Abstract
Common and rare variants in the LRRK2 locus are associated with Parkinson’s disease (PD) risk, but the downstream effects of these variants on protein levels remain unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7006 aptamers (6138 unique proteins) in 3107 individuals). The dataset comprised six different and independent cohorts (five using the SomaScan7K (ADNI, DIAN, MAP, Barcelona-1 (Pau), and Fundació ACE (Ruiz)) and the PPMI cohort using the SomaScan5K panel). We identified eleven independent SNPs in the LRRK2 locus associated with the levels of 25 proteins as well as PD risk. Of these, only eleven proteins have been previously associated with PD risk (e.g., GRN or GPNMB). Proteome-wide association study (PWAS) analyses suggested that the levels of ten of those proteins were genetically correlated with PD risk, and seven were validated in the PPMI cohort. Mendelian randomization analyses identified GPNMB, LCT, and CD68 causal for PD and nominate one more (ITGB2). These 25 proteins were enriched for microglia-specific proteins and trafficking pathways (both lysosome and intracellular). This study not only demonstrates that protein phenome-wide association studies (PheWAS) and trans-protein quantitative trail loci (pQTL) analyses are powerful for identifying novel protein interactions in an unbiased manner, but also that LRRK2 is linked with the regulation of PD-associated proteins that are enriched in microglial cells and specific lysosomal pathways.
Original language | English |
---|---|
Article number | 107 |
Journal | npj Parkinson's Disease |
Volume | 9 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2023 |
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In: npj Parkinson's Disease, Vol. 9, No. 1, 107, 12.2023.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Proteome wide association studies of LRRK2 variants identify novel causal and druggable proteins for Parkinson’s disease
AU - Dominantly Inherited Alzheimer Network (DIAN) Consortia
AU - Phillips, Bridget
AU - Western, Daniel
AU - Wang, Lihua
AU - Timsina, Jigyasha
AU - Sun, Yichen
AU - Gorijala, Priyanka
AU - Yang, Chengran
AU - Do, Anh
AU - Nykänen, Niko Petteri
AU - Alvarez, Ignacio
AU - Aguilar, Miquel
AU - Pastor, Pau
AU - Morris, John C.
AU - Schindler, Suzanne E.
AU - Fagan, Anne M.
AU - Puerta, Raquel
AU - García-González, Pablo
AU - de Rojas, Itziar
AU - Marquié, Marta
AU - Boada, Mercè
AU - Ruiz, Agustin
AU - Perlmutter, Joel S.
AU - Ibanez, Laura
AU - Perrin, Richard J.
AU - Sung, Yun Ju
AU - Cruchaga, Carlos
N1 - Funding Information: ADNI resources: Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: DIAN resources: Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA), the Alzheimer’s Association (SG-20-690363-DIAN), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), Spanish Institute of Health Carlos III (ISCIII), Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation, and Fonds de Recherche du Québec – Santé. This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and the contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. Funding Information: We thank all the participants and their families, as well as the many involved institutions and their staff. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/) and the Departments of Neurology and Psychiatry at Washington University School of Medicine. ADNI resources: Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. DIAN resources: Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA), the Alzheimer’s Association (SG-20-690363-DIAN), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), Spanish Institute of Health Carlos III (ISCIII), Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation, and Fonds de Recherche du Québec – Santé. This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and the contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. ACE Alzheimer Center Barcelona acknowledges all patients and their families for their collaboration. For CSF biomarker research, A.R. and M.B. received support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, PI19/01301, PI22/01403 from the Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and funded by Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de Hacer Europa”). A.R. and M.B. have also received support from CIBERNED (Instituto de Salud Carlos III (ISCIII). A.R. is also supported by the EXIT project, EU Euronanomed3 Program JCT2017, Grant No. AC17/00100 and PREADAPT project; the Joint Program for Neurodegenerative Diseases (JPND), Grant No. AC19/00097; Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and funded by Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de Hacer Europa”). I. de Rojas is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. *Data used in the preparation of this article were obtained from the Alzheimer’s Disease. Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. This work was supported by grants from the National Institutes of Health (R01AG044546 (C.C.), P01AG003991(CC, JCM), RF1AG053303 (C.C.), RF1AG058501 (C.C.), U01AG058922 (C.C.), RF1AG074007 (Y.J.S.)), the Chuck Zuckerberg Initiative (C.Z.I.), the Michael J. Fox Foundation (L.I. and C.C.), and the Department of Defense (L.I.—W81XWH2010849). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444 (J.C.M.), P01AG03991 (J.C.M.), and P01AG026276 (J.C.M.). Funding Information: ACE Alzheimer Center Barcelona acknowledges all patients and their families for their collaboration. For CSF biomarker research, A.R. and M.B. received support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, PI19/01301, PI22/01403 from the Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and funded by Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de Hacer Europa”). A.R. and M.B. have also received support from CIBERNED (Instituto de Salud Carlos III (ISCIII). A.R. is also supported by the EXIT project, EU Euronanomed3 Program JCT2017, Grant No. AC17/00100 and PREADAPT project; the Joint Program for Neurodegenerative Diseases (JPND), Grant No. AC19/00097; Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and funded by Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de Hacer Europa”). I. de Rojas is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. *Data used in the preparation of this article were obtained from the Alzheimer’s Disease. Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf . This work was supported by grants from the National Institutes of Health (R01AG044546 (C.C.), P01AG003991(CC, JCM), RF1AG053303 (C.C.), RF1AG058501 (C.C.), U01AG058922 (C.C.), RF1AG074007 (Y.J.S.)), the Chuck Zuckerberg Initiative (C.Z.I.), the Michael J. Fox Foundation (L.I. and C.C.), and the Department of Defense (L.I.—W81XWH2010849). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444 (J.C.M.), P01AG03991 (J.C.M.), and P01AG026276 (J.C.M.). Funding Information: We thank all the participants and their families, as well as the many involved institutions and their staff. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/ ) and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Common and rare variants in the LRRK2 locus are associated with Parkinson’s disease (PD) risk, but the downstream effects of these variants on protein levels remain unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7006 aptamers (6138 unique proteins) in 3107 individuals). The dataset comprised six different and independent cohorts (five using the SomaScan7K (ADNI, DIAN, MAP, Barcelona-1 (Pau), and Fundació ACE (Ruiz)) and the PPMI cohort using the SomaScan5K panel). We identified eleven independent SNPs in the LRRK2 locus associated with the levels of 25 proteins as well as PD risk. Of these, only eleven proteins have been previously associated with PD risk (e.g., GRN or GPNMB). Proteome-wide association study (PWAS) analyses suggested that the levels of ten of those proteins were genetically correlated with PD risk, and seven were validated in the PPMI cohort. Mendelian randomization analyses identified GPNMB, LCT, and CD68 causal for PD and nominate one more (ITGB2). These 25 proteins were enriched for microglia-specific proteins and trafficking pathways (both lysosome and intracellular). This study not only demonstrates that protein phenome-wide association studies (PheWAS) and trans-protein quantitative trail loci (pQTL) analyses are powerful for identifying novel protein interactions in an unbiased manner, but also that LRRK2 is linked with the regulation of PD-associated proteins that are enriched in microglial cells and specific lysosomal pathways.
AB - Common and rare variants in the LRRK2 locus are associated with Parkinson’s disease (PD) risk, but the downstream effects of these variants on protein levels remain unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7006 aptamers (6138 unique proteins) in 3107 individuals). The dataset comprised six different and independent cohorts (five using the SomaScan7K (ADNI, DIAN, MAP, Barcelona-1 (Pau), and Fundació ACE (Ruiz)) and the PPMI cohort using the SomaScan5K panel). We identified eleven independent SNPs in the LRRK2 locus associated with the levels of 25 proteins as well as PD risk. Of these, only eleven proteins have been previously associated with PD risk (e.g., GRN or GPNMB). Proteome-wide association study (PWAS) analyses suggested that the levels of ten of those proteins were genetically correlated with PD risk, and seven were validated in the PPMI cohort. Mendelian randomization analyses identified GPNMB, LCT, and CD68 causal for PD and nominate one more (ITGB2). These 25 proteins were enriched for microglia-specific proteins and trafficking pathways (both lysosome and intracellular). This study not only demonstrates that protein phenome-wide association studies (PheWAS) and trans-protein quantitative trail loci (pQTL) analyses are powerful for identifying novel protein interactions in an unbiased manner, but also that LRRK2 is linked with the regulation of PD-associated proteins that are enriched in microglial cells and specific lysosomal pathways.
UR - http://www.scopus.com/inward/record.url?scp=85164464354&partnerID=8YFLogxK
U2 - 10.1038/s41531-023-00555-4
DO - 10.1038/s41531-023-00555-4
M3 - Article
C2 - 37422510
AN - SCOPUS:85164464354
SN - 2373-8057
VL - 9
JO - npj Parkinson's Disease
JF - npj Parkinson's Disease
IS - 1
M1 - 107
ER -