RESUMO
We present ensemblQueryR, an R package for querying Ensembl linkage disequilibrium (LD) endpoints. This package is flexible, fast and user-friendly, and optimised for high-throughput querying. ensemblQueryR uses functions that are intuitive and amenable to custom code integration, familiar R object types as inputs and outputs as well as providing parallelisation functionality. For each Ensembl LD endpoint, ensemblQueryR provides two functions, permitting both single- and multi-query modes of operation. The multi-query functions are optimised for large query sizes and provide optional parallelisation to leverage available computational resources and minimise processing time. We demonstrate improved computational performance of ensemblQueryR over an exisiting tool in terms of random access memory (RAM) usage and speed, delivering a 10-fold speed increase whilst using a third of the RAM. Finally, ensemblQueryR is near-agnostic to operating system and computational architecture through Docker and singularity images, making this tool widely accessible to the scientific community.
RESUMO
Background and Objectives: The genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets. Methods: We performed a GWAS meta-analysis of early PD motor severity and progression up to 3 years from study entry. We used linear mixed-effect models with additive effects, corrected for age at diagnosis, sex, and the first 5 genetic principal components to assess variability in axial, limb, and total Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores. Results: We included 3,572 unrelated European ancestry patients with PD from 5 observational cohorts and 1 drug trial. The average AAO was 62.6 years (SD = 9.83), and 63% of participants were male. We found an average increase in the total MDS-UPDRS III score of 2.3 points/year. We identified an association between PD axial motor progression and variation at the GJA5 locus at 1q12 (ß = -0.25, SE = 0.04, p = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-expression quantitative trait loci [eQTL] analysis) showed that the lead variant was associated with expression of ACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTL p-values in blood and brain RNA expression data sets: <10-14 in eQTLGen and 10-7 in PsychEncode). Discussion: Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets that might modify disease progression.
