Wszolek
(34)
,
Cyrus P Zabetian
(35)
,
Anat Mirelman
(43, 44)
,
Nir Giladi
(43, 44)
,
Avi Orr Urtreger
(43, 44)
,
Paul Cannon
(2)
,
Brian Fiske
(45)
,
Tatiana Foroud
(1)
1
Indiana University School of Medicine
2 23andMe Inc.
3 Google LLC
4 St. Olav's University Hospital - St. Olavs Hospital HF
5 Columbia University [New York]
6 John P. Hussman Institute for Human Genomics [Miami, FL, USA]
7 Department of Human Genetics - Dr. John T. Macdonald Foundation [Miami, FL, USA]
8 University of Miami
9 CAU - Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel
10 Eberhard Karls Universität Tübingen = University of Tübingen
11 Hertie Institute for Clinical Brain Research [Tubingen]
12 MSSM - Icahn School of Medicine at Mount Sinai [New York]
13 ICM - Institut du Cerveau = Paris Brain Institute
14 CHU Pitié-Salpêtrière [AP-HP]
15 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
16 NIA - National Institute on Aging [Bethesda, USA]
17 University of Pennsylvania
18 UF|MBI - McKnight Brain Institute [Gainesville]
19 UF - University of Florida [Gainesville]
20 Universität zu Lübeck = University of Lübeck [Lübeck]
21 ASST Pini-CTO
22 UBC - University of British Columbia [Canada]
23 Toronto Western Hospital
24 Stanford University
25 UCD - University College Dublin [Dublin]
26 The Mater Hospital - Mater Misericordiae University Hospital
27 Conway Institute of Biomolecular and Biomedical Research [Dublin, Irlande]
28 College of Physicians and Surgeons - G.H. Sergievsky Center [New-York, NY, USA]
29 Albany Medical College
30 BU - Boston University [Boston]
31 UAB - University of Alabama at Birmingham [ Birmingham]
32 University of Toronto
33 Tampa - University of South Florida Morsani College of Medicine
34 Mayo Clinic [Jacksonville]
35 University of Washington [Seattle]
36 UC San Francisco - University of California [San Francisco]
37 Veterans Affairs Palo Alto Health Care System [Palo Alto, CA, USA]
38 Clinic Barcelona Hospital Universitari
39 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
40 UB - Universitat de Barcelona
41 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
42 UOR - University of Reading
43 Tel Aviv Sourasky Medical Center [Tel Aviv]
44 TAU - Tel Aviv University
45 The Michael J Fox Foundation for Parkinson's Research
2 23andMe Inc.
3 Google LLC
4 St. Olav's University Hospital - St. Olavs Hospital HF
5 Columbia University [New York]
6 John P. Hussman Institute for Human Genomics [Miami, FL, USA]
7 Department of Human Genetics - Dr. John T. Macdonald Foundation [Miami, FL, USA]
8 University of Miami
9 CAU - Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel
10 Eberhard Karls Universität Tübingen = University of Tübingen
11 Hertie Institute for Clinical Brain Research [Tubingen]
12 MSSM - Icahn School of Medicine at Mount Sinai [New York]
13 ICM - Institut du Cerveau = Paris Brain Institute
14 CHU Pitié-Salpêtrière [AP-HP]
15 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
16 NIA - National Institute on Aging [Bethesda, USA]
17 University of Pennsylvania
18 UF|MBI - McKnight Brain Institute [Gainesville]
19 UF - University of Florida [Gainesville]
20 Universität zu Lübeck = University of Lübeck [Lübeck]
21 ASST Pini-CTO
22 UBC - University of British Columbia [Canada]
23 Toronto Western Hospital
24 Stanford University
25 UCD - University College Dublin [Dublin]
26 The Mater Hospital - Mater Misericordiae University Hospital
27 Conway Institute of Biomolecular and Biomedical Research [Dublin, Irlande]
28 College of Physicians and Surgeons - G.H. Sergievsky Center [New-York, NY, USA]
29 Albany Medical College
30 BU - Boston University [Boston]
31 UAB - University of Alabama at Birmingham [ Birmingham]
32 University of Toronto
33 Tampa - University of South Florida Morsani College of Medicine
34 Mayo Clinic [Jacksonville]
35 University of Washington [Seattle]
36 UC San Francisco - University of California [San Francisco]
37 Veterans Affairs Palo Alto Health Care System [Palo Alto, CA, USA]
38 Clinic Barcelona Hospital Universitari
39 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
40 UB - Universitat de Barcelona
41 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
42 UOR - University of Reading
43 Tel Aviv Sourasky Medical Center [Tel Aviv]
44 TAU - Tel Aviv University
45 The Michael J Fox Foundation for Parkinson's Research
Dongbing Lai
- Fonction : Auteur
- PersonId : 1245031
- ORCID : 0000-0001-7803-580X
Alexis Brice
- Fonction : Auteur
- PersonId : 1104774
- ORCID : 0000-0002-0941-3990
- IdRef : 050512935
Kathrin Brockman
- Fonction : Auteur
- PersonId : 1297244
- ORCID : 0000-0002-7515-8596
Christine Klein
- Fonction : Auteur
- PersonId : 1373175
- ORCID : 0000-0003-2102-3431
Jeanne Latourelle
- Fonction : Auteur
Owen A Ross
- Fonction : Auteur
- PersonId : 1339573
- ORCID : 0000-0003-4813-756X
Naomi P Visanji
- Fonction : Auteur
- PersonId : 1373176
- ORCID : 0000-0001-5968-7845
Cyrus P Zabetian
- Fonction : Auteur
- PersonId : 1373177
- ORCID : 0000-0002-7739-4306
Anat Mirelman
- Fonction : Auteur
- PersonId : 1333427
- ORCID : 0000-0002-1520-2292
- IdRef : 27427311X
Résumé
Objective: 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.
Methods: 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.
Results: 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.
Interpretation: 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;90:82-94.
Domaines
Médecine humaine et pathologie
Fichier principal
Annals of Neurology - 2021 - Lai - Genomewide Association Studies of LRRK2 Modifiers of Parkinson s Disease.pdf (2.45 Mo)
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