Genetic modifiers of Huntington's disease: beyond CAG

Huntington's disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the huntingtin (HTT) gene. Although the variation in age at onset is partly explained by the lengths of the expanded repeat, the unexplained variation is heritable, emphasizing the role of the so-called genetic background on disease expression. Identification of modifier genes can confirm intracellular pathways already suspected to be involved in pathophysiological processes related to HD pathogenesis, but it may also point to completely new pathways and processes that have not yet been considered. Most importantly, confirmed modifier genes provide new targets for the development of therapies. Up to now, a wide range of susceptible HD modifier genes related to different biochemical pathways has been examined. On the basis of the published literature in this field, this review provides an overview of HD modifiers and integrates them into selected pathophysiology aspects.