Unveiling Sex-based Differences in Parkinson's Disease: A Comprehensive Meta-analysis of Transcriptomic Studies

Abstract

Background:In recent decades, increasing longevity (among other factors) has fostered a rise in Parkinson's disease incidence. Although not exhaustively studied in this devastating disease, the impact of sex represents a critical variable in Parkinson’s Disease as epidemiological and clinical features differ between males and females. Methods: To study sex bias in Parkinson’s Disease, we conducted a systematic review to select sex-labeled transcriptomic data from three relevant brain tissues: the frontal cortex, the striatum, and the substantia nigra. We performed differential expression analysis on each study chosen. Then we summarized the individual differential expression results with three tissue-specific meta-analyses and a global all-tissues meta-analysis. Finally, results from the meta-analysis were functionally characterized using different functional profiling approaches. Results: The tissue-specific meta-analyses linked Parkinson’s Disease to the enhanced expression of MED31 in the female frontal cortex and the dysregulation of 237 genes in the substantia nigra. The global meta-analysis detected 15 genes with sex-differential patterns in Parkinson’s disease, which participate in mitochondrial function, oxidative stress, neuronal degeneration, and cell death. Furthermore, functional analyses identified pathways, protein-protein interaction networks, and transcription factors that differed by sex. While male patients exhibited changes in oxidative stress based on metal ions, inflammation, and angiogenesis, female patients exhibited dysfunctions in mitochondrial and lysosomal activity, antigen processing and presentation functions, and glutamic and purine metabolism. All results generated during this study are readily available by accessing an open web resource (http://bioinfo.cipf.es/metafun-pd/) for consultation and reuse in further studies. Conclusions: Our in-silico approach has highlighted sex-based differential mechanisms in typical Parkinson Disease hallmarks (inflammation, mitochondrial dysfunction, and oxidative stress). Additionally, we have identified specific genes and transcription factors for male and female Parkinson Disease patients that represent potential candidates as biomarkers to diagnosis.

An integrated approach to identifying sex-specific genes, transcription factors, and pathways relevant to Alzheimer’s disease

“…All data and results generated in the different steps of the meta-analysis are available in the Metafun-AD web tool [41], which is freely accessible to any user and allows the confirmation of the results described in this manuscript and the exploration of other results of interest. The front end was developed using Quarto 1.2 [42] , and the interactive graphics used in this web resource have been implemented with plotly [43].…”

Unveiling sex-based differences in Parkinson's disease: a comprehensive meta-analysis of transcriptomic studies

“…All data and results generated in the different steps of the meta-analysis are available in the Metafun-PD web tool [44], which is freely accessible to any user and allows the confirmation of the results described in this manuscript and the exploration of other results of interest. The frontend was developed using the Angular Framework, the interactive graphics used in this web resource have been implemented with plotly [45], and the exploratory analysis cluster plot was generated with the ggplot2 R package [46].…”

“…The Metafun-PD web tool [44] contains information about the 7 studies and 267 samples involved in this study. This resource includes statistical indicators of each performed analysis for each study, which users can explore to identify profiles of interest.…”