Rare Gene Discovered That Nearly Doubles Risk of Developing a Neurodegenerative Disease


A multi-institutional team of researchers from the HudsonAlpha Institute for Biotechnology, the University of California, San Francisco (UCSF), and the University of Alabama at Birmingham (UAB), have identified a rare genetic variant that sigifnicantly incresases the risk of developing diseases like Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD).

“Finding evidence for a risk factor that contributes to multiple neurodegenerative diseases is exciting,” said Richard M. Myers, Ph.D., president and science director of HudsonAlpha, in a press release. “We already know that these diseases share some pathologies. This work shows that the underlying causes of those pathologies may also be shared.”

The team’s research, “Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases” was published April 23 in The American Journal of Human Genetics. For their study, the investigators sequenced and analyzed whole genomes of more than 1,100 people of European descent— 435 cases of early-onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD) and 671 controls. They found that rare variation in the gene TET2 nearly doubled the risk of developing diseases like Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD).

“The project wouldn’t have been possible without extensive collaboration between institutions,” said first author Nicholas Cochran, Ph.D., a senior scientist in the Myers Lab. “You end up being able to find things that you can’t find working alone.”

Jennifer Yokoyama, Ph.D., an assistant professor of neurology at UCSF, collaborated with Cochran on technical details and also managed the project’s sample collection, the majority of which were collected over decades at the UCSF Memory and Aging Center—and then sequenced and analyzed at HudsonAlpha.

Once they had the sequencing results, the researchers noticed that many of the patients had early-onset versions of neurodegenerative disease, suggesting there would be a genetic component of their illness. During genome analysis, the researchers looked at both coding and non-coding regions of the genome for DNA sequence variants, a strategy that allowed them to be more confident that any possible genes they discovered would be implicated in these diseases

Upon identifying TET2, the investigators then compared their findings with existing genetic data from more than 32,000 healthy people and people with neurodegenerative diseases. This data confirmed that variants in TET2, in both protein-coding and non-coding regions, were more likely to be present in the genomes of people with AD, ALS, or FTD than in people without these diseases.

“Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes,” the researchers wrote. “Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.”

Next steps for this continued research will focus on how changes in TET2 levels or function could contribute to aging and neurodegenerative disease.

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