Frequency of loss of function variants in LRRK2 in Parkinson disease

COURAGE-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease) Consortium, French Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium (IPDGC)

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1416-1422
Number of pages7
JournalJAMA Neurology
Volume75
Issue number11
DOIs
StatePublished - Nov 2018

Funding

FundersFunder number
Alzheimer’s Disease Genetics Consortium
Austrian Stroke Prevention Study
Cohorts for Heart and Aging Research in GenomicR01 AG033193
Data Tecnica International
Erasmus Rucphen Family StudyN01HC85081, U01HL080295, N01HC85082, N01HC85080, HHSN268201200036C, N01HC85086, N01HC85083, N01HC85079, HHSN268200800007C, U01HL130114, N01HC55222
Forschungszentrum für Umwelt und Gesundheit
France-Parkinson Association
French National Agency of Research
German Federal Ministry of Education, Science, Research, and Technology
German National Foundation
Icelandic Research CouncilIUT20-46
MCR
MRC Sudden Death Brain BankMR/N026004/1, MR /L010933/1
MSA CoalitionANR-08-MNP-012
National Alzheimer’s Coordinating CenterU01AG016976
National Institute on Aging Genetics of Alzheimer’s Disease Data Storage SiteU24AG041689
PHRCAOR-08010
Parkinson’s Disease Consortium
UCL Hospitals
Wellcome Trust Case-Control Consortium085475, 076113, 090355
Wellcome Trust Disease Centre8047, J-0804
National Institutes of Health
U.S. Department of Defense
U.S. Department of Health and Human ServicesW81XWH-09-2-0128
National Institute on AgingZ01AG000949, U01 AG032984
National Heart, Lung, and Blood InstituteHHSN268201100009C
National Institute of Neurological Disorders and StrokeR01AG20098, P50NS071674, R01AG023629, R01NS037167, R01AG15928
National Institute of Environmental Health Sciences
U.S. National Library of Medicine
Michael J. Fox Foundation for Parkinson's ResearchR01CA141668
Minnesota Department of Health
American Parkinson Disease Association
Foundation for Barnes-Jewish Hospital
McGill University
University of DundeeMR/G0901254
Wellcome Trust
EU Joint Programme – Neurodegenerative Disease ResearchDFG SH599 /6-1, 01ED1406
Consortium canadien en neurodégénérescence associée au vieillissement083948/Z /07/Z
Medical Research CouncilWT089698/Z /09/Z, G1100643, G0700943
National Institute for Health Research
Parkinson's UK
UCL Institute of Neurology, University College London
University of Sheffield
Bundesministerium für Bildung und Forschung031A430A
King Faisal Specialist Hospital and Research Centre
Haridus- ja Teadusministeerium
Landspítali Háskólasjúkrahús
Fondation de FranceANR-10-IAIHU-06
Assistance publique-Hôpitaux de Paris
Canada First Research Excellence Fund

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