Title :

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

Author(s) :

Hensman Moss, Davina J. [Auteur]
Pardinas, Antonio F. [Auteur]
Langbehn, Douglas [Auteur]
Lo, Kitty [Auteur]
Leavitt, Blair R. [Auteur]
Roos, Raymund A. C. [Auteur]
Durr, Alexandra [Auteur]
Mead, Simon [Auteur]
Holmans, Peter A. [Auteur]
Jones, Lesley [Auteur]
Tabrizi, Sarah J. [Auteur]

Journal title :

The Lancet. Neurology

Abbreviated title :

Lancet Neurol

Volume number :

16

Pages :

701-711

Publication date :

2017-09-01

ISSN :

1474-4465

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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 × 10-10-8-7-9-4-4-3-8 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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
CNRS
Inserm
Université de Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Research team(s) :

Troubles cognitifs dégénératifs et vasculaires

Submission date :

2019-11-27T13:36:41Z