Cargando…
Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease
A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia (PDD), a major determinant for quality of life, we performed...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
2021
|
| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459648/ https://www.ncbi.nlm.nih.gov/pubmed/33958783 http://dx.doi.org/10.1038/s41588-021-00847-6 |
| _version_ | 1784571571381207040 |
|---|---|
| author | Liu, Ganqiang Peng, Jiajie Liao, Zhixiang Locascio, Joseph J. Corvol, Jean-Christophe Zhu, Frank Dong, Xianjun Maple-Grødem, Jodi Campbell, Meghan C. Elbaz, Alexis Lesage, Suzanne Brice, Alexis Mangone, Graziella Growdon, John H. Hung, Albert Y. Schwarzschild, Michael A. Hayes, Michael T. Wills, Anne-Marie Herrington, Todd M. Ravina, Bernard Shoulson, Ira Taba, Pille Kõks, Sulev Beach, Thomas G. Cormier-Dequaire, Florence Alves, Guido Tysnes, Ole-Bjørn Perlmutter, Joel S. Heutink, Peter Amr, Sami S. van Hilten, Jacobus J. Kasten, Meike Mollenhauer, Brit Trenkwalder, Claudia Klein, Christine Barker, Roger A. Williams-Gray, Caroline H. Marinus, Johan Scherzer, Clemens R. |
| author_facet | Liu, Ganqiang Peng, Jiajie Liao, Zhixiang Locascio, Joseph J. Corvol, Jean-Christophe Zhu, Frank Dong, Xianjun Maple-Grødem, Jodi Campbell, Meghan C. Elbaz, Alexis Lesage, Suzanne Brice, Alexis Mangone, Graziella Growdon, John H. Hung, Albert Y. Schwarzschild, Michael A. Hayes, Michael T. Wills, Anne-Marie Herrington, Todd M. Ravina, Bernard Shoulson, Ira Taba, Pille Kõks, Sulev Beach, Thomas G. Cormier-Dequaire, Florence Alves, Guido Tysnes, Ole-Bjørn Perlmutter, Joel S. Heutink, Peter Amr, Sami S. van Hilten, Jacobus J. Kasten, Meike Mollenhauer, Brit Trenkwalder, Claudia Klein, Christine Barker, Roger A. Williams-Gray, Caroline H. Marinus, Johan Scherzer, Clemens R. |
| author_sort | Liu, Ganqiang |
| collection | PubMed |
| description | A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia (PDD), a major determinant for quality of life, we performed a genome-wide survival study (GWSS) of 11.2 million variants in 3,821 PD patients over 31,053 longitudinal visits. We discover and replicate RIMS2 as a progression locus (P = 2.78 × 10(−11); hazard ratio (HR) = 4.77), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10(−8)) and WWOX (HR = 2.12, P = 2.37 × 10(−8)), and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility. |
| format | Online Article Text |
| id | pubmed-8459648 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2021 |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-84596482021-11-06 Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease Liu, Ganqiang Peng, Jiajie Liao, Zhixiang Locascio, Joseph J. Corvol, Jean-Christophe Zhu, Frank Dong, Xianjun Maple-Grødem, Jodi Campbell, Meghan C. Elbaz, Alexis Lesage, Suzanne Brice, Alexis Mangone, Graziella Growdon, John H. Hung, Albert Y. Schwarzschild, Michael A. Hayes, Michael T. Wills, Anne-Marie Herrington, Todd M. Ravina, Bernard Shoulson, Ira Taba, Pille Kõks, Sulev Beach, Thomas G. Cormier-Dequaire, Florence Alves, Guido Tysnes, Ole-Bjørn Perlmutter, Joel S. Heutink, Peter Amr, Sami S. van Hilten, Jacobus J. Kasten, Meike Mollenhauer, Brit Trenkwalder, Claudia Klein, Christine Barker, Roger A. Williams-Gray, Caroline H. Marinus, Johan Scherzer, Clemens R. Nat Genet Article A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia (PDD), a major determinant for quality of life, we performed a genome-wide survival study (GWSS) of 11.2 million variants in 3,821 PD patients over 31,053 longitudinal visits. We discover and replicate RIMS2 as a progression locus (P = 2.78 × 10(−11); hazard ratio (HR) = 4.77), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10(−8)) and WWOX (HR = 2.12, P = 2.37 × 10(−8)), and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility. 2021-05-06 2021-06 /pmc/articles/PMC8459648/ /pubmed/33958783 http://dx.doi.org/10.1038/s41588-021-00847-6 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
| spellingShingle | Article Liu, Ganqiang Peng, Jiajie Liao, Zhixiang Locascio, Joseph J. Corvol, Jean-Christophe Zhu, Frank Dong, Xianjun Maple-Grødem, Jodi Campbell, Meghan C. Elbaz, Alexis Lesage, Suzanne Brice, Alexis Mangone, Graziella Growdon, John H. Hung, Albert Y. Schwarzschild, Michael A. Hayes, Michael T. Wills, Anne-Marie Herrington, Todd M. Ravina, Bernard Shoulson, Ira Taba, Pille Kõks, Sulev Beach, Thomas G. Cormier-Dequaire, Florence Alves, Guido Tysnes, Ole-Bjørn Perlmutter, Joel S. Heutink, Peter Amr, Sami S. van Hilten, Jacobus J. Kasten, Meike Mollenhauer, Brit Trenkwalder, Claudia Klein, Christine Barker, Roger A. Williams-Gray, Caroline H. Marinus, Johan Scherzer, Clemens R. Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease |
| title | Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease |
| title_full | Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease |
| title_fullStr | Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease |
| title_full_unstemmed | Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease |
| title_short | Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease |
| title_sort | genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in parkinson’s disease |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459648/ https://www.ncbi.nlm.nih.gov/pubmed/33958783 http://dx.doi.org/10.1038/s41588-021-00847-6 |
| work_keys_str_mv | AT liuganqiang genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT pengjiajie genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT liaozhixiang genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT locasciojosephj genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT corvoljeanchristophe genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT zhufrank genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT dongxianjun genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT maplegrødemjodi genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT campbellmeghanc genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT elbazalexis genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT lesagesuzanne genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT bricealexis genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT mangonegraziella genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT growdonjohnh genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT hungalberty genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT schwarzschildmichaela genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT hayesmichaelt genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT willsannemarie genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT herringtontoddm genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT ravinabernard genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT shoulsonira genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT tabapille genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT kokssulev genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT beachthomasg genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT cormierdequaireflorence genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT alvesguido genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT tysnesolebjørn genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT perlmutterjoels genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT heutinkpeter genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT amrsamis genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT vanhiltenjacobusj genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT kastenmeike genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT mollenhauerbrit genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT trenkwalderclaudia genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT kleinchristine genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT barkerrogera genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT williamsgraycarolineh genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT marinusjohan genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease AT scherzerclemensr genomewidesurvivalstudyidentifiesanovelsynapticlocusandpolygenicscoreforcognitiveprogressioninparkinsonsdisease |