Article ; Online: Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson's disease cohort.
2021 Volume 30, Issue 6, Page(s) 454–466
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 ...
| 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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| MeSH term(s) | Adolescent ; Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Cohort Studies ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Male ; Middle Aged ; Mutation, Missense ; Parkinson Disease/genetics ; Parkinson Disease/pathology ; Young Adult | |||||
| Chemical Substances | LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) | |||||
| Language | English | |||||
| Publishing date | 2021-02-24 | |||||
| Publishing country | England | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural | |||||
| ZDB-ID | 1108742-0 | |||||
| ISSN | 1460-2083 ; 0964-6906 | |||||
| ISSN (online) | 1460-2083 | |||||
| ISSN | 0964-6906 | |||||
| DOI | 10.1093/hmg/ddab058 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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