ArticleHuman molecular genetics2021
Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson's disease cohort.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Coding and Noncoding Variation in LRRK2 and Parkinson's Disease Risk.Movement disorders : official journal of the Movement Disorder Society · 2022Pooled it
- Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.Human molecular genetics · 2026Article
- Individualized Bayesian Inference Identifies Novel Genetic Variants for Parkinson's Disease.Genetic epidemiology · 2026Article
- Article
- Large-scale functional annotation establishes a reference framework for humanmedRxiv : the preprint server for health sciences · 2026Article
- Elucidating the molecular interplay between LRRK2 and Rab GTPases.bioRxiv : the preprint server for biology · 2026Article
- Functional and Structural Characterization of LRRK2 p.V1447L in Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Targeting specific kinase substrates rescues increased colitis severity induced by the Crohn's disease-linked LRRK2-N2081D variant.The Journal of clinical investigation · 2025Article
- The p.Gly2019Ser is a common LRRK2 pathogenic variant among Egyptians with familial and sporadic Parkinson's disease.NPJ Parkinson's disease · 2024Article
- A novel missense mutation of CCDC34 causes male infertility with oligoasthenoteratozoospermia in a consanguineous Pakistani family.Asian journal of andrology · 2024Article
- TheResearch square · 2024Article
- Macular structural integrity estimates are associated with Parkinson's disease genetic risk.Acta neuropathologica communications · 2024Article
- Single molecule array measures of LRRK2 kinase activity in serum link Parkinson's disease severity to peripheral inflammation.Molecular neurodegeneration · 2024Article
- The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson's disease comorbidity.Genome medicine · 2024Article
- The Impact of 90 Parkinson's Disease-Risk Single Nucleotide Polymorphisms on Urinary Bis(monoacylglycerol)phosphate Levels in the Prodromal and PD Cohorts.International journal of molecular sciences · 2024Article
- Pharmacotherapy for Disease Modification in Early Parkinson's Disease: How Early Should We Be?Journal of Parkinson's disease · 2024Review
- Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.Science (New York, N.Y.) · 2023Article
- Mutant LRRK2 exacerbates immune response and neurodegeneration in a chronic model of experimental colitis.Acta neuropathologica · 2023Article
- The New p.F1700L LRRK2 Variant Causes Parkinson's Disease by Extensively Increasing Kinase Activity.Movement disorders : official journal of the Movement Disorder Society · 2023Article
- Overview of the Impact of Pathogenic LRRK2 Mutations in Parkinson's Disease.Biomolecules · 2023Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Pathogenic missense variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified through linkage analysis in familial Parkinson disease (PD). Subsequently, other missense variants with lower effect sizes on PD risk have emerged, as well as non-coding polymorphisms (e.g. rs76904798) enriched in PD cases in genome-wide association studies. Here we leverage recent whole-genome sequences from the Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) and the Genome Aggregation (gnomAD) databases to characterize novel missense variants in LRRK2 and explore their relationships with known pathogenic and PD-linked missense variants. Using a computational prediction tool that successfully classifies known pathogenic LRRK2 missense variants, we describe an online web-based resource that catalogs characteristics of over 1200 LRRK2 missense variants of unknown significance. Novel high-pathogenicity scoring variants, some identified exclusively in PD cases, tightly cluster within the ROC-COR-Kinase domains. Structure-function predictions support that some of these variants exert gain-of-function effects with respect to LRRK2 kinase activity. In AMP-PD participants, all p.R1441G carriers (N = 89) are also carriers of the more common PD-linked variant p.M1646T. In addition, nearly all carriers of the PD-linked p.N2081D missense variant are also carriers of the LRRK2 PD-risk variant rs76904798. These results provide a compendium of LRRK2 missense variants and how they associate with one another. While the pathogenic p.G2019S variant is by far the most frequent high-pathogenicity scoring variant, our results suggest that ultra-rare missense variants may have an important cumulative impact in increasing the number of individuals with LRRK2-linked PD.
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