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

Davina J Hensman Moss; Antonio F Pardiñas; Douglas Langbehn; Kitty Lo; Blair R Leavitt; Raymund Roos; Alexandra Durr; Simon Mead; TRACK-HD investigators; REGISTRY investigators; Peter Holmans; Lesley Jones; Sarah J Tabrizi; Sophie Andrews

doi:10.1016/S1474-4422(17)30161-8

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

Journal article

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

Davina J Hensman Moss, Antonio F Pardiñas, Douglas Langbehn, Kitty Lo, Blair R Leavitt, Raymund Roos, Alexandra Durr, Simon Mead, TRACK-HD investigators, REGISTRY investigators, …

Lancet Neurology, Vol.16(9), pp.701-711

2017

DOI: https://doi.org/10.1016/S1474-4422(17)30161-8

PMID: 28642124

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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.

Details

Title: Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study
Authors: Davina J Hensman Moss (Author) - University College London
Antonio F Pardiñas (Author) - Cardiff University
Douglas Langbehn (Author) - University of Iowa
Kitty Lo (Author) - The University of Sydney
Blair R Leavitt (Author) - University of British Columbia
Raymund Roos (Author) - Leiden University
Alexandra Durr (Author) - Institut du Cerveau
Simon Mead (Author) - University College London
TRACK-HD investigators (Institution)
REGISTRY investigators (Author)
Peter Holmans (Author) - Cardiff University
Lesley Jones (Author) - Cardiff University
Sarah J Tabrizi (Author) - University of Glasgow
Sophie Andrews (Consortium Member)
Publication details: Lancet Neurology, Vol.16(9), pp.701-711
Publisher: Lancet Publishing Group
Date published: 2017
DOI: 10.1016/S1474-4422(17)30161-8
ISSN: 1474-4465; 1474-4422
PMID: 28642124
Copyright note: Copyright © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Organisation Unit: Thompson Institute
Language: English
Record Identifier: 99659596702621
Output Type: Journal article

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