Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
No Canadian affiliation. An affiliation-only frame — the usual design — would never have seen this work. It is one of the works that make the case for inverting the frame.
Machine scores (provisional)
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The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
- Teacher spread
- 0.291 · how far apart the two teachers sit on this one work
- Validation status
score_only:v0-immature-baseline· verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it
Abstract
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.
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The record
- Venue
- Brain
- Topic
- Lysosomal Storage Disorders Research
- Field
- Medicine
- Canadian institutions
- —
- Funders
- National Institute of Environmental Health SciencesNational Institute of Neurological Disorders and StrokeNational Institute on AgingNational Institutes of HealthNational Cancer InstituteServierMedical Research CouncilHersenstichtingNederlandse Organisatie voor Wetenschappelijk OnderzoekGenentechErasmus Medisch CentrumAvid RadiopharmaceuticalsBundesministerium für Bildung und ForschungZonMwParkinson's UKPfizerBiogenHuffington FoundationNational Center for Research ResourcesAgence Nationale de la RechercheWellcome TrustU.S. Department of DefenseEli Lilly and CompanyItä-Suomen YliopistoTexas Children's HospitalInstitute of GeneticsACMG Foundation for Genetic and Genomic MedicineWellcomeAmerican Parkinson Disease AssociationBristol-Myers SquibbEuropean CommissionHelsingin YliopistoNational Institute of General Medical SciencesH. Lundbeck A/SPrinses Beatrix SpierfondsBurroughs Wellcome FundAmerican Academy of NeurologyMichael J. Fox Foundation for Parkinson's ResearchU.S. Department of Health and Human ServicesHelsingin ja Uudenmaan SairaanhoitopiiriGlaxoSmithKlineEU Joint Programme – Neurodegenerative Disease Research
- Keywords
- GlucocerebrosidaseExome sequencingDiseaseBiologyGeneticsParkinson's diseaseCandidate geneLysosomal storage diseaseLRRK2ExomeGeneBioinformaticsMedicineMutationPathology
- Has abstract in OpenAlex
- yes