New tool could show how genetic variants raise Parkinson’s risk
Researchers use program to detect, analyze variants across genome
A new screening method may shed light on the interactions between genetic variants that increase the risk of Parkinson’s disease, providing potential avenues for improving risk prediction and personalized care, a study found.
The tool, Variant-variant Interaction through Variable Thresholds (VARI3), is designed to detect and interpret how genetic variants, which often act in combination, contribute to the disease.
“Exactly how variants at the genotype level work together to influence disease risk has been largely ignored,” Bernabe Ignacio Bustos, PhD, a postdoctoral fellow at Northwestern University and one of the study’s co-first authors, said in a university news story. “This is the first tool that helps identify and then characterize variant-variant interactions at a genome-wide level.”
The genome is the complete set of genetic material present on an organism.
The study, “Genome-wide epistasis analysis reveals significant epistatic signals associated with Parkinson’s disease risk,” was published in Brain.
Genetic variants known to influence risk
Although the exact causes of Parkinson’s disease remain unclear, genome-wide association studies (GWAS) have unveiled 94 genetic variants associated with a higher risk of developing the disease. GWAS involves looking for genetic variants — changes in the DNA of a given gene — that might be linked to a particular disease. This may represent only a third of all the genetic drivers of Parkinson’s, according to Bustos.
Genes do not work in isolation, but often influence each other, a phenomenon known as epistasis. GWAS often lack the large-scale data needed to investigate how these variants interact, limiting insights into their combined effects.
“Most of what we know about the genetic factors identified from Parkinson’s disease genome-wide association studies comes from studies that treat these factors as acting independently to increase Parkinson’s disease risk,” Bustos said. “These studies ignore the possibility that genetic variants may be working in combination with each other or interact with each other to modify a person’s chance of getting the disease.”
The researchers developed VARI3 to analyze genetic variant interactions across the entire genome and determine how they contribute to Parkinson’s disease risk.
VARI3 allows researchers to select high-risk variants to test their interactions with all other genomic variants found in the genome. It integrates a new tool, the Two-Locus to Odds Ratio (TLTO), to interpret how specific combinations of genotypes influence disease risk.
“Instead of a hypothesis-driven approach focusing on only a small number of variants or genes, VARI3 allows the user to look at all variants across the genome,” Bustos said. “It does this by automating the selection of a primary set of variants based on high allele [gene variant] frequency and their association with disease risk and then tests the interaction of these primary variants against all variants across the entire genome.”
To develop the tool, the researchers used data from 14 patient groups of European ancestry in collaboration with members of the International Parkinson’s Disease Genomics Consortium. They identified 14 genetic variant interactions associated with a significant increase for Parkinson’s risk.
They then tested the VARI3 tool in four independent Parkinson’s disease datasets, with a total of 13,377 Parkinson’s patients and 413,789 people without the disease who served as controls. The sample included people of Native American ancestry.
The analysis confirmed interactions of gene variants nearby the SNCA gene and within the MAPT and WNT3 genes were linked with the risk of Parkinson’s in both European and Native American ancestry populations.
“This is exciting as, not only are we seeing that variants do work together to increase Parkinson’s disease risk, but we’re also beginning to see that different genotype combinations within an epistatic association are influencing how genes are expressed,” Bustos said.
The findings shed light on the mechanisms of action of genetic variants alone and in combination, paving the way for new therapeutic targets and biomarkers. The insights could also inform personalized care strategies by integrating genetic findings with other risk factors.
Bustos said the team plans to conduct further experiments to confirm the findings and understand exactly how these interactions affect cells and contribute to disease risk in diverse racial and ethnic populations.
“Our goal is to use this information to build a risk prediction tool that combine these genetic findings with other known risk factors, which could help physicians more accurately predict an individual’s risk for Parkinson’s disease and provide personalized advice or care,” Bustos said.
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