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

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

The impact of sward height, forage quality and competitive conditions on foraging behaviour of free-ranging rabbits (Oryctolagus cuniculus L.)

The habitat choice of the small hindgut fermenter, the European rabbit (Oryctolagus cuniculus L.), was studied in relation to sward height, forage quality, population size fuctuations and spatial distribution of burrows in a temperate grassland. In a multi-phase differential clipping experiment with alternating short and tall vegetation strips, rabbits tended to graze near the closest burrows in situations of equal vegetation heights, while a clear preference for short swards was found during summer (July). In this period, general crude protein content was signifcantly lower than in spring (April) and autumn (September), apparently leading to a potential forage quality defcit. The summer behavioural pattern with short sward preference coincided with the relatively higher crude protein content of short swards as compared to tall swards in this period, and with higher intraspecifc competition, due to signifcantly larger numbers of animals present in summer. In autumn, rabbit densities decreased, while crude protein content of both short and tall vegetation increased to a higher, though not signifcantly different level, comparable with spring crude protein content. In those conditions, signifcant preference for low vegetation height could no longer be detected. Data suggest that selection for nutritive quality appears when intraspecifc competition is high and nutritive quality remains under a certain threshold value. When, in autumn, competition decreases and nutritive quality increases again, short sward preference disappears. We conclude that short sward preference is primarily caused by the better forage quality of re-growth in periods of forage quality limitation, while this preference disappears when forage quality limitation no longer occurs