In a study published in Neuron, four new genetic risk factors for multiple system atrophy (MSA) were identified through a comprehensive look at the entire genomes of people with the disorder. This work was made possible through a collaboration of more than 20 institutions around the world including laboratories at NINDS, NIA, and the Uniformed Services University for the Health Sciences. Together, the researchers generated the largest genome-sequence dataset for MSA to date, which will be shared with the research community to stimulate discoveries about this devastating disease. The project was led by Sonja W. Scholz, M.D., Ph.D., senior investigator and chief of the Neurodegenerative Diseases Research Section at NINDS.
MSA is an adult-onset sporadic disorder that, along with Parkinson’s disease and Lewy body dementia, is classified as a “synucleinopathy,” meaning that one of its characteristics is an abnormal buildup of α-synuclein protein. Unlike Parkinson’s disease and Lewy body dementia, MSA remains poorly understood because it is very rare (there are roughly 15,000 people living with MSA in the United States), sporadic, and its symptoms can vary from case to case.
To help fill this gap in our understanding of MSA, researchers amassed the complete genomes of 888 people of European ancestry with MSA. Just over half had pathologic confirmation of the MSA diagnosis through examination of brain tissue after death. These data were compared to the genomes of 7,128 controls to better understand the genetic underpinnings of MSA. Doing so required an international collaboration with institutions from the United States and Europe.
The team used sophisticated genome-wide analysis techniques to look at more than 9 million different gene variants within this dataset. Ultimately, four new risk loci for MSA were identified, and the researchers were able to highlight specific genes associated with an increased susceptibility to MSA.
However, this genome analysis was only the first part of the story. To better understand what the consequences of genomic changes in MSA might be, the researchers also performed a transcriptomics analysis—a look at possible changes in brain mRNA, the instructions to make proteins that are created from a person’s genomic (DNA) blueprint. This analysis helped uncover the impact that the genomic changes linked to MSA could have on specific types of cells, including neurons and oligodendrocytes, the cells that support cell-to-cell communication in the brain.
One candidate risk gene, GAB1, has been linked to oligodendrocyte development, and mouse models that have had the gene deleted show defects in myelin—a protective sheath around neurons that plays a key role in signaling. People with MSA also show defects in myelin early in the disease, which further supports GAB1 as a possible candidate gene.
A second gene of interest is KCTD7, which makes a protein found in the cerebellum that is involved in modulating neuronal excitability. Mutations in KCTD7 have already been linked to other neurodegenerative disorders, and the transcript analyses done in this paper strongly implicate a role in the pathogenesis of MSA as well.
These findings are only the start of uncovering the root cause(s) of MSA and the findings will need to be replicated in another batch of MSA genomes. However, this may be difficult due to the rareness of the disorder. To support additional research into MSA and its genetic underpinnings, Scholz and her team are sharing their genome data freely with the research community. This continues the group’s policy of open data sharing that also applied to another large-scale analysis on Lewy body dementia and frontotemporal dementia. Here, it is hoped that by sharing these comprehensive genomic and transcriptomic analyses, additional research will build upon these findings towards the goal of developing targeted treatments for MSA.
Article:
Chia R. et al. “Genome-sequence analyses identify novel risk loci for multiple system atrophy.” Neuron. May 2, 2024. DOI: 10.1016/j.neuron.2024.04.002