Susanna Ylönen1, Ari Siitonen1, Michael A Nalls2, Pauli Ylikotila3, Jaana Autere4, Johanna Eerola-Rautio5, Raphael Gibbs2, Mikko Hiltunen6, Pentti J Tienari5, Hilkka Soininen6, Andrew B Singleton2, Kari Majamaa7. 1. Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland; Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. 2. Laboratory for Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. 3. Institute of Clinical Medicine, Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland. 4. Neuro Center, Kuopio University Hospital, Kuopio, Finland. 5. Department of Neurology, Helsinki University Hospital, Research Programs Unit, Molecular Neurology, Biomedicum, University of Helsinki, Helsinki FIN-02900, Finland. 6. Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. 7. Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland; Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. Electronic address: kari.majamaa@oulu.fi.
Abstract
INTRODUCTION: Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. METHODS: The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls. We screened for known genetic risk variants in GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT. In addition, DNA from 225 patients with early-onset Parkinson's disease was subjected to whole exome sequencing (WES). RESULTS: We detected a significant difference in the length variation of the CAG repeat in POLG1 between patients with early-onset PD compared to controls. The p.N370S and p.L444P variants in GBA contributed to a relative risk of 3.8 in early-onset PD and 2.5 in late-onset PD. WES revealed five variants in LRRK2 and SMPD1 that were found in the patients but not in the Finnish ExAC sequences. These are possible risk variants that require further confirmation. The p.G2019S variant in LRRK2, common in North African Arabs and Ashkenazi Jews, was not detected in any of the 849 PD patients. CONCLUSIONS: The POLG1 CAG repeat length variation and the GBA p.L444P variant are associated with PD in the Finnish population.
INTRODUCTION: Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. METHODS: The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls. We screened for known genetic risk variants in GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT. In addition, DNA from 225 patients with early-onset Parkinson's disease was subjected to whole exome sequencing (WES). RESULTS: We detected a significant difference in the length variation of the CAG repeat in POLG1 between patients with early-onset PD compared to controls. The p.N370S and p.L444P variants in GBA contributed to a relative risk of 3.8 in early-onset PD and 2.5 in late-onset PD. WES revealed five variants in LRRK2 and SMPD1 that were found in the patients but not in the Finnish ExAC sequences. These are possible risk variants that require further confirmation. The p.G2019S variant in LRRK2, common in North African Arabs and Ashkenazi Jews, was not detected in any of the 849 PDpatients. CONCLUSIONS: The POLG1 CAG repeat length variation and the GBA p.L444P variant are associated with PD in the Finnish population.
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