Abstract
The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk.
| Original language | English |
|---|---|
| Journal | Neurobiology of Aging |
| Volume | 97 |
| Pages (from-to) | 148.e17-148.e24 |
| ISSN | 0197-4580 |
| DOIs | |
| Publication status | Published - 13.07.2020 |
Funding
Nalls’ participation in this project is part of a consulting contract between the National Institute on Aging and Data Tecnica International, LLC. He also consults for Lysosomal Therapeutics Inc, Neuron 23 Inc, Illumina Inc, the Michael J. Fox Foundation, and Aspen Neurosciences. Brockmann has received a research grant from the University of Tübingen (Clinician Scientist) and the German Society of Parkinson’s disease (dpv), funding from the Michael J. Fox Foundation (MJFF) and the German Centre for Neurodegenerative Diseases (DZNE, MIGAP), travel grants from the Movement Disorders Society, and speaker honoraria from AbbVie, Lundbeck, UCB, and Zambon. Dr Tolosa received honoraria for consultancy from Novartis, TEVA, Bial, Accorda, Boehringer Ingelheim, UCB, Solvay, Lundbeck, and BIOGEN and has received funding for research from Spanish Network for Research on Neurodegenerative Disorders (CIBERNED)-Instituto Carlos III (ISCIII), and The Michael J. Fox Foundation for Parkinson’s Research (MJFF). Dr Alcalay’s research is funded by the National Institute of Health, the Parkinson’s Foundation, and the Michael J. Fox Foundation. He received consultation fees from Genzyme/Sanofi, Restorbio, and Roche. Dr Grosset has received honoraria from Merz Pharma Vectura plc, and consultancy fees from The Glasgow Memory Clinic. Dr Gan-Or’s research is supported by grants from Parkinson Canada, the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canadian Glycomics Network (GlycoNet), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program, the Fonds de recherche du Québec - Santé (FRQS) Chercheurs-boursiers, and Parkinson Quebec. Dr Gan-Or received consultation fees from Denali, Inception Sciences, Idorsia, Lysosomal Therapeutics Inc, and Prevail Therapeutics. In the last 12 months, Dr Brice received grants from ENP-Ecole des Neurosciences Paris, Institut de France, ANR-EPIG and France Parkinson and FRC. Dr Farrer has received royalty payments from Athena Diagnostics for USA Patent 7,544,786 related to LRRK2 Gly2019Ser. Mayo Foundation and MJF have also received royalties from H Lundbeck and Merck related to the development of LRRK2 murine models including LRRK2 Gly2019Ser. Dr Morris is employed by University College London. In the last 12 months he reports paid consultancy from Biogen, UCB, AbbVie, Denali, and Biohaven; lecture fees/honoraria from Biogen, UCB, C4X Discovery, GE-Healthcare, Wellcome Trust, Movement Disorders Society; research grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, Drake Foundation, and Medical Research Council. Dr Morris is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). The remaining authors disclose no conflicts. The authors would like to thank all of the Parkinson’s disease patients and unaffected relatives who donated their time and biological samples to be part of this study. The authors would also like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). For a complete overview of IPDGC members, acknowledgments, and funding, please see http://pdgenetics.org/partners . This work was supported by Parkinson's UK (grant numbers: J-1101, H-1703), University College London (UCL), the NIHR Rare Diseases Translational Research Consortium, the Medical Research Council (MRC) (award number MR/N026004/1), the Intramural Research Programs of the National Institute of Neurological Disorders, and Stroke (NINDS) and the National Institute on Aging (NIA), UK Dementia Research Institute which receives its funding from DRI Ltd (funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK), Alzheimer's Society and Alzheimer’s Research UK, Wellcome Trust Hardy (award number 202903/Z/16/Z), Dolby Family Fund, National Institute for Health Research University College London Hospitals Biomedical Research Centre, BRCNIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London. Funding sources had no involvement in study design, collection, analysis and interpretation of data.
Research Areas and Centers
- Research Area: Medical Genetics
