Genetic factors that modify clinical onset of HD
By: Jong-Min Lee, PhD on behalf of the Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium
HD is due to a dominantly inherited CAG trinucleotide repeat expansion in the HTT gene that is both necessary and sufficient to cause clinical manifestations. The size of the expanded CAG repeat largely determines the rate of the pathogenic process that leads to clinical symptoms of HD. However, the size of the expansion does not perfectly predict individual age at onset of clinical disease, suggesting the existence of genetic and possibly environmental disease modifiers that interact with HTT-driven disease pathogenesis to alter the timing of clinical symptoms of HD.
In order to identify human genetic factors capable of delaying or hastening age at onset of motor signs, the GeM-HD Consortium capitalized on the power of genome-wide association (GWA) analysis by using naturally occurring single-nucleotide polymorphisms (SNPs) in the DNA as genetic markers. DNA samples were collected from 4,082 HD patients to determine genome-wide SNP genotypes and, from corresponding clinical information, the difference between observed and CAG-predicted age at onset (i.e. residual age at onset) was calculated. Subsequent statistical analysis aimed at identifying genetic variations correlated with residual age at onset revealed two genome-wide significant regions representing three independent modifier effects. A region on chromosome 15 harbors two independent modifier association signals in the HD population: one that hastens age at onset by approximately 6 years, and the other that delays it by approximately 1.4 years. A region on chromosome 8 carries a modification signal that delays onset by approximately 1.6 years. In addition, near-significant signals at MLH1, a gene on chromosome 3 involved in DNA repair, and analyses that capture signal from SNPs by pathway rather than individual gene, suggest a potential role for DNA mismatch repair/maintenance processes in modifying disease pathogenesis before onset.1
These findings demonstrate that HD can be modified prior to clinical disease onset, supporting the potential of genetic modifier pathways as therapeutic targets. Many additional genetic modifiers may still remain undetected in this 4,082-person GWA study due to sample size and to the magnitude of individual modifier effects. Observations that HTT participates in a wide variety of cellular functions support the likelihood that there may be numerous genetic modifiers of HD.
We created a user-friendly website called Genetic Modifiers of Motor Onset Age (GeM MOA), accessible through Huntington’s Disease in High Definition, to disseminate the full set of GWA results and to facilitate alternative genetic-based approaches to HD modifiers.2 Registered users can view association results by searching a gene symbol, a SNP name, or a region of interest. We strongly advise that the data be interpreted with care; for example, as most SNP signals represent indirect association, the location of the SNP does not necessarily implicate the nearest gene. Conversely, the absence of even suggestive p-values near a gene may not dictate a lack of potential for it to modify HD, as this may instead reflect a lack of naturally occurring variations that impact the gene’s function. Nevertheless, the discovery of significant genetic modifiers of HD provides the proof of principle that disease modification in HD is possible. The GeM MOA website is designed to accelerate the search for targets for development of therapeutic interventions, validated in humans, that are effective before the emergence of clinical disease.
1Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.
2Correia K, Harold D, Kim KH, et al. The genetic modifiers of motor onset age (GeMOA) website: Genome-wide association analysis for genetic modifiers of Huntington’s disease. J Huntingtons Dis. 2015 Sep 29;4(3):279-84. doi: 10.3233/JHD-150169.
Highlights from the Journal of Huntington’s Disease
With this edition, we are pleased to begin bringing you highlights of recent research published in the Journal of Huntington’s Disease. Edited by Drs. Blair Leavitt and Leslie Thompson, the journal features original research in basic science, translational research, and clinical medicine. To read about the beginnings of the journal, see HD Insights, Vol. 2.