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Cited by 312Genetic Neurodegenerative DiseasesGenetic Associations and EpidemiologyNeurological disorders and treatments

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

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Moss, Davina J Hensman, Pardiñas, Antonio F, Langbehn, Douglas, Lo, Kitty, Leavitt, Blair R, Roos, Raymund, Durr, Alexandra, Mead, Simon +786 more·2017·The Lancet Neurology
DOI 10.1016/s1474-4422(17)30161-8
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Abstract

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.

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Authors
Moss, D. J. H., Pardiñas, A. F., Langbehn, D., Lo, K., Leavitt, B. R., Roos, R., Durr, A., Mead, S., Coleman, A., Santos, R. D., Decolongon, J., Sturrock, A., Bardinet, E., Ret, C. J., Justo, D., Lehericy, S., Marelli, C., Nigaud, K., Valabrègue, R., van den Bogaard, S., Dumas, E. M., van der Grond, J., t'Hart, E., Jurgens, C., Witjes-Ane, M.-N., Arran, N., Callaghan, J., Stopford, C., Frost, C., Jones, R., Hobbs, N., Lahiri, N., Ordidge, R., Owen, G., Pepple, T., Read, J., Say, M., Wild, E., Patel, A., Fox, N. C., Gibbard, C., Malone, I., Crawford, H., Whitehead, D., Keenan, S., Cash, D. M., Berna, C., Bechtel, N., Bohlen, S., Man, A. 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Affiliations
  • Cardiff University (GB)
  • University of Iowa (US)
  • UCL Queen Square Institute of Neurology (GB)
  • University of British Columbia (CA)
  • MRC Prion Unit (GB)
  • University College London (GB)
  • National Oceanography Centre (GB)
  • Centre Hospitalier Universitaire Amiens-Picardie (FR)
  • Centre National de la Recherche Scientifique (FR)
  • Leiden University Medical Center (NL)
ORCID
Venue
The Lancet Neurology
Publisher
Elsevier BV
Published
2017-09
Volume
16
Issue
9
Pages
701-711
ISSN
1474-4422 (ISSN-L)
DOI
10.1016/s1474-4422(17)30161-8
OpenAlex
W2722517739
Cited by
312
References
59
Citations by year
2026: 21 · 2025: 30 · 2024: 35 · 2023: 26 · 2022: 36 · 2021: 42 · 2020: 51 · 2019: 35 · 2018: 30 · 2017: 6
FWCI
16.32
Type
journal article
Language
en
Update notices
erratum (2017-09-01)
Open access
Licence
Locations
  • The Lancet Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • Research Bank (Australian Catholic University) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • HAL (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • BORIS (University Library Bern) (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Florence Research (University of Florence) (submittedVersion)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • UnissResearch (Università degli Studi di Sassari) (submittedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
  • RWTH Publications (RWTH Aachen) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
  • Open Access CRIS of the University of Bern
Funders
  • Research Councils UK
  • CHDI Foundation
  • UCLH Biomedical Research Centre
  • Seventh Framework Programme (2012–305121)
  • Medical Research Council (MR/L010305/1)
  • Brain Research Trust
  • Guarantors of Brain
  • Roche
  • Novartis
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
Keywords
Huntington's disease, disease progression, MSH3, CAG repeat expansion, huntingtin gene, motor function decline, functional capacity, age of onset, disease modifiers, somatic repeat expansion, registry study
MeSH terms
MutS Homolog 3 Protein, Adult, DNA-Binding Proteins, Humans, Huntington Disease, Longitudinal Studies, Registries, Severity of Illness Index, Disease Progression, Principal Component Analysis, Genome-Wide Association Study

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