eprintid: 1559952
rev_number: 65
eprint_status: archive
userid: 608
dir: disk0/01/55/99/52
datestamp: 2017-09-04 15:16:27
lastmod: 2021-12-01 23:40:50
status_changed: 2017-09-04 15:16:27
type: article
metadata_visibility: show
creators_name: Moss, DJH
creators_name: Pardinas, AF
creators_name: Langbehn, D
creators_name: Lo, K
creators_name: Leavitt, BR
creators_name: Roos, R
creators_name: Durr, A
creators_name: Mead, S
creators_name: Holmans, P
creators_name: Jones, L
creators_name: Tabrizi, SJ
title: Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: DF9
divisions: FA5
divisions: D07
divisions: F84
divisions: F86
divisions: D13
divisions: G26
keywords: Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences & Neurology, AGE-OF-ONSET, CAG REPEAT, DNA, INSTABILITY, TRAITS, POWER, HD
note: © 2017 Elsevier Ltd. All rights reserved. This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
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.
date: 2017-09
date_type: published
publisher: ELSEVIER SCIENCE INC
official_url: http://doi.org/10.1016/S1474-4422(17)30161-8
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
article_type_text: Article
verified: verified_manual
elements_id: 1299168
doi: 10.1016/S1474-4422(17)30161-8
lyricists_name: Cash, David
lyricists_name: Fox, Nicholas
lyricists_name: Gibbard, Clare
lyricists_name: Hensman Moss, Davina
lyricists_name: Malone, Ian
lyricists_name: Mead, Simon
lyricists_name: Owen, Gail
lyricists_name: Read, Joy
lyricists_name: Scahill, Rachael
lyricists_name: Tabrizi, Sarah
lyricists_name: Warner, Thomas
lyricists_name: Wild, Edward
lyricists_id: DMCAS28
lyricists_id: NCIFO25
lyricists_id: CRGIB31
lyricists_id: DHENS32
lyricists_id: IBMAL93
lyricists_id: SMEAD68
lyricists_id: GOWEN97
lyricists_id: JEREA20
lyricists_id: RSCAH26
lyricists_id: SJTAB21
lyricists_id: TTWAR25
lyricists_id: EJWIL36
actors_name: Tabrizi, Sarah
actors_name: Laslett, David
actors_id: SJTAB21
actors_id: DLASL34
actors_role: owner
actors_role: impersonator
full_text_status: public
publication: Lancet Neurology
volume: 16
number: 9
pagerange: 701-711
pages: 11
issn: 1474-4465
citation:        Moss, DJH;    Pardinas, AF;    Langbehn, D;    Lo, K;    Leavitt, BR;    Roos, R;    Durr, A;                 ... Tabrizi, SJ; + view all <#>        Moss, DJH;  Pardinas, AF;  Langbehn, D;  Lo, K;  Leavitt, BR;  Roos, R;  Durr, A;  Mead, S;  Holmans, P;  Jones, L;  Tabrizi, SJ;   - view fewer <#>    (2017)    Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study.                   Lancet Neurology , 16  (9)   pp. 701-711.    10.1016/S1474-4422(17)30161-8 <https://doi.org/10.1016/S1474-4422%2817%2930161-8>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1559952/1/Tabrizi_Hensman%20Moss%20et%20al%202017%20LN%20Manuscript.pdf
document_url: https://discovery.ucl.ac.uk/id/eprint/1559952/11/Tabrizi_Hensman%20Moss%20et%20al%20Final%20Sup%20Info.pdf
document_url: https://discovery.ucl.ac.uk/id/eprint/1559952/16/Tabrizi_Complete%20supplementary%20tables%20to%20upload.pdf
document_url: https://discovery.ucl.ac.uk/id/eprint/1559952/23/Tabrizi_Manuscript%20figures.pdf