Journal article
Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study
Lancet neurology, Vol.16(9), pp.701-711
09/2017
DOI: 10.1016/S1474-4422(17)30161-8
PMID: 28642124
Abstract
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.
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.
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
) 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
DHFR p=8·37 × 10
MTRNR2L2 p=2·15 × 10
) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10
DHFR p=8·45 × 10
MTRNR2L2 p=1·20 × 10
). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10
), 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.
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.
The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.
Details
- Title: Subtitle
- Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study
- Creators
- Davina J Hensman Moss - UCL Huntington's Disease Centre, University College London, London, UKAntonio F Pardiñas - MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UKDouglas Langbehn - Carver College of Medicine, Department of Psychiatry and Biostatistics, University of Iowa, Iowa City, IA, USAKitty Lo - UCL Institute of Neurology, Department of Neurodegenerative Disease and UCL Genetics Institute, Division of Biosciences, University College London, London, UKBlair R Leavitt - Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, CanadaRaymund Roos - Department of Neurology, Leiden University Medical Centre, Leiden, NetherlandsAlexandra Durr - ICM, Inserm U 1127, CNRS UMR 7225, UPMC Univ Paris 06 UMR S 1127, Sorbonne Universités, Paris, France; Department of Genetics, Pitié-Salpêtrière University Hospital, Paris, FranceSimon Mead - MRC Prion Unit, University College London, London, UKPeter Holmans - MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UKLesley Jones - MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. Electronic address: jonesl1@cardiff.ac.ukSarah J Tabrizi - UCL Huntington's Disease Centre, University College London, London, UK. Electronic address: s.tabrizi@ucl.ac.ukTRACK-HD investigators
- Contributors
- Hans J Johnson (Contributor) - University of Iowa, Electrical and Computer Engineering
- Resource Type
- Journal article
- Publication Details
- Lancet neurology, Vol.16(9), pp.701-711
- Publisher
- England
- DOI
- 10.1016/S1474-4422(17)30161-8
- PMID
- 28642124
- ISSN
- 1474-4422
- eISSN
- 1474-4465
- Grant note
- MR/P007015/1 / Medical Research Council 200181/Z/15/Z / Wellcome Trust MC_U123160651 / Medical Research Council MC_PC_16031 / Medical Research Council MR/L02053X/1 / Medical Research Council
- Language
- English
- Date published
- 09/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Psychiatry; The Iowa Institute for Biomedical Imaging; The Iowa Initiative for Artificial Intelligence; Iowa Informatics Initiative
- Record Identifier
- 9984003414802771
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