[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 34.237.76.91. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Brief Report
November 2018

Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease

Author Affiliations
  • 1Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
  • 2Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
  • 3Department of Molecular Neurosciences, Institute of Neurology, University College London (UCL), London, United Kingdom
  • 4Department of Human Genetics, McGill University, Montréal, Quebec, Canada
  • 5Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada
  • 6Institut National de la Santé et de la Recherche Medicale U1127, Centre National de la Recherche Scientifique–Unité Mixte de Recherché (UMR) 7225, Sorbonne Universités, Université Pierre-et-Marie-Curie, University of Paris 06, UMR S1127, Institut du Cerveau et de la Moelle Épinière, Paris, France
  • 7Department of Neurology, Oslo University Hospital, Oslo, Norway
  • 8Dementia Research Institute, UCL, London, United Kingdom
  • 9Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
  • 10Department of Medical Sciences and Institute for Research in Biomedicine, University of Aveiro, Aveiro, Portugal
  • 11Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York
  • 12Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York
  • 13Movement Disorders Institute, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
  • 14Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  • 15Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
  • 16Parkinson Institute of Milan, Azienda Socio Sanitaria Territoriale Gaetano Pini/CTO, Milano, Italy
  • 17Department of Neuroscience, Rita Levi Montalcini, University of Turin, Turin, Italy
  • 18Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  • 19Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
  • 20Department of Clinical Neuroscience, UCL Institute of Neurology, London, United Kingdom
  • 21Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland
  • 22Data Tecnica International, Glen Echo, Maryland
JAMA Neurol. 2018;75(11):1416-1422. doi:10.1001/jamaneurol.2018.1885
Key Points

Question  Do loss of function variants in LRRK1 and/or LRRK2 increase the risk of developing Parkinson disease?

Findings  This case-control cohort study screened 11 095 participants with Parkinson disease and 12 615 controls using next-generation sequencing data for loss of function variants in LRRK1 and LRRK2. No significant enrichment in cases with Parkinson disease (0.205% and 0.117%, respectively) was found compared with controls (0.139% and 0.087%, respectively).

Meaning  LRRK1 and LRRK2 loss of function variants do not increase the risk of Parkinson disease; kinase inhibition or allele-specific targeting of mutant LRRK2 remain viable therapeutic strategies in a subset of patients with Parkinson disease.

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.

×