Erasmus University Medical Center [Rotterdam] (Erasmus MC), Ctr Life Sci Technol, Div Gen Technol, Tsurumi Ku, RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Neurology, ANS - Neurodegeneration, ANS - Amsterdam Neuroscience, Intensive Care Medicine, ANS - Neuroinfection & -inflammation, Graduate School, ACS - Amsterdam Cardiovascular Sciences, APH - Aging & Later Life, Amsterdam Neuroscience - Neurodegeneration, Human genetics, Internal Medicine, Erasmus MC other
المصدر:
Brain-A Journal of Neurology Brain-A Journal of Neurology, Oxford University Press (OUP), 2017, 140 (12), pp.3191-3203. ⟨10.1093/brain/awx285⟩ Brain, 140, 3191-3203 Brain, 140(12), 3191-3203. Oxford University Press Brain, 140, 12, pp. 3191-3203 Brain : a journal of neurology, 140(12), 3191-3203 Brain, 140, 3191-3203. Oxford University Press Brain 140(12), 3191-3203 (2017). doi:10.1093/brain/awx285 Robak, L A, Jansen, I E, van Rooij, J, Uitterlinden, A G, Kraaij, R, Jankovic, J, Heutink, P, Shulman, J M, International Parkinson’s Disease Genomics Consortium (IPDGC), IPDGC Consortium members & International Parkinson’s Disease Genomics Consortium (IPDGC) 2017, ' Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease ', Brain : a journal of neurology, vol. 140, no. 12, pp. 3191-3203 . https://doi.org/10.1093/brain/awx285Test
Item does not contain fulltext Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.
