Elsevier

The Lancet Neurology

Volume 16, Issue 9, September 2017, Pages 701-711
The Lancet Neurology

Articles
Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

https://doi.org/10.1016/S1474-4422(17)30161-8Get rights and content

Summary

Background

Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure.

Methods

We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken.

Findings

Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset.

Interpretation

The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation.

Funding

The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Introduction

Huntington's disease is an autosomal dominant fatal neurodegenerative condition caused by a CAG repeat expansion in huntingtin gene, HTT.1 It is a movement, cognitive, and psychiatric disorder, but symptoms, age of disease onset, and disease progression vary.2 Age of onset reflects the trajectory of disease pathology up to the point of motor onset.1, 3 However, the transition from premanifest to manifest Huntington's disease is gradual,4, 5 making clinical definition challenging. Furthermore, psychiatric and cognitive changes might not be concurrent with motor onset.6 Despite this imprecision in defining onset, the inverse correlation of HTT CAG repeat length and age at motor onset accounts for 50–70% of the observed variance in onset.7 Part of the remaining difference in age of onset was also recently shown to be genetically encoded, and genes of the DNA damage response were identified as being likely to modify onset of Huntington's disease.8

The need for clinical trials close to disease onset has motivated a number of observational studies.5, 9, 10 These new data provide the opportunity to investigate the association between onset and progression and whether they are influenced by the same biology, and permit the study of individuals before clinical onset. TRACK-HD5, 6 was a prospective, observational, biomarker study that represents the most deeply phenotyped cohort of people with premanifest and symptomatic Huntington's disease, with annual visits involving motor, cognitive, psychiatric and imaging assessments. We used TRACK-HD data5, 6 to generate a novel unified Huntington's disease progression measure for use in a genetic association analysis. We developed a similar measure in participants from the REGISTRY study9 to replicate our findings. We used these disease progression measures as quantitative variables in genome-wide association analyses of the TRACK-HD and REGISTRY data, and aimed to replicate this finding in a meta-analysis.

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.

Section snippets

Study design and participants

In this genome-wide association study, we examined prospective data from TRACK-HD to develop a measure of disease progression reflecting correlated progression on brain imaging, motor, and cognitive symptom domains. We used this disease progression measure as a quantitative variable in a genome-wide association study to identify associated genetic loci, and aimed to replicate this finding by generating a parallel progression measure in the less intensively phenotyped REGISTRY study.

TRACK-HD5, 6

Results

In the analysis of variables from TRACK-HD, we did individual principal compenent analyses of each domain and found that the first principal component scores were highly correlated between the domains (p<0·0001 in all cases, appendix). We observed no phenotypic subtypes of symptom clusters in motor, cognitive, or imaging domains; rather, longitudinal change in TRACK-HD not predictable by CAG repeat length and age was distributed on a correlated continuum (figure 2). We therefore repeated PCA of

Discussion

The evidence from our study suggests that MSH3 is probably a modifier of disease progression in Huntington's disease. We did an unbiased genetic screen using a novel disease progression measure in the TRACK-HD study, and identified a significant locus on chromosome 5, which encompasses three genes: MTRNR2L2, MSH3, and DHFR. This locus replicated in an independent group of participants from the European Huntington's disease REGISTRY study using a parallel disease progression measure, and was

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