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Hum Mol Genet. 2016 Dec 15;25(24):5483-5489. doi: 10.1093/hmg/ddw348.

Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: evidence for oligogenic inheritance.

Author information

Department of Clinical Neuroscience, Institute of Neurology, University College London, London, UK.
Department of Psychological Medicine and Neurology, Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
Department of Clinical Genetics, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Division of Life Science, Hong Kong University of Science and Technology, Hong Kong SAR, People's Republic of China.
School of Pharmacy, University of Reading, Whiteknights, Reading, UK.
Centre for Integrated Neuroscience and Neurodynamics, University of Reading, Whiteknights, Reading, UK.
Reta Lila Weston Institute, University College London Institute of Neurology, Queen Square, London, UK.
Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
Division of Medicine, University College London, London, UK and 15UCL Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK.


Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognised primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.

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