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

Les étudiants français doivent-ils fréquenter les universités des États-Unis d'Amérique ou celles de la Grande-Bretagne ?

Minssen Bernard, Hartog Philip Joseph, Gerrans H. T., Sadler M. S. Les étudiants français doivent-ils fréquenter les universités des États-Unis d'Amérique ou celles de la Grande-Bretagne ?. In: Revue internationale de l'enseignement, tome 57, Janvier-Juin 1909. pp. 535-542

Les étudiants français doivent-ils fréquenter les universités des États-Unis d'Amérique ou celles de la Grande-Bretagne ?

Minssen Bernard, Hartog Philip Joseph, Gerrans H. T., Sadler M. S. Les étudiants français doivent-ils fréquenter les universités des États-Unis d'Amérique ou celles de la Grande-Bretagne ?. In: Revue internationale de l'enseignement, tome 57, Janvier-Juin 1909. pp. 535-542

What's domain-specific about theory of mind?

© Psychology PressTwenty years ago, Baron-Cohen and colleagues argued that autistic performance on false belief tests was explained by a deficit in metarepresentation. Subsequent research moved from the view that the mind has a domain-general capacity for metarepresentation to the view that the mind has a domain-specific mechanism for metarepresentation of mental states per se, i.e., the theory of mind mechanism (ToMM). We argue that 20 years of data collection in lesion patients and children with autism supports a more parsimonious view closer to that of the 1985 paper. Lower-level domain-specific mechanisms - e.g., tracking gaze, joint attention - interacting with higher-level domain-general mechanisms for metarepresentation, recursion, and executive function can account for observed patterns of deficits in both autism and neurological patients. The performance of children with autism or orbitofrontal patients on ToM tests can be explained more parsimoniously by their deficits in lower-level domain-specific mechanisms for processing social information. Without proper inputs, the intact capacity for metarepresentation by itself cannot make correct ToM inferences. Children with autism have no impairment in false photograph tests because their metarepresentational capacity is intact and they have no impairment in inputs required for such tests. TPJ patients have equivalent deficits on ToM and non-ToM metarepresentational tasks, consistent with a failure in domain-general processing. If deficits on ToM tasks can result from deficits in low-level input systems or in higher-level domain-general capacities, postulating a separate ToM mechanism may have been an unnecessary theoretical move.Valerie E. Stone; Philip Gerran

Return Chasing as a Driver in Individual Retirement Savings Investment Choices: Evidence from Australia

Behavioral finance, Investment choice, Retirement savings,

Knowledge and Perceptions of Superannuation in Australia

Superannuation, Retirement income, Private pensions, Consumer knowledge,