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Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson's disease cohort.

Publication ,  Journal Article
Bryant, N; Malpeli, N; Ziaee, J; Blauwendraat, C; Liu, Z; AMP PD Consortium; West, AB
Published in: Hum Mol Genet
April 30, 2021

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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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

April 30, 2021

Volume

30

Issue

6

Start / End Page

454 / 466

Location

England

Related Subject Headings

  • Young Adult
  • Parkinson Disease
  • Mutation, Missense
  • Middle Aged
  • Male
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Humans
  • Genome-Wide Association Study
  • Genetics & Heredity
  • Genetic Predisposition to Disease
 

Citation

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Bryant, N., Malpeli, N., Ziaee, J., Blauwendraat, C., Liu, Z., AMP PD Consortium, & West, A. B. (2021). Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson's disease cohort. Hum Mol Genet, 30(6), 454–466. https://doi.org/10.1093/hmg/ddab058
Bryant, Nicole, Nicole Malpeli, Julia Ziaee, Cornelis Blauwendraat, Zhiyong Liu, AMP PD Consortium, and Andrew B. West. “Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson's disease cohort.Hum Mol Genet 30, no. 6 (April 30, 2021): 454–66. https://doi.org/10.1093/hmg/ddab058.
Bryant N, Malpeli N, Ziaee J, Blauwendraat C, Liu Z, AMP PD Consortium, et al. Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson's disease cohort. Hum Mol Genet. 2021 Apr 30;30(6):454–66.
Bryant, Nicole, et al. “Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson's disease cohort.Hum Mol Genet, vol. 30, no. 6, Apr. 2021, pp. 454–66. Pubmed, doi:10.1093/hmg/ddab058.
Bryant N, Malpeli N, Ziaee J, Blauwendraat C, Liu Z, AMP PD Consortium, West AB. Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson's disease cohort. Hum Mol Genet. 2021 Apr 30;30(6):454–466.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

April 30, 2021

Volume

30

Issue

6

Start / End Page

454 / 466

Location

England

Related Subject Headings

  • Young Adult
  • Parkinson Disease
  • Mutation, Missense
  • Middle Aged
  • Male
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Humans
  • Genome-Wide Association Study
  • Genetics & Heredity
  • Genetic Predisposition to Disease