ORCID Profile
0000-0003-2048-4332
Current Organisations
University College London
,
National Hospital for Neurology and Neurosurgery
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Publications
Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability
Publisher: Springer Science and Business Media LLC
Date: 17-04-2019
DOI: 10.1038/S41531-019-0076-6
Abstract: Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or in idual brain regions, but rather in global cellular processes detectable across several cell types.
Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson’s disease
Publisher: BMJ
Date: 29-11-2019
DOI: 10.1136/JMEDGENET-2019-106283
Abstract: Classical randomisation of clinical trial patients creates a source of genetic variance that may be contributing to the high failure rate seen in neurodegenerative disease trials. Our objective was to quantify genetic difference between randomised trial arms and determine how imbalance can affect trial outcomes. 5851 patients with Parkinson’s disease of European ancestry data and two simulated virtual cohorts based on public data were used. Data were res led at different sizes for 1000 iterations and randomly assigned to the two arms of a simulated trial. False-negative and false-positive rates were estimated using simulated clinical trials, and per cent difference in genetic risk score (GRS) and allele frequency was calculated to quantify variance between arms. 5851 patients with Parkinson’s disease (mean (SD) age, 61.02 (12.61) years 2095 women (35.81%)) as well as simulated patients from virtually created cohorts were used in the study. Approximately 90% of the iterations had at least one statistically significant difference in in idual risk SNPs between each trial arm. Approximately 5%–6% of iterations had a statistically significant difference between trial arms in mean GRS. For significant iterations, the average per cent difference for mean GRS between trial arms was 130.87%, 95% CI 120.89 to 140.85 (n=200). Glucocerebrocidase (GBA) gene-only simulations see an average 18.86%, 95% CI 18.01 to 19.71 difference in GRS scores between trial arms (n=50). When adding a drug effect of −0.5 points in MDS-UPDRS per year at n=50, 33.9% of trials resulted in false negatives. Our data support the hypothesis that within genetically unmatched clinical trials, genetic heterogeneity could confound true therapeutic effects as expected. Clinical trials should undergo pretrial genetic adjustment or, at the minimum, post-trial adjustment and analysis for failed trials.
Related Organisations
University College London
Location: United Kingdom of Great Britain and Northern Ireland
University Of Cambridge
Location: United Kingdom of Great Britain and Northern Ireland
Royal College Of Physicians
Location: United Kingdom of Great Britain and Northern Ireland
National Hospital For Neurology And Neurosurgery
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Kerri J Kinghorn.