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

Range-wide genetic analysis reveals limited structure and suggests asexual patterns in the rare forb Senecio macrocarpus

Genetic diversity and recombination underlie the long-term persistence and evolution of species and are strongly influenced by population size, breeding system and plant longevity. Here, we study genetic structure in the rare Senecio macrocarpus in southeastern Australia to guide current conservation practices. Thirteen neutral microsatellite markers and two chloroplast regions were used to survey the 20 known S.macrocarpus populations and one sympatric S.squarrosus population, a morphologically similar species. All markers showed severe excess or deficit of heterozygotes and linkage disequilibrium was significant. Microsatellite markers revealed 100 multi-locus genotypes (MLGs) from 523 S.macrocarpus individuals and a further 4 MLGs from 27 S.squarrosus individuals. MLGs varied in frequency and distribution. At the extremes, one MLG was found 108 times across the sampling region and 66 MLGs were found once. The MLGs of all 38 seedlings genotyped were identical to their seed parents implying an asexual origin. Chloroplast regions showed little variation within S. macrocarpus but differed from S. squarrosus. Chromosome counts for S. macrocarpus revealed the same ploidy level as S. squarrosus (2n=6x=60) and pollen-ovule ratios were typical of erechthitoid Senecio species showing self-compatibility. Results suggest that establishment of small populations occur primarily from one extensive source population with indications that both apomixis and selfing may be contributing to its reproduction cycle. We suggest that this species may contribute to future evolutionary processes despite limited genotypic variation and restricted distribution. Its conservation will safeguard evolutionary processes that might occur through occasional outcrossing and hybridization events between sympatric species

How to analyze time and change in qualitative longitudinal materials? : Insights from a literature review of longitudinal qualitative studies in nursing.

Background Longitudinal qualitative research can give new insights in social processes and experiences over time. In recent years, there has been a growing interest in conducting longitudinal qualitative research within nursing. However, the definition of what constitutes longitudinal qualitative research is unclear, the methodological literature scarce, and the variation of procedures great. This review of longitudinal qualitative articles within the nursing field aims to identify and describe various types of qualitative longitudinal approaches. Materials and Method Searches in pubmed identified over a hundred qualitative nursing articles with data collection over time. These articles were analyzed regarding 1) described analysis procedure, 2) how the results related to aspects of time and change, and 3) if results were person oriented vs category oriented. Results Five different types of longitudinal qualitative approaches were identified. In total, a large part of the papers described as having a longitudinal design performed a data collection over time, but did not integrate ideas of time or change in their analysis or results. Four fruitful approaches to analyzing longitudinal qualitative data were identified; time-line, pool, phase and pattern-oriented approaches. Articles classified as using any of these approaches have a clear perspective of time or change in the results. However, depending on type of approach different aspects of time, change, and process are in focus. Further, using different approaches yielded different kinds of results. Conclusion All approaches have pros and cons and researchers need to make informed decisions when choosing which approach they will take when analyzing qualitative longitudinal material