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, F. Q.; 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.; Hilten, Jacobus J. van; Kasten, Meike; Mollenhauer, Brit; Trenkwalder, Claudia; Klein, Christine; Barker, Roger A.; Williams‐Gray, Caroline H.; Marinus, Johan; Scherzer, Clemens R.

doi:10.1038/s41588-021-00847-6

Cited by 93 publications

(110 citation statements)

References 86 publications

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“…Eusebi et al [35] reported that LID development was significantly correlated with higher PRS (HR = 1.39, 95% CI = 1.08-1.78), indicating the association between the aggregate burden of known genetic risk variants of PD and LID development. However, a recent study conducted by Liu et al [36] did not find the association between PRS and motor progression and explained that disease initiation and progression might be driven by different genetics.…”

Section: Prs and Pd Clinical Outcomesmentioning

confidence: 93%

Polygenic Risk Scores Contribute to Personalized Medicine of Parkinson’s Disease

Dehestani

Liu

Gasser

2021

JPM

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the loss of dopaminergic neurons. The vast majority of PD patients develop the disease sporadically and it is assumed that the cause lies in polygenic and environmental components. The overall polygenic risk is the result of a large number of common low-risk variants discovered by large genome-wide association studies (GWAS). Polygenic risk scores (PRS), generated by compiling genome-wide significant variants, are a useful prognostic tool that quantifies the cumulative effect of genetic risk in a patient and in this way helps to identify high-risk patients. Although there are limitations to the construction and application of PRS, such as considerations of limited genetic underpinning of diseases explained by SNPs and generalizability of PRS to other populations, this personalized risk prediction could make a promising contribution to stratified medicine and tailored therapeutic interventions in the future.

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Section: Prs and Pd Clinical Outcomesmentioning

confidence: 93%

Polygenic Risk Scores Contribute to Personalized Medicine of Parkinson’s Disease

Dehestani

Liu

Gasser

2021

JPM

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“…It was recently shown that loss of TAX1BP1 results in accumulation of protein aggregates in the brain (Sarraf et al, 2020), which could be consistent with our results suggesting that reduction of TAX1BP1 increases cell transfer of aSyn. Finally, the POLR2A locus was recently identified as a putative genetic modifier of progression from PD to PD dementia (Liu et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of α-synuclein

et al. 2021

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Summary Neuropathological and experimental evidence suggests that the cell-to-cell transfer of α-synuclein has an important role in the pathogenesis of Parkinson’s disease (PD). However, the mechanism underlying this phenomenon is not fully understood. We undertook a small interfering RNA (siRNA), genome-wide screen to identify genes regulating the cell-to-cell transfer of α-synuclein. A genetically encoded reporter, GFP-2A-αSynuclein-RFP, suitable for separating donor and recipient cells, was transiently transfected into HEK cells stably overexpressing α-synuclein. We find that 38 genes regulate the transfer of α-synuclein-RFP, one of which is ITGA8 , a candidate gene identified through a recent PD genome-wide association study (GWAS). Weighted gene co-expression network analysis (WGCNA) and weighted protein-protein network interaction analysis (WPPNIA) show that those hits cluster in networks that include known PD genes more frequently than expected by random chance. The findings expand our understanding of the mechanism of α-synuclein spread.

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“…11,12,13,14,15 Extracellular-vesicle-associated tau and amyloid β42 have also been reported to correlate with cognition in PD. 16 Additionally, genetic variants have been linked to cognitive trajectory in PD, 17,18,19 with the most well-replicated effects on cognition seen for the APOE E4 allele 20,21,22,23 and PD-associated GBA variants. 17,24,25,26 Studies to date, however, have limitations that hamper translation of biomarkers of PD cognitive decline into clinical contexts.…”

Section: Introductionmentioning

confidence: 99%

Plasma MIA, CRP, and albumin predict cognitive decline in Parkinson’s Disease

Shen

Amari

Zack

et al. 2022

Preprint

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Objective: Using a multi-cohort, Discovery-Replication-Validation design, we sought new plasma biomarkers that predict which PD individuals will experience cognitive decline. Methods: In 108 Discovery Cohort PD individuals and 83 Replication Cohort PD individuals, we measured 940 plasma proteins on an aptamer-based platform. Using proteins associating with subsequent cognitive decline in both cohorts, we trained a logistic regression model to predict which PD patients showed fast (>=1 point drop/year on Montreal Cognitive Assessment (MoCA)) vs. slow (<1 point drop/year on MoCA) cognitive decline in the Discovery Cohort,testing it in the Replication Cohort. We developed alternate assays for the top three proteins and confirmed their ability to predict cognitive decline - defined by change in MoCA or development of incident Mild Cognitive Impairment (MCI) or dementia - in a Validation Cohort of 118 PD individuals. We investigated the top plasma biomarker for causal influence by Mendelian randomization. Results: A model with only three proteins (Melanoma Inhibitory Activity Protein (MIA), C-Reactive Protein (CRP), albumin) separated Fast vs. Slow cognitive decline subgroups with an AUC of 0.80 in the Validation Cohort. Validation Cohort PD individuals in the top quartile of risk for cognitive decline based on this model were 4.4 times more likely to develop incident MCI or dementia than those in the lowest quartile. Genotypes at MIA SNP rs2233154 associated with MIA levels and cognitive decline, providing evidence for MIA's causal influence. Conclusions: An easily-obtained plasma-based predictor identifies PD individuals at risk for cognitive decline. MIA may participate causally in development of cognitive decline.

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Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease

Cited by 93 publications

References 86 publications

Polygenic Risk Scores Contribute to Personalized Medicine of Parkinson’s Disease

Polygenic Risk Scores Contribute to Personalized Medicine of Parkinson’s Disease

An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of α-synuclein

Plasma MIA, CRP, and albumin predict cognitive decline in Parkinson’s Disease

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