The redshift distribution of the X-ray background

The X-ray background (XRB) is produced by a large number of faint sources distributed over a wide range of redshifts. The XRB carries information on the spatial distribution and evolution of these sources. The goals of the paper are: 1. to determine the redshift distribution of the soft X-ray background photons produced by all types of extragalactic sources, in order to relate fluctuations of the background to the large scale structures, 2. to determine the redshift distribution of the soft XRB produced by AGN in order to calculate the evolution of the AGN X-ray luminosity density. A set of major X-ray surveys is used to determine the redshift distributions of the X-ray sources selected at various flux levels. Simple analytic fits to the data allow us to determine the smooth relationship between the redshift distribution and the source flux. The redshift distribution of the integral XRB flux is obtained by averaging the fits over the source counts. It is shown that the distribution of extragalactic XRB photons in the 0.5-2 keV band is adequately represented by the function: dn/dlog z = 5.24 z^1.52 exp(-z/0.63). The huge voids postulated to explain the cold spots in the CMB maps create dips in the total XRB flux. However, the expected magnitude of the effect is comparable to the fluctuation amplitude of the XRB generated by the individual sources contributing to the background. The cosmic evolution of the AGN X-ray luminosity density up to redshift of ~5 is calculated in an elegant and straightforward way. Systematic uncertainties of the present method are assessed and shown to be small. At redshift greater than one the present results could be compared directly with some recent estimates obtained in a standard way and the agreement between both methods is very good.Comment: 13 pages, 4 figures, submitted to A

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