SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease.

Blauwendraat, C; Reed, X; Kia, DA; Gan-Or, Z; Lesage, S; Pihlstrøm, L; Guerreiro, R; Gibbs, JR; Sabir, M; Ahmed, S; et al. Blauwendraat, C; Reed, X; Kia, DA; Gan-Or, Z; Lesage, S; Pihlstrøm, L; Guerreiro, R; Gibbs, JR; Sabir, M; Ahmed, S; Ding, J; Alcalay, RN; Hassin-Baer, S; Pittman, AM; Brooks, J; Edsall, C; Hernandez, DG; Chung, SJ; Goldwurm, S; Toft, M; Schulte, C; Bras, J; Wood, NW; Brice, A; Morris, HR; Scholz, SW; Nalls, MA; Singleton, AB; Cookson, MR; COURAGE-PD (Comprehensive Unbiased Risk Factor Assessment for Ge (2018) Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease. JAMA Neurol, 75 (11). pp. 1416-1422. ISSN 2168-6157 https://doi.org/10.1001/jamaneurol.2018.1885
SGUL Authors: Pittman, Alan Michael

[img] PDF Accepted Version
Restricted to Repository staff only
Available under License ["licenses_description_publisher" not defined].

Download (524kB)

Abstract

Importance: Pathogenic variants in LRRK2 are a relatively common genetic cause of Parkinson disease (PD). Currently, the molecular mechanism underlying disease is unknown, and gain and loss of function (LOF) models of pathogenesis have been postulated. LRRK2 variants are reported to result in enhanced phosphorylation of substrates and increased cell death. However, the double knockout of Lrrk2 and its homologue Lrrk1 results in neurodegeneration in a mouse model, suggesting that disease may occur by LOF. Because LRRK2 inhibitors are currently in development as potential disease-modifying treatments in PD, it is critical to determine whether LOF variants in LRRK2 increase or decrease the risk of PD. Objective: To determine whether LRRK1 and LRRK2 LOF variants contribute to the risk of developing PD. Design, Setting, and Participants: To determine the prevailing mechanism of LRRK2-mediated disease in human populations, next-generation sequencing data from a large case-control cohort (>23 000 individuals) was analyzed for LOF variants in LRRK1 and LRRK2. Data were generated at 5 different sites and 5 different data sets, including cases with clinically diagnosed PD and neurologically normal control individuals. Data were collected from 2012 through 2017. Main Outcomes and Measures: Frequencies of LRRK1 and LRRK2 LOF variants present in the general population and compared between cases and controls. Results: Among 11 095 cases with PD and 12 615 controls, LRRK1 LOF variants were identified in 0.205% of cases and 0.139% of controls (odds ratio, 1.48; SE, 0.571; 95% CI, 0.45-4.44; P = .49) and LRRK2 LOF variants were found in 0.117% of cases and 0.087% of controls (odds ratio, 1.48; SE, 0.431; 95% CI, 0.63-3.50; P = .36). All association tests suggested lack of association between LRRK1 or LRRK2 variants and PD. Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that, as expected, LRRK2 protein levels are reduced by approximately half compared with wild-type alleles. Conclusions and Relevance: Together these findings indicate that haploinsufficiency of LRRK1 or LRRK2 is neither a cause of nor protective against PD. Furthermore, these results suggest that kinase inhibition or allele-specific targeting of mutant LRRK2 remain viable therapeutic strategies in PD.

Item Type: Article
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: JAMA Neurol
ISSN: 2168-6157
Language: eng
Dates:
DateEvent
November 2018Published
23 July 2018Published Online
4 May 2018Accepted
Projects:
Project IDFunderFunder ID
083948/Z/07/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
WT089698/Z/09/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
8047Parkinson's UKhttp://dx.doi.org/10.13039/501100000304
J-0804Parkinson's UKhttp://dx.doi.org/10.13039/501100000304
G0700943Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G1100643Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
076113Wellcome Trusthttp://dx.doi.org/10.13039/100004440
085475Wellcome Trusthttp://dx.doi.org/10.13039/100004440
090355Wellcome Trusthttp://dx.doi.org/10.13039/100004440
WT089698Wellcome Trusthttp://dx.doi.org/10.13039/100004440
MR/G0901254Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/N026004/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/L010933/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/N026004/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 30039155
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110098
Publisher's version: https://doi.org/10.1001/jamaneurol.2018.1885

Actions (login required)

Edit Item Edit Item