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 language | English |
|---|---|
| Pages (from-to) | 1416-1422 |
| Number of pages | 7 |
| Journal | JAMA Neurology |
| Volume | 75 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2018 |
| Externally published | Yes |
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In: JAMA Neurology, Vol. 75, No. 11, 11.2018, p. 1416-1422.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Frequency of loss of function variants in LRRK2 in Parkinson disease
AU - Blauwendraat, Cornelis
AU - Reed, Xylena
AU - Kia, Demis A.
AU - Gan-Or, Ziv
AU - Lesage, Suzanne
AU - Pihlstrøm, Lasse
AU - Guerreiro, Rita
AU - Gibbs, J. Raphael
AU - Sabir, Marya
AU - Ahmed, Sarah
AU - Ding, Jinhui
AU - Alcalay, Roy N.
AU - Hassin-Baer, Sharon
AU - Pittman, Alan M.
AU - Brooks, Janet
AU - Edsall, Connor
AU - Hernandez, Dena G.
AU - Chung, Sun Ju
AU - Goldwurm, Stefano
AU - Toft, Mathias
AU - Schulte, Claudia
AU - Bras, Jose
AU - Wood, Nicholas W.
AU - Brice, Alexis
AU - Morris, Huw R.
AU - Scholz, Sonja W.
AU - Nalls, Mike A.
AU - Singleton, Andrew B.
AU - Cookson, Mark R.
AU - Gasser, Thomas
AU - Sharma, Manu
AU - Simón-Sánchez, Javier
AU - Heutink, Peter
AU - Giri, Anamika
AU - Brockmann, Kathrin
AU - Oertel, Wolfgang
AU - Klein, Christine
AU - Mohamed, Fatima
AU - Malard, Lucile
AU - Elbaz, Alexis
AU - Corti, Olga
AU - Drouet, Valérie
AU - Corvol, Jean Christophe
AU - Tesei, Silvana
AU - Canesi, Margherita
AU - Valente, Enza Maria
AU - Petrucci, Simona
AU - Ginevrino, Monia
AU - Aasly, Jan
AU - Krüger, Rejko
AU - COURAGE-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease) Consortium
AU - French Parkinson's Disease Consortium
AU - International Parkinson's Disease Genomics Consortium (IPDGC)
N1 - Funding Information: receiving support from a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH), and consulting for the Michael J. Fox Foundation, Vivid Genomics, Lysosomal Therapies, Inc, and SK Therapeutics, Inc, among others. No other disclosures were reported. Funding Information: The Alzheimer’s Disease Sequencing Project (ADSP) is comprised of two Alzheimer’s Disease (AD) genetics consortia and three National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSAC). The two AD genetics consortia are the Alzheimer’s Disease Genetics Consortium (ADGC) funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institute of Health (NIH) institutes and other foreign governmental and non-governmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs. Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate and the Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate and U01AG052410 to Dr. Pericak-Vance. Data generation and harmonization in the Follow-up Phases is supported by U54AG052427 (to Drs. Schellenberg and Wang). Funding Information: Funding/Support: This work was supported in part by project numbers 1ZIA-NS003154, Z01-AG000949-02, and Z01-ES101986 from the Intramural Research Programs of the NINDS, the NIA, and the National Institute of Environmental Health Sciences, NIH, Department of Health and Human Services; award W81XWH-09-2-0128 from the Department of Defense; the Michael J Fox Foundation for Parkinson’s Research; and grants R01NS037167, R01CA141668, and P50NS071674 from the NIH (Greater St Louis Chapter of the American Parkinson Disease Association [APDA], Barnes Jewish Hospital Foundation). The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. In Germany, this study was supported by the German Federal Ministry of Education and Research (BMBF) under the funding code 031A430A, the EU Joint Programme– Neurodegenerative Diseases Research (JPND) project under the aegis of JPND (http://www.jpnd .eu) through the BMBF under funding code 01ED1406, and the Helmholtz Initiative on Personalized Medicine (iMed); grant DFG SH599 /6-1 from the German National Foundation (Manu Sharmu, PhD); the Michael J Fox Foundation; and the MSA Coalition (Manu Sharma, PhD). The French genome-wide association study work was supported by ANR-08-MNP-012 from the French National Agency of Research. In France, this study was supported by the France-Parkinson Association; Fondation de France; grant ANR-10-IAIHU-06 from the French program Investissements d’Avenir; and grant PHRC, AOR-08010 from Assistance Publique-Hôpitaux de Paris for the French clinical data. In Iceland, this study was supported by the Landspitali University Hospital Research Fund (SSv) and Icelandic Research Council (SSv). In Estonia, this study was supported by institutional research funding IUT20-46 from the Estonian Ministry of Education and Research (Sulev Koks, PhD). The McGill study was funded by the Michael J. Fox Foundation and the Canadian Consortium on Neurodegeneration in Aging (CCNA). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://biowulf.nih .gov) and DNA panels, samples, and clinical data from the NINDS Human Genetics Resource Center DNA and Cell Line Repository. Genome-wide association data was generated by the Wellcome Trust Case-Control Consortium 2 (WTCCC2) from UK patients with Parkinson’s disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. Genotyping of UK replication cases on ImmunoChip was part of the WTCCC2 project, supported by grant 083948/Z /07/Z from the Wellcome Trust. Population control data from the United Kingdom was made available through WTCCC1. In the United Kingdom, this study was supported by the MRC and grant WT089698/Z /09/Z from the Wellcome Trust Disease Centre (Dr Wood and John Hardy, PhD); grants 8047 and J-0804 from Parkinson’s UK; and grants G0700943 and G1100643 from the MRC. This study used data generated by the Wellcome Trust Case-Control Consortium (www.wtccc.org.uk), supported by awards 076113, 085475 and 090355 from the Wellcome Trust. Sequencing and genotyping performed at McGill University was supported by grants from the Michael J. Fox Foundation, the CCNA, and in part funding from the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives program. DNA extraction work performed in the United Kingdom was undertaken at UCL Hospitals, supported by the Department of Health’s National Institute for Health Research Biomedical Research Centres funding. This study was supported in part by Joint Call in Neurodegeneration award WT089698 from the Wellcome Trust/MRC to the Parkinson’s Disease Consortium, whose members are from the UCL Institute of Neurology, University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee; and grant MR/G0901254 from the MRC. The Braineac project was supported by the MRC through the MRC Sudden Death Brain Bank (John Hardy, PhD). This study was also supported by grants MR/N026004/1 and MR /L010933/1 from the MCR and Michael J. Fox Foundation for Parkinson’s Research (Patrick A. Lewis, PhD). This study was also supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia, and the Michael J. Fox Foundation for Parkinson’s Research and grant MR/N026004/1 from the MRC (D.T.). Funding Information: Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigators institutions, and at the National Cell Repository for Alzheimer’s Disease (NCRAD, U24AG021886) at Indiana University funded by NIA. Associated Phenotypic Data used in primary and secondary data analyses were provided by Study Investigators, the NIA funded Alzheimer’s Disease Centers (ADCs), and the National Alzheimer’s Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by NIA, and at the Database for Genotypes and Phenotypes (dbGaP) funded by NIH. This research was supported in part by the Intramural Research Program of the National Institutes of health, National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by NIA, and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations. Funding Information: The CHARGE cohorts, with funding provided by 5RC2HL102419 and HL105756, include the following: Atherosclerosis Risk in Communities (ARIC) Study which is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), Austrian Stroke Prevention Study (ASPS), Cardiovascular Health Study (CHS), Erasmus Rucphen Family Study (ERF), Framingham Heart Study (FHS), and Rotterdam Study (RS). CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629, R01AG15928, and R01AG20098 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2018 American Medical Association. All rights reserved.
PY - 2018/11
Y1 - 2018/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056328533&partnerID=8YFLogxK
U2 - 10.1001/jamaneurol.2018.1885
DO - 10.1001/jamaneurol.2018.1885
M3 - Article
C2 - 30039155
AN - SCOPUS:85056328533
SN - 2168-6149
VL - 75
SP - 1416
EP - 1422
JO - JAMA Neurology
JF - JAMA Neurology
IS - 11
ER -