Genetic Modifiers of Huntington's Disease

Future Perspective

In theory, the final goal in HD modifier studies is to obtain a complete understanding of the unexplained variance in AO that is attributable to genetic factors, other than the length of the CAG repeat in HTT. Yet, to reach this goal rapidly is an unrealistic assumption, possibly since hundreds or thousands of SNPs, all with very small effect sizes, reflect influences on the disease. It is possible that many more rare variations at a frequency far below 5% have yet to be identified. Beside genome-wide association studies, genome sequencing technologies, which become more readily available and affordable, will certainly contribute to reaching these goals. Further modifier variations, both common and rare, can be identified by comparing the DNA sequences of patients with the same expansion size, but at the extremes of a quantitative trait (such as AO, but also disease progression or other phenotypes).

Once the most promising modifier variations have been identified, their functional effects need to be assessed using model organisms, such as transgenics and in vitro functional studies. Elucidating the precise mechanisms by which the variations exert their biological effects yields basic information directly applicable to disease interventions.

Although there are currently only a few examples of reproducible associations with AO in HD, the majority of reviewed markers show heterogeneity in effect sizes across studies. This highlights the need for future studies concerning differences in sample and methodological characteristics that can explain such heterogeneity and point to ways of identifying truly meaningful associations. The lack of replication in many association studies, including the gene modifier search in HD, is not only due to the small numbers of study subjects, but also to limitations of study design and phenotyping. In HD, the importance of the precise determination of the AO deserves special consideration, as robust gene modifier studies require the most rigorous phenotyping.

On average, psychiatric and cognitive symptoms significantly predate clinical motor onset by a few years. Assessing the variability in AO attributable to the CAG repeat length reveals that the portion of variance in AO strongly depends on its definition. Different population origins, various LD patterns and the composition of the cohort in terms of CAG distribution may, of course, represent additional causes for lack of replication. As can be inferred from Table 1, the R² statistics for the study cohorts vary between 0.308 and 0.901, partly depending on how many CAG repeats from the extreme tail of the CAG distribution are included in the sample.

Therefore, replication of the association with the specific polymorphism or a positive association with other variations at the locus, points to the importance of the particular candidate gene and helps to ensure that the association observed represents a true association and is not a chance finding or artifact. Robust associations of modifier variations are just the basis, and further research is needed in order to determine if the associated modifier markers represent truly causal variations, as their function generally remains unknown. Fine localization of the causal variations is, and will remain, a major challenge, complicated primarily by strong LD between alleles of SNPs in the associated region, lack of knowledge regarding intronic or intergenic regulatory elements, including endogenous sense–antisense miRNA genes and other nonprotein-coding RNA as well as possible interference of copy number variations or SNP–SNP interactions.

Furthermore, environmental factors are also likely play a role in modifying the onset and course of HD. Yet, determining the relative contribution of environmental factors remains difficult, because most phenotypes are most likely the result of interactions between genetic and environmental influences. The genetic modifier contribution to the AO may vary by an individual's level of environmental (toxic) exposure. Conversely, environmental exposure may have different effects depending on one's genetic background. Therefore, valuable insights into the complex molecular events that drive the HD pathology will also emerge as we learn to dissect these complicated gene/environment relationships.

Having identified those causal variations and inter-relations, a question arises as to which of these true disease-modifying loci also influence other (disease) phenotypes? The effect of a specific genetic background on the disease expression of a particular single gene disorder could also possibly contribute to the specificity of more common disease patterns. Effects of certain sequence variations may be relatively weak in healthy individuals, whereas the altered metabolism of patients with a monogenic disease may unmask the effects of such modifiers. Building up a molecular taxonomy of common disease phenotypes and pathways based on true genetic associations could help in assessing consequences of modulating the function of a gene or pathway in the search for new therapies. Elucidating a large part of factors that contribute to the manifestation of HD will advance our understanding of the etiology of the disease, while at the same time providing useful therapeutic targets for drug discovery that reach beyond the effective symptomatic treatment.

Future Neurology. 2012;7(1):93-109. © 2012  Future Medicine Ltd.