Scientists have discovered that the individual contribution of gene variants known to increase the risk of Parkinson’s disease can be influenced by other genes and dictate disease age of onset.
These findings, from the study “SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson’s Disease,” were published in the journal Movement Disorders.
The specific causes behind Parkinson’s, a neurodegenerative disease marked by a gradual loss of muscle control and cognitive difficulties, are still not fully understood. But scientists believe its onset and progression are dictated by a combination of genetic, environmental, and lifestyle factors.
Previous genome-wide association studies (GWAS) and candidate gene studies have identified several single nucleotide polymorphisms (SNPs) in certain genes — such as in the synuclein alpha (SNCA) and in the microtubule-associated protein Tau (MAPT) genes — that may increase a person’s risk of developing Parkinson’s.
SNPs, pronounced “snips,” are variations in a single nucleotide — the building blocks of DNA — in the DNA sequence of a gene. GWAS are studies based on a method that scans the genome — all of the genes present in human DNA — looking for specific types of genetic alterations found more frequently in people with a particular disease.
Some investigators went as far as proposing that the contribution of some of these high-risk genetic variants may be affected by other genes. That phenomenon, known as epistasis, brings a whole new layer of complexity to the heritability of Parkinson’s.
Researchers from the Institute of Neurosciences of the University of Barcelona (UBNeuro) and their collaborators set out to investigate whether genetic variants of genes from the mTOR signaling pathway — a key regulator of cell metabolism, growth, proliferation, and survival that is impaired in Parkinson’s — could affect a person’s chance of developing the disease, either by themselves or in combination with other high risk variants (epistatic effect).
To answer that question, they started by selecting a group of 64 SNPs from 57 genes involved in the mTOR signaling cascade that they wanted to focus on in the study.
Then, they collected blood samples from 898 people with Parkinson’s and 921 healthy individuals (controls). These samples were used as a source of DNA that was then sequenced to assess the presence of the 64 gene variants being studied.
To confirm the findings obtained in the first group of patients and controls, called the discovery cohort, researchers screened the genome of 4,170 people with Parkinson’s and 3,014 healthy individuals — a confirmation cohort — that had been stored at the online repository of the International Parkinson’s Disease Genomics Consortium (IPDGC).
In the first group of patients and controls, they found three gene variants of mTOR markers that, together with a known risk variant of SNCA (rs356219), increased the risk of Parkinson’s by more than two times. The three gene variants were rs8111699, present in the STK11 gene; rs456998, present in the FCHSD1 gene; and rs1732170, present in the GSK3B gene.
Moreover, they also discovered two additional gene variants of mTOR markers — rs11868112, present in the RPTOR gene, and rs6456121, found in the RPS6KA2 gene — that together with rs356219 dictated the age of onset of the disease. These associations also were found in the confirmation cohort.
“There are known genetic markers, such as the genetic markers of the synuclein gene, which are associated with an earlier start of the symptoms, but in this study we focused on the influence of the association of other markers which were not known yet,” Cristina Malagelada, lecturer of the department of biomedicine of the faculty of medicine and health sciences of the University of Barcelona, and lead author of the study, said in a press release.
“Identifying this group of markers that influence each other and which condition the starting point of the disease allow delimiting the research of new therapeutic targets in these candidate genes”, Malagelada added.
“[A] relevant implication of our findings is that classical association of individual markers reported in PD, especially in large genomewide association studies, could be revisited in light of potential epistatic complex interactions among markers that until the present have been overlooked and poorly explored in the disease,” the researchers concluded.