Functional annotation signatures of disease susceptibility loci improve SNP association analysis.

BACKGROUND: Genetic association studies are conducted to discover genetic loci that contribute to an inherited trait, identify the variants behind these associations and ascertain their functional role in determining the phenotype. To date, functional annotations of the genetic variants have rarely played more than an indirect role in assessing evidence for association. Here, we demonstrate how these data can be systematically integrated into an association study's analysis plan. RESULTS: We developed a Bayesian statistical model for the prior probability of phenotype-genotype association that incorporates data from past association studies and publicly available functional annotation data regarding the susceptibility variants under study. The model takes the form of a binary regression of association status on a set of annotation variables whose coefficients were estimated through an analysis of associated SNPs in the GWAS Catalog (GC). The functional predictors examined included measures that have been demonstrated to correlate with the association status of SNPs in the GC and some whose utility in this regard is speculative: summaries of the UCSC Human Genome Browser ENCODE super-track data, dbSNP function class, sequence conservation summaries, proximity to genomic variants in the Database of Genomic Variants and known regulatory elements in the Open Regulatory Annotation database, PolyPhen-2 probabilities and RegulomeDB categories. Because we expected that only a fraction of the annotations would contribute to predicting association, we employed a penalized likelihood method to reduce the impact of non-informative predictors and evaluated the model's ability to predict GC SNPs not used to construct the model. We show that the functional data alone are predictive of a SNP's presence in the GC. Further, using data from a genome-wide study of ovarian cancer, we demonstrate that their use as prior data when testing for association is practical at the genome-wide scale and improves power to detect associations. CONCLUSIONS: We show how diverse functional annotations can be efficiently combined to create 'functional signatures' that predict the a priori odds of a variant's association to a trait and how these signatures can be integrated into a standard genome-wide-scale association analysis, resulting in improved power to detect truly associated variants.

Immunological Signatures Identifying Different Stages of Latent Mycobacterium tuberculosis Infection and Discriminating Latent from Active Tuberculosis in Humans

Objectives: One third of the world population is considered latently infected with Mycobacterium tuberculosis(LTBI) and sterilizing this reservoir of bacteria that may reactivate is required for tuberculosis (TB) elimination. Thegroup of individuals with LTBI is heterogeneous with some of them being more at risk to develop TB disease thanothers. Improved diagnosis of subjects with LTBI is needed, allowing to differentiate subjects with LTBI from thosewith active TB, and to select among LTBI subjects those who are more at risk to develop active TB. We havecharacterized at the cellular level both the quantitative and qualitative T cell responses to different mycobacterialantigens in selected populations of infected subjects in order to identify new biomarkers that could help to identify M.tuberculosis-infected subjects and to stratify them in risk groups for reactivation of the infection.Methods: Lymphoblast frequencies and cytokine production (IFN-γ, TNF-α, IL-2) among CD4+ and CD8+ T cellswere analyzed by flow cytometry after in vitro stimulation with the latency antigen heparin-binding haemagglutinin(HBHA) or early-secreted antigen Target-6 (ESAT-6) of peripheral blood mononuclear cells from clinically wellcharacterized M. tuberculosis-infected humans (28 LTBI, 22 TB disease,12 controls). The LTBI group definedaccording to the Center for Disease Control guidelines was subdivided into QuantiFERON-TB Gold in-Tube (QFT)positive and negative subgroups.Results: Similar to TB patients, QFT+ LTBI subjects had higher proportions of HBHA-induced TNF-αsingle+ CD4+lymphocytes than QFT- LTBI subjects (p<0.05). Compared to LTBI subjects, TB patients had higher frequencies ofESAT-6-induced CD8+ lymphoblasts (p<0.001), higher proportions of ESAT-6-induced IFN-γ+TNF-α+ CD4+ Tlymphocytes (p<0.05), and lower proportions of HBHA-induced IFN-γ+TNF-α+IL-2+ (p<0.05) CD4+ T lymphocytes.Conclusions: These data provide new biomarkers to discriminate active TB from LTBI, and more interestingly,help to identify LTBI subjects with increased likelihood to develop TB disease.

Effects of formalin preservation on stable carbon and nitrogen isotope signatures in Calanoid copepods: implications for the use of Continuous Plankton Recorder Survey samples in stable isotope analyses

Preserved and archived organic material offers huge potential for the conduct of retrospective and long-term historical ecosystem reconstructions using stable isotope analyses, but because of isotopic exchange with preservatives the obtained values require validation. The Continuous Plankton Recorder (CPR) Survey is the most extensive long-term monitoring program for plankton communities worldwide and has utilised ships of opportunity to collect samples since 1931. To keep the samples intact for subsequent analysis, they are collected and preserved in formalin; however, previous studies have found that this may alter stable carbon and nitrogen isotope ratios in zooplankton. A maximum ~0.9‰ increase of δ15N and a time dependent maximum ~1.0‰ decrease of δ13C were observed when the copepod, Calanus helgolandicus, was experimentally exposed to two formalin preservatives for 12 months. Applying specific correction factors to δ15N and δ13C values for similarly preserved Calanoid species collected by the CPR Survey within 12 months of analysis may be appropriate to enable their use in stable isotope studies. The isotope values of samples stored frozen did not differ significantly from those of controls. Although the impact of formalin preservation was relatively small in this and other studies of marine zooplankton, changes in isotope signatures are not consistent across taxa, especially for δ15N, indicating that species-specific studies may be required. Copyright © 2011 John Wiley & Sons, Ltd.

Time signatures of impulsively generated coronal fast wave trains

Impulsively generated short-period fast magneto-acoustic wave trains, guided by solar and stellar coronal loops, are numerically modelled. In the developed stage of the evolution, the wave trains have a characteristic quasi-periodic signature. The quasi-periodicity results from the geometrical dispersion of the guided fast modes, determined by the transverse profile of the loop. A typical feature of the signature is a tadpole wavelet Spectrum: a narrow-spectrum tail precedes a broad-band head. The instantaneous period of the oscillations in the wave train decreases gradually with time. The period and the spectral amplitude evolution are shown to be determined by the steepness of the transverse density profile and the density contrast ratio in the loop. The propagating wave trains recently discovered with the Solar Eclipse Coronal Imaging System (SECIS) instrument are noted to have similar wavelet spectral features, which strengthens the interpretation of SECIS results as guided fast wave trains.

Monotonically normal topological vector spaces are stratifiable

We prove that for any Hausdorff topological vector space E over the field R there exists A subset of E such that E is homeomorphic to a subset of A x R and A x R is homeomorphic to a subset of E. Using this fact we prove that E is monotonically normal if and only if E is stratifiable.