Researchers recently developed an integrated functional genomics approach that resulted in the identification of 50 genes that can be used to modify Parkinson's disease(PD) pathology in a disease animal model.
GWAS and TWAS in Analyzing Genome
Within a single screening strategy, the team combined several computational and in vivo biological approaches. The team was able to identify and validate many PD gene candidates in a relatively short period of time. Identifying and functionally validating the role of a gene in a genetic disorder typically takes several years.
Genome-Wide Association Studies (GWAS) have been used to examine the genomes of large groups of people in order to identify genomic variants. These variants are statistically associated with an increased risk of a complex genetic disorder.
The method can identify genetic loci/gene variants that may be associated with a specific disease. However, more in-depth in vitro studies in cultured cells and/or in vivo studies in animal models are required to show the biological involvement of those variants in the pathogenesis of that disease. These processes are both labor-intensive and time-consuming.
According to Your Genome, the identification of SNPs linked to diseases like type 2 diabetes, Alzheimer's disease, Parkinson's disease, and Crohn's disease has been made possible by GWS.
Then, more recently, a technique known as transcriptome-wide association study (TWAS) was developed to predict genetic risk for complex diseases. The researchers gained insight into the potential function of these variants by combining TWAS and GWAS with a machine learning algorithm.
Gene Validation
The lead author of this study, graduate student Jiayang Li, and others developed a multi-step approach that combined several computational and in vivo validation methods to speed up the gene validation process.
Li said that they identified 160 potential PD candidate genes using GWAS and TWAS. These were then analyzed using other cutting-edge computational tools, which yielded 80 high-confidence PD genes. Then they established a link between these candidates and PD-associated pathology by assessing whether their expression patterns were altered in the brain and blood transcriptomes of PD patients.
Finally, they performed several in silico and in vivo analyses to assess functional relationships between these candidates. They also tried to identify which biological pathways they are involved in, which yielded 50 PD risk genes and 14 potentially neuroprotective genes.
Botas, according to Medical Xpress, stated that their success in identifying so many new variants, as well as the remarkable consistency in the results obtained at each step of this screen, validates this as a powerful method for identifying and validating new PD candidate genes.
Furthermore, as long as genomic information is readily available, this approach can be broadly applied to a wide range of complex genetic disorders. He said that they anticipate that this study will have a broad impact on disease areas far beyond Parkinson's disease.
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Multidisciplinary Approach
The researchers from the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Baylor College of Medicine published the study in Human Molecular Genetics.
The study was led by Dr. Juan Botas, a Baylor College professor and Duncan NRI investigator. The study's highlight is a new multidisciplinary high-throughput approach developed by the team to identify and functionally validate dozens of PD-causing and neuroprotective genes.
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