Research in context
Evidence before this study
Huntington's disease is caused by a tract of 36 or more CAG repeats in exon 1 of the huntingtin gene, HTT. Genetic modifiers of age at motor onset have been identified that highlight pathways which, if modulated in people, might delay Huntington's disease onset. Onset of disease is preceded by a long prodromal phase accompanied by substantial brain cell death; age at motor onset is difficult to assess accurately and is not available in disease-free at-risk individuals. We searched PubMed, for English language articles published until Oct 31, 2016, with the search terms “Huntington* disease” AND “genetic modifier” AND “onset”, which identified 13 studies. We then searched for “Huntington* disease” AND “genetic modifier” AND “progression”, which identified one review article. Among the 13 studies of genetic modification of Huntington's disease onset, most were small candidate gene studies; these were superseded by the one large study of genome-wide genetic modifiers of Huntington's disease, which identified three genome-wide significant loci, one on chromosome 8 and two on chromosome 15, these are thought likely to be associated with RRM2B and FAN1, respectively. This study also implicated DNA handling in Huntington's disease modification.
Added value of this study
We examined the prospective data from TRACK-HD and developed a measure of disease progression that reflected correlated progression in the brain imaging, motor, and cognitive symptom domains. We used the disease progression measure as a quantitative variable in a genome-wide association study and detected a locus on chromosome 5 containing three significant genes, MTRNR2L2, MSH3, and DHFR. The index variant encodes an aminoacid change in MSH3. We replicated this finding by generating a parallel progression measure in the less intensively phenotyped REGISTRY study and detected a similar signal on chromosome 5 that is probably attributable to the same variants. A meta-analysis of the two studies strengthened the associations. The progression measures and age of onset were correlated, but this was not responsible for the genetic association with disease progression. We also detected a signal on chromosome 15 in the REGISTRY study at the locus previously associated with age of onset.
Implications of all the available evidence
The progression measures used in this study can be generated in asymptomatic and symptomatic participants using a subset of the clinically relevant parameters gathered in TRACK-HD. We used these measures to identify genetic modifiers of disease progression in Huntington's disease. We identified a signal in only 216 participants, which was replicated in a larger sample and strengthened in the meta-analysis, reducing the chance of it being a false positive. This finding argues for the power of improving phenotypic measures in genetic studies and implies that this locus has a large effect on disease progression. The index associated genetic variant in TRACK-HD encodes a Pro67Ala change in MSH3, which implicates MSH3 as the associated gene on chromosome 5. Altering levels of Msh3 in Huntington's disease mouse models reduces somatic instability and crossing Msh3 null mice with Huntington's disease mouse models prevents somatic instability of the HTT CAG repeat and reduces pathological phenotypes. Polymorphisms in MSH3 have been linked to somatic instability in patients with myotonic dystrophy type 1. MSH3 is a non-essential neuronally expressed member of the DNA mismatch repair pathway and these data reinforce its candidacy as a therapeutic target in Huntington's disease and potentially in other neurodegenerative expanded repeat disorders.