Study Finds New Genetic Variants That Affect Huntington’s Disease Symptom Onset

A multi-institutional team with researchers from the Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium recently published in the journal Cell a new breakthrough in Huntington’s disease by identifying new genetic variants that can accelerate or delay symptom onset in patients. The study is entitled “Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease”.

Huntington’s disease is a progressive, neurodegenerative, genetic disorder characterized by the lack of muscle coordination, unsteady gait, mental decline and behavioral symptoms. The disease is caused by an expanded CAG triplet repeat in a gene called huntingtin in chromosome 4, leading to the production of a mutant huntingtin protein that accumulates in the brain interfering with its proper functioning. There is no effective treatment for Huntington’s disease and it is estimated that one in every 10,000 to 30,000 individuals in the United States suffer from the disease.

It was previously found that the number of CAG triplet repeats within the huntingtin gene is the main determinant of the age at which the disease symptoms appear. The greater the number of CAG repeats, the earlier is the symptom onset. However, there are cases where disease symptoms appear earlier or later than what the CAG repeat number alone would predict, indicating that additional DNA changes in other genes may also play a role in symptom onset.

In the study, the team conducted the first genome-wide association (GWA) analysis to screen whole genomes from Huntington’s disease patients in order to find chromosomal regions that might contain genetic variants linked to the disease.

“Most previous research into ways of delaying the onset of HD [Huntington’s disease] symptoms have focused on studying the mutant protein in cells or in animal models, but the relevance of abnormalities in those systems to what actually happens in patients remains a huge assumption,” explained the study’s corresponding author Dr. James Gusella, Director of the Center for Human Genetic Research (CHGR) at Massachusetts General Hospital, in a news release. “Our approach does not rely on model systems but on DNA samples and clinical data from human patients. In essence, we are analyzing the results of a ‘clinical trial’ conducted by nature, a trial in which naturally occurring variations in genes other than the HD gene intervened to influence the course of the disease. Now it is up to scientists to figure out how those genetic interventions work and to build on them to develop effective therapies based on understanding how these processes operate in humans.”

In total, samples from 4,082 Huntington’s disease patients were analyzed in the study. Researchers identified two sites at chromosome 15 where variants were found to significantly associate with early (on average six years earlier) or late (an average of one-and-a-half-year delay) symptom onset, plus an additional variant on chromosome 8 associated with an earlier symptom onset (average of one-and-a-half-year earlier). The data suggests that DNA repair mechanisms (specifically a gene called MLH1) may play an important role in Huntington’s disease, however, it is not clear how these variants actually influence symptom onset.

“What we can say for sure is that the modifier variants located on these chromosomal regions affect the disease process prior to the appearance of symptoms,” said Dr. Gusella. “Figuring out the exact DNA sequence variations responsible and how they influence the disease process should provide us with a guide for developing drugs that we hope could have a much larger effect than the one to six years produced by the natural variations, possibly even preventing symptom onset altogether. We believe that we are closer to finding such therapies, but it’s impossible to predict a specific timeline.”

The research team concluded that novel specific genetic variants on chromosomes 15 and 8 can modify the age at onset of Huntington’s disease, and suggest that these variants could offer new potential therapeutic targets for the disorder.

“Another exciting thing about this study is the way it presents an entirely new window on the disease in human patients that complements previous lab-based approaches. This work has been enabled by more than a decade of large natural history studies in which patients and their families have been essential participants. The fact that even more are continuing to enroll worldwide to participate in the investigation of their disease should accelerate our approach.” concluded Dr. Gusella.