Proteome wide association studies of LRRK2 variants identify novel causal and druggable proteins for Parkinson's disease.

Autor:	Phillips B; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA., Western D; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA., Wang L; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA., Timsina J; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA., Sun Y; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA., Gorijala P; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA., Yang C; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA., Do A; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Division of Biostatistics, Washington University, St. Louis, MO, 63110, USA., Nykänen NP; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA., Alvarez I; Memory Disorders Unit, Department of Neurology, University Hospital Mutua Terrassa, Terrassa, Spain., Aguilar M; Memory Disorders Unit, Department of Neurology, University Hospital Mutua Terrassa, Terrassa, Spain., Pastor P; Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain., Morris JC; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Schindler SE; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Fagan AM; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Puerta R; Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.; Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain., García-González P; Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.; Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain., de Rojas I; Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.; Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain., Marquié M; Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.; Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain., Boada M; Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.; Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain., Ruiz A; Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.; Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain., Perlmutter JS; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Ibanez L; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Perrin RJ; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Sung YJ; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Division of Biostatistics, Washington University, St. Louis, MO, 63110, USA., Cruchaga C; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.
Jazyk:	angličtina
Zdroj:	NPJ Parkinson's disease [NPJ Parkinsons Dis] 2023 Jul 08; Vol. 9 (1), pp. 107. Date of Electronic Publication: 2023 Jul 08.
DOI:	10.1038/s41531-023-00555-4
Abstrakt:	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. (© 2023. The Author(s).)
Databáze:	MEDLINE
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