Research is first to recognize role of sequence repeats in risk, scientists said
Variations in small, repetitive DNA sequences called short tandem repeats (STRs) are associated with an altered risk of developing Parkinson’s disease, a new study reports.
“We demonstrate for the first time that these complex repeat regions in fact influence a person’s risk of disease and chip away at understanding all the complex genetic factors that are behind this devastating disease,” said Steven Lubbe, PhD, a professor at Northwestern University and co-author of the study, in a press release.
The study, “Genome-wide contribution of common short-tandem repeats to Parkinson’s disease genetic risk,” was published in Brain.
The causes of Parkinson’s are not completely understood, but it’s well established that genetics play a significant role in determining the risk of developing the disease. Most genetic mutations that have been linked to Parkinson’s are single nucleotide polymorphisms, or SNPs, a change in one nucleotide that are the building blocks of DNA that form the “letters” in the genetic code.
STRs and other short, repetitive sequences are common in DNA. In fact, repetitive elements make up more than 50% of the total human genome. Unlike some genes, these sequences don’t provide instructions for making proteins. Their functions remain poorly understood, but emerging research is showing they may play important roles in determining health and disease outcomes.
A research team led by scientists in the U.S. analyzed genetic data from more than a dozen prior studies to assess whether variations in STRs affect Parkinson’s risk. The analysis included data on nearly 40,000 people: 16,642 with Parkinson’s and 22,445 without, all of European ancestry.
To identify Parkinson’s-associated STR variations, the researchers performed genome-wide association analyses, looking for variations that were statistically more common among people with Parkinson’s that may suggest a link with disease risk.
Results identified 34 STR variants that were significantly associated with risk.
Most (88%) of the Parkinson’s-associated STRs were located near genes that have previously been implicated in Parkinson’s, which implies these STRs may affect risk by modulating the nearby genes’ activity. For example, the strongest signal was for an STR in the KANSL1 gene, which has been tied to Parkinson’s risk previously.
Other STRs were near four genes that haven’t been linked with Parkinson’s, namely NDUFAF2, TRIML2, MIRNA-129-, and NCOR1.
“These independent short tandem repeats will be used as candidates for further functional follow-up studies to see in more detail what the functional consequences are of those variants and their influence on these genes in Parkinson’s disease,” said Bernabé Ignacio Bustos, PhD, a postdoctoral research fellow in Lubbe’s laboratory and lead author of the study.
The researchers also showed that including STR data alongside SNP data increased the power of statistical models to identify the genetic contribution to Parkinson’s risk.
“Inclusion of these findings into current risk prediction models is important to help identify those with the greatest risk of developing Parkinson’s disease,” Lubbe said.
Analyses of genetic activity in brain tissue revealed associations between the risk-associated STRs and the activity of Parkinson’s-related genes.
“We show that STRs at known and novel [genes] contribute to Parkinson’s disease risk and have functional effects in disease-relevant tissues and pathways,” the researchers said, adding that further studies may unravel the biological mechanisms linking these variations with Parkinson’s risk.
“Unfortunately, at the cellular level, we do not yet [know] how these repeats lead to Parkinson’s disease, but they represent candidate variants for further functional studies which will hopefully take us one step closer to identifying a novel therapeutic target,” Lubbe said.
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