Finding Factors that Affect Huntington’s Disease Onset

Understanding how DNA sequence variations influence the onset of Huntington’s disease could suggest new therapeutic approaches.SilverV/iStock/Thinkstock.

Huntington’s disease is an inherited neurodegenerative disorder. Symptoms usually begin in midlife and include uncontrolled movements, emotional disturbances and, eventually, dementia. Although studies in humans and animals have discovered clues as to how the disorder works, there are no effective treatments.

Huntington’s disease is caused by expansions within a gene that codes for a protein called huntingtin. The gene is characterized by multiple repeats of the 3-letter sequence CAG in the DNA code. Most people have 6 to 34 CAG repeats in the gene. Disease-causing versions of the huntingtin gene contain more than 35 CAG repeats. In general, the greater the number of CAGs, the greater the chance that symptoms will appear earlier in life.

Past studies have suggested that the onset of Huntington’s disease is also affected by other heritable factors. Researchers in the Genetic Modifiers of Huntington’s Disease Consortium postulated that studying people with expanded CAG repeats might help to pinpoint these other factors. While such factors might be common in the general population, their effects would be detectable only in the presence of excess CAG repeats.

The international team launched a genome-wide association study, which typically involves searching for changes to the DNA code that are associated with disease. For the current study, however, they took a novel approach. Since they already knew the disease-causing gene, they used the technique to search for changes associated with the timing of disease onset. The scientists analyzed DNA samples from more than 4,000 people with Huntington’s disease who had 40 to 55 CAGs. The study was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Results appeared on July 30, 2015, in Cell.

Two sites on chromosome 15 were strongly linked to disease onset. One was associated with hastening the disease by about 6 years on average. The other was associated with slowing the disease by about a year and a half. Another site on chromosome 8 was tied to earlier onset of about a year and a half. Further analysis will be needed to pinpoint the precise factors responsible for these effects.

A systematic analysis also uncovered 14 biological pathways linked to the onset of disease. They fall into 3 general areas: DNA repair, mitochondrial division, and oxidoreductase activity, which plays an important role in the basic metabolism of the cell.

“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,” says corresponding author Dr. James Gusella of Massachusetts General Hospital. Figuring out the exact DNA sequence variations responsible and how they lead to disease could open the door to new therapeutic approaches. “Our hope is to find ways that we can slow or delay the onset of Huntington’s devastating symptoms. This could be possible because we now have a list of clinically proven genetic factors that influence the disease.”