Meta-Analysis

. 2021 Jan:97:148.e17-148.e24.

doi: 10.1016/j.neurobiolaging.2020.07.002. Epub 2020 Jul 13.

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease

Emmeline E Brown¹, Cornelis Blauwendraat², Joanne Trinh³, Mie Rizig¹, Mike A Nalls⁴, Etienne Leveille⁵, Jennifer A Ruskey⁵, Hallgeir Jonvik¹, Manuela M X Tan¹, Sara Bandres-Ciga⁶, Sharon Hassin-Baer⁷, Kathrin Brockmann⁸, Jon Infante⁹, Eduardo Tolosa¹⁰, Mario Ezquerra¹⁰, Sawssan Ben Romdhan¹¹, Mustapha Benmahdjoub¹², Mohamed Arezki¹², Chokri Mhiri¹², John Hardy¹³, Andrew B Singleton², Roy N Alcalay¹⁴, Thomas Gasser¹⁵, Donald G Grosset¹⁶, Nigel M Williams¹⁷, Alan Pittman¹⁸, Ziv Gan-Or¹⁹, Ruben Fernandez-Santiago¹⁰, Alexis Brice²⁰, Suzanne Lesage²⁰, Matthew Farrer²¹, Nicholas Wood¹, Huw R Morris²²; International Parkinson Disease Genomics Consortium (IPDGC)

Affiliations

¹ Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, London, UK.
² Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
⁴ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA.
⁵ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada.
⁶ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain.
⁷ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Neurology, Sheba Medical Center, Tel HaShomer, Israel; Movement Disorders Institute, Sheba Medical Center, Tel HaShomer, Israel.
⁸ Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, University Clinic Tu¨bingen, Tu¨bingen, Germany.
⁹ Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria; "Centro de Investigación Biomédica en Red de Enfermedades, Neurodegenerativas (CIBERNED)", Santander, Spain.
¹⁰ Laboratory of Parkinson Disease & Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) - Hospital Clínic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII), Barcelona, Spain.
¹¹ Research Unit in Neurogenetics, Clinical Investigation Center (CIC) at the CHU Habib Bourguiba, Sfax, Tunisia.
¹² Frantz Fanon Hospital, CHU Blida, Blida, Algeria.
¹³ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK; UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK; UCL Movement Disorders Centre, University College London, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
¹⁴ Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
¹⁵ Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tu¨bingen, Tu¨bingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tu¨bingen, Germany.
¹⁶ Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, UK.
¹⁷ Division of Psychological Medicine & Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
¹⁸ Department of Clinical Genetics, St George's, University of London, London, UK.
¹⁹ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
²⁰ Research Unit U1127 at INSERM, Research Unit UMR 7225 at the French National Centre for Scientific Research (CNRS) Research Unit UMR_1127 at Sorbonne Université, Institutet du Cerveau et de la Moëlle épinière (ICM), Paris, France.
²¹ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
²² Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, London, UK. Electronic address: h.morris@ucl.ac.uk.

PMID: 32873436
PMCID: PMC7762821
DOI: 10.1016/j.neurobiolaging.2020.07.002

Meta-Analysis

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease

Emmeline E Brown et al. Neurobiol Aging. 2021 Jan.

. 2021 Jan:97:148.e17-148.e24.

doi: 10.1016/j.neurobiolaging.2020.07.002. Epub 2020 Jul 13.

Authors

Affiliations

¹ Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, London, UK.
² Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
⁴ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA.
⁵ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada.
⁶ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain.
⁷ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Neurology, Sheba Medical Center, Tel HaShomer, Israel; Movement Disorders Institute, Sheba Medical Center, Tel HaShomer, Israel.
⁸ Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, University Clinic Tu¨bingen, Tu¨bingen, Germany.
⁹ Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria; "Centro de Investigación Biomédica en Red de Enfermedades, Neurodegenerativas (CIBERNED)", Santander, Spain.
¹⁰ Laboratory of Parkinson Disease & Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) - Hospital Clínic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII), Barcelona, Spain.
¹¹ Research Unit in Neurogenetics, Clinical Investigation Center (CIC) at the CHU Habib Bourguiba, Sfax, Tunisia.
¹² Frantz Fanon Hospital, CHU Blida, Blida, Algeria.
¹³ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK; UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK; UCL Movement Disorders Centre, University College London, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
¹⁴ Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
¹⁵ Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tu¨bingen, Tu¨bingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tu¨bingen, Germany.
¹⁶ Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, UK.
¹⁷ Division of Psychological Medicine & Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
¹⁸ Department of Clinical Genetics, St George's, University of London, London, UK.
¹⁹ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
²⁰ Research Unit U1127 at INSERM, Research Unit UMR 7225 at the French National Centre for Scientific Research (CNRS) Research Unit UMR_1127 at Sorbonne Université, Institutet du Cerveau et de la Moëlle épinière (ICM), Paris, France.
²¹ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
²² Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, London, UK. Electronic address: h.morris@ucl.ac.uk.

PMID: 32873436
PMCID: PMC7762821
DOI: 10.1016/j.neurobiolaging.2020.07.002

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.

Keywords: Genetic modifiers; Leucine-rich repeat kinase 2; Parkinsonism; Parkinson’s disease.

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Figures

**Fig. 1**
Survival analysis of AAO in *DNM3* rs2421947 (A–D) and *VAMP4* rs11578699 genotype groups (E, F). *DNM3* rs2421947 Kaplan-Meier and Kaplan-Meier median plots of (A) European idiopathic PD (n = 1956); (B) Ashkenazi Jewish p.G2019S carriers (n = 153) Kaplan-Meier plot and median plot; (C) European p.G2019S carriers (n = 286); and (D) North African p.G2019S carriers (n = 285). *VAMP4* rs2421947 Kaplan-Meier and Kaplan-Meier median plots of (E) European and Ashkenazi Jewish p.G2019S carriers (n = 302); and (F) North African p.G2019S carriers (n = 484). Abbreviations: AAO, age at onset; *DNM3*, Dynamin 3; PD, Parkinson’s disease; *VAMP4*, vesicle-associated membrane protein 4.

**Fig. 2**
Forest plot of meta-analyses for *DNM3* rs2421947 and *VAMP4* rs11578699. (A, C, and E) Cox proportional hazards model meta-analyses of *LRRK*2 p.G2019S carriers; (B, D, and F) linear regression meta-analyses of *LRRK*2 p.G2019S patients. (A, B) Meta-analyses of *DNM3* rs2421947 GG versus CG and CC genotypes of novel data from this manuscript from 724 *LRRK2* p.G2019S carriers; (C, D) Meta-analyses of *DNM3* rs2421947 GG versus CG and CC genotypes from 1478 *LRRK2* p.G2019S carriers including 754 previously published; (E, F) *VAMP4* rs11578699 meta-analyses of CC versus TT and TC. Percentage contribution and numbers of individuals included in each analysis are indicated. Analyses are carried out on ethnicity subgroups: Ashkenazi Jewish (Summary: AJ), European (Summary: EU), and North African (Summary: NA). Abbreviations: *DNM3*, Dynamin 3; *LRRK2*, leucine-rich repeat kinase 2; *VAMP4*, vesicle-associated membrane protein 4.

**Fig. 3**
Kaplan-Meier analysis by *VAMP4* rs11578699 genotype in PD cases carrying *LRRK2* risk variant (rs10878226). Abbreviations: *LRRK2*, leucine-rich repeat kinase 2; PD, Parkinson’s disease; *VAMP4*, vesicle-associated membrane protein 4.

See this image and copyright information in PMC

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Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease

Affiliations

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous