Novel approach pinpoints genetic variants linked to Parkinson’s disease risk microbiologystudy

Investigators have developed a novel approach that can better identify and characterize genetic variant interactions associated with increased risk of Parkinson’s disease, improving the understanding of the genetic heritability of the disease, according to a recent study published in Brain.

“Exactly how variants at the genotype level work together to influence disease risk has been largely ignored. This is the first tool that helps identify and then characterize variant-variant interactions at a genome-wide level,” said Bernabe Ignacio Bustos, Ph.D., a postdoctoral fellow in the laboratory of Dimitri Krainc, MD, Ph.D., the Aaron Montgomery Ward Professor and chair of the Ken and Ruth Davee Department of Neurology, and a co-first of the study.

Parkinson’s disease impacts more than six million people worldwide, according to the Michael J. Fox Foundation for Parkinson’s Research, and occurs when specific populations of neurons lose their ability to make dopamine, which impacts movement.

Identifying genetic drivers of the disease has long been a priority of the field: several genes are currently known to cause Parkinson’s disease, and 94 genetic risk variants have been identified from previous genome-wide association studies. Despite this progress, however, these studies have only been able to identify approximately one-third of genetic drivers of Parkinson’s disease, Bustos said.

“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.”

According to Bustos, current genome-wide association studies do not have the large cohort sizes needed to reach the required statistical power to study variant-variant interactions—also called epistasis, or when the expression of one gene is modified by the expression of one or more other genes.

To address this gap, the investigators developed a genome-wide epistasis screening approach, called Variant-variant interaction through variable thresholds (VARI3), to analyze genetic variant interactions across the entire genome and determine how they contribute to Parkinson’s 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. It does this by automating the selection of a primary set of variants based on high allele frequency and their association with disease risk and then tests the interaction of these primary variants against all variants across the entire genome.

“Another feature that makes this pipeline unique is that it introduces a specialized tool, two-locus to odds ratio (TLTO), which allows us to interpret the risk associated with the different genotype combinations seen between two variants rather than just the single variants involved in the epistatic interaction,” Bustos said.

In the study, the investigators designed and used VARI3 with a combined dataset consisting of 14 patient cohorts of European ancestry in collaboration with members of the International Parkinson’s Disease Genomics Consortium, and identified 14 genetic variant interactions associated with a significant increase in Parkinson’s disease risk.

Next, using four independent Parkinson’s disease datasets, the investigators identified genotype combination risk profiles that are associated with overlapping genotype combination specific expression patterns.

Further analysis also demonstrated that the epistatic effect on Parkinson’s disease of those variants was observed in both patients with European ancestry and with Native American ancestry.

“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 demonstrate how genetic variants work both alone and together to influence Parkinson’s disease risk, which may inform the development of novel therapeutic targets or biomarkers for determining disease risk.

According to Bustos, his team aims to confirm their findings in a laboratory to understand exactly how these interactions impact cells and contribute to disease risk and how these genetic interactions affect people from diverse racial and ethnic backgrounds.

“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.