Huntington’s disease (HD) is a genetic disorder caused by a mutation in the huntingtin gene (HTT) located on chromosome 4. The mutation that causes HD is an extended number of CAG repeats, which is normally in the range of 10-35. CAG stands for a set of three nucleotides that make up a codon. Huntington’s disease occurs when an individual has 40 or more CAG repeats in their huntingtin gene, which results in mutant huntingtin protein formation. Essentially, it is as though someone took a single word that was supposed to be in a sentence, and repeated it so many times that the original sentence no longer makes sense. Genes can manifest themselves in different forms, called alleles. Different alleles express different characteristics in organisms. Humans possess two alleles for each gene, with one allele inherited from each parent. HD is inherited in an autosomal dominant fashion— meaning that only one copy of the mutated allele, known as the “HD disease allele”, is necessary for development of HD. Consequently, if one parent has the mutated gene, then all children of that parent have a 50% chance of inheriting a mutated allele and therefore developing HD. More information on the genetics of HD is available here.
Genetic testing has made leaps and bounds in recent decades in order to allow individuals to determine their gene status with relative ease, though the decision to undergo the process of testing can be emotionally challenging. More information on genetic testing can be found here. However, despite advancements in genetic testing accuracy, identifying when an at-risk individual will being to show obvious motor, behavioral or cognitive symptoms— referred to as the age of onset (AO)— remains a major challenge in HD research. The AO is often predicted based on the number of CAG repeats an individual has — the more repeats, the sooner they will develop symptoms. However, this correlation of repeats to AO can only accounts for about 67% of the variation in age of onset. This means that two individuals with the same number of repeats can develop symptoms up to 20 years apart. So what about the other 33% of variation? Although the answer to this question remains unclear, the remaining variation has been found to have a relatively high degree of heritability, suggesting that additional genetic factors other than the CAG repeat mutation modify AO.
Genetic modifiers refer to the way in which an individual’s natural genetic variation, other than the disease allele, contributes to the development of symptoms. In order for a gene to be considered an HD genetic modifier, it must somehow influence the manifestation of phenotypes, such as onset, types and severity of symptoms, associated with the central HD mutation. Previous work on genetic modifiers for Huntington’s disease has been limited by a variety of factors, including generalizability, patient population size, and genetic research capabilities and accuracy. However with the recent utilization of genome-wide association (GWA) analysis as well as international collaborations, researchers have finally been able to identify several candidate HD genetic modifiers.
Genome-Wide Association Study^
A Genome-Wide Association (GWA) analysis, the primary tool utilized by the authors of the publication “Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease”, allows researchers to rapidly scan the entire genome of many patients in order to identify genetic variations that are strongly associated with a particular disease or phenotype of a disease. GWA studies are difficult to perform in that they require thousands of patients to participate in the study. Each individual is unique because they have a distinctive genome containing small genetic differences. Since GWA studies examine the whole genome of a patient, it is necessary to have many genomes examined in order to find a mutation that is strongly correlated to a particular disease.
The GeM-HD Consortium and Study^
The GeM-HD Consortium^
Fortunately, many clinics in the United States and around the world have been collecting DNA samples from HD patients for years and possess a large amount of medical records about each HD patient. A team of geneticists created a group called the Genetic Modifiers of Huntington’s Disease (GeM-HD) consortium and gathered many DNA samples and information from these clinics in order to conduct a comprehensive GWA study. The GeM-HD consortium brought together many HD researchers as well as data from big studies that involved HD patients, including HD-MAPS, TREND-HD, PREDICT-HD, PHAROS, MaHDC, EHDN and COHORT. The GeM-HD consortium was able to amass DNA samples and medical records of over 4000 HD patients. The patients who participated in this study were selected to have a similar genetic background: they were all of European origin (to control for genetic ancestry effects) and had a CAG count within a specific range of CAG repeats (to minimize effects from extreme CAG repeats).
Discoveries made by the GeM-HD consortium^
The GeM-HD consortium discovered a few sites that were associated with the age of onset of HD. Two sites, on chromosome 8 and 15, exhibited genetic differences that were found to be strongly associated to the disease. The researchers determined that the genetic difference on the chromosome 8 site seemed to accelerate the onset of HD by 1.6 years. They also discovered that the site on chromosome 15 displayed two independent genetic variants that exhibited different effects: one genetic difference accelerates the onset of the disease by 6.1 years, while the other one delays the onset by 1.4 years.
Future of this study^
While the researchers were able to narrow down the generic location of the genetic modifiers of HD, further research and data analysis is needed in order to understand specifically which genes are contributing to the delay or acceleration of the age of onset of HD, and what their normal function is. The GeM-HD consortium was still able to highlight a number of genes that could possibly be implicated in the varying age of onset. Based on previous research, they theorized that some of the genetic effects they discovered could be implicated in DNA handling and repair. Since DNA stores all of the genetic information, it is very important that DNA is preserved correctly in our genome. Although errors can occur in the DNA of some cells, DNA-repair pathways exist to correct these errors. DNA handling and repair pathways are essential for the survival of cells in the body because a faulty DNA-repair pathway that does not repair DNA errors in cells may lead to the self-destruction of these cells.
Rather encouragingly, this study suggests that the course of disease is being successfully altered in HD patients. However, further research is still needed to understand the role that these genetic modifiers are playing in the body both in unaffected and in HD patients. Hopefully, a better understanding of these genetic modifiers can lead to innovative therapeutics that are able to delay the onset of HD. This type of research was only made possible thanks to the thousands of HD patients who agreed to donate their DNA and participate in research studies. Thank you to all of the individuals and families who have allowed this research to happen.
Written by Habib Khoury and Caitlin Esparza