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JAMA Neurol. 2018 Nov 1;75(11):1416-1422. doi: 10.1001/jamaneurol.2018.1885.

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

Author information

Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Department of Molecular Neurosciences, Institute of Neurology, University College London (UCL), London, United Kingdom.
Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
Institut 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.
Department of Neurology, Oslo University Hospital, Oslo, Norway.
Dementia Research Institute, UCL, London, United Kingdom.
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
Department of Medical Sciences and Institute for Research in Biomedicine, University of Aveiro, Aveiro, Portugal.
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.
Movement Disorders Institute, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Parkinson Institute of Milan, Azienda Socio Sanitaria Territoriale Gaetano Pini/CTO, Milano, Italy.
Department of Neuroscience, Rita Levi Montalcini, University of Turin, Turin, Italy.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Department of Clinical Neuroscience, UCL Institute of Neurology, London, United Kingdom.
Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland.
Data Tecnica International, Glen Echo, Maryland.



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.


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.


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.

[Available on 2019-07-23]

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