👤 Natalia S Ogonowski

Parkinson's disease (PD) is a genetically complex neurodegenerative disorder. Up to 15% of cases are considered monogenic. However, research on monogenic PD has largely focused on populations of European ancestry, leaving gaps in our understanding of genetic variability in other populations. This study addresses this gap by analysing the allele frequencies of pathogenic and likely pathogenic variants in known monogenic PD genes across eight global populations, using data from the gnomAD database. We compiled a list of 27 genes associated with Mendelian PD from the Online Mendelian Inheritance in Man (OMIM) database, and identified pathogenic and likely pathogenic variants using ClinVar. We then performed pairwise comparisons of allele frequencies across populations included in the gnomAD database. Variants with significant frequency differences were further assessed using in silico pathogenicity predictions. We identified 81 variants across 17 genes with statistically significant allele frequency differences between at least two populations. Variants in Our findings reveal substantial population-specific differences in the allele frequencies of pathogenic variants linked to monogenic PD, emphasising the need for broader genetic studies beyond European populations. These insights have important implications for PD research, genetic screening, and understanding the pathogenesis of PD in diverse populations. Show less

Optical coherence tomography (OCT) is a non-invasive technique to measure retinal layer thickness, providing insights into retinal ganglion cell integrity. Studies have shown reduced retinal nerve fibre layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thickness in Parkinson's disease (PD) patients. However, it is unclear if there is a common genetic overlap between the macula and peripapillary estimates with PD and if the genetic risk of PD is associated with changes in ganglion cell integrity estimates in young adults. Western Australian young adults underwent OCT imaging. Their pRNFL, GCIPL, and overall retinal thicknesses were recorded, as well as their longitudinal changes between ages 20 and 28. Polygenic risk scores (PRS) were estimated for each participant based on genome-wide summary data from the largest PD genome-wide association study conducted to date. We further evaluated whether PD PRS was associated with changes in thickness at a younger age. To evaluate the overlap between retinal integrity estimates and PD, we annotated and prioritised genes using mBAT-combo and performed colocalisation through the GWAS pairwise method and HyPrColoc. We used a multi-omic approach and single-cell expression data of the retina and brain through a Mendelian randomisation framework to evaluate the most likely causal genes. Genes prioritised were analysed for missense variants that could have a pathogenic effect using AlphaMissense. We found a significant association between the Parkinson's disease polygenic risk score (PD PRS) and changes in retinal thickness in the macula of young adults assessed at 20 and 28 years of age. Gene-based analysis identified 27 genes common to PD and retinal integrity, with a notable region on chromosome 17. Expression analyses highlighted NSF, CRHR1, and KANSL1 as potential causal genes shared between PD and ganglion cell integrity measures. CRHR1 showed consistent results across multiple omics levels. Our findings suggest that retinal measurements, particularly in young adults, could be a potential marker for PD risk, indicating a genetic overlap between retinal structural integrity and PD. The study highlights specific genes and loci, mainly on chromosome 17, as potential shared etiological factors for PD and retinal changes. Our results highlight the importance of further longitudinal studies to validate retinal structural metrics as early indicators of PD predisposition. Show less