UseCases_ArguminSci_Discourse  

PubMed:28642124 JSONTXT 9 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T1 0-117 DRI_Background denotes Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study.
T2 130-215 DRI_Approach denotes Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT.
T3 216-382 DRI_Background denotes 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.
T4 383-527 DRI_Approach denotes Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure.
T5 537-821 DRI_Approach denotes 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).
T6 822-1048 DRI_Approach denotes 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).
T7 1049-1230 DRI_Outcome denotes 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.
T8 1241-1437 DRI_Background denotes 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.
T9 1438-1589 DRI_Approach denotes 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).
T10 1590-1687 DRI_Outcome denotes The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (
T11 1687-1695 Token_Label.OUTSIDE denotes p=1·12 ×
T12 1696-1768 DRI_Outcome denotes 10(-10)) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2.
T13 1769-1839 DRI_Approach denotes The genes in this locus were associated with progression in TRACK-HD (
T14 1839-1872 Token_Label.OUTSIDE denotes MSH3 p=2·94 × 10(-8)DHFR p=8·37 ×
T15 1873-1878 DRI_Approach denotes 10(-7
T16 1880-1897 Token_Label.OUTSIDE denotes MTRNR2L2 p=2·15 ×
T17 1898-1942 DRI_Approach denotes 10(-9)) and to a lesser extent in REGISTRY (
T18 1942-1999 Token_Label.OUTSIDE denotes MSH3 p=9·36 × 10(-4)DHFR p=8·45 × 10(-4)MTRNR2L2 p=1·20 ×
T19 2000-2008 DRI_Approach denotes 10(-3)).
T20 2009-2131 DRI_Approach denotes The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (
T21 2131-2139 Token_Label.OUTSIDE denotes p=1·58 ×
T22 2140-2200 DRI_Approach denotes 10(-8)), and encodes an aminoacid change (Pro67Ala) in MSH3.
T23 2201-2545 DRI_Approach denotes 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.
T24 2546-2619 DRI_Background denotes These associations remained significant after adjusting for age of onset.
T25 2636-2779 DRI_Outcome denotes The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis.
T26 2780-2956 DRI_Outcome denotes 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.
T27 2957-3112 DRI_Outcome denotes Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation.
T28 3122-3273 DRI_Unspecified denotes The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.