16 research outputs found
Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes
Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants
Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.</p
External Beam Radiation Therapy of Squamous Cell Carcinoma in the Beak of an African Grey Parrot ( Psittacus timneh
Microbial Translocation and Inflammation Occur in Hyperacute Immunodeficiency Virus Infection and Compromise Host Control of Virus Replication
<div><p>Within the first three weeks of human immunodeficiency virus (HIV) infection, virus replication peaks in peripheral blood. Despite the critical, causal role of virus replication in determining transmissibility and kinetics of progression to acquired immune deficiency syndrome (AIDS), there is limited understanding of the conditions required to transform the small localized transmitted founder virus population into a large and heterogeneous systemic infection. Here we show that during the hyperacute “pre-peak” phase of simian immunodeficiency virus (SIV) infection in macaques, high levels of microbial DNA transiently translocate into peripheral blood. This, heretofore unappreciated, hyperacute-phase microbial translocation was accompanied by sustained reduction of lipopolysaccharide (LPS)-specific antibody titer, intestinal permeability, increased abundance of CD4+CCR5+ T cell targets of virus replication, and T cell activation. To test whether increasing gastrointestinal permeability to cause microbial translocation would amplify viremia, we treated two SIV-infected macaque ‘elite controllers’ with a short-course of dextran sulfate sodium (DSS)–stimulating a transient increase in microbial translocation and a prolonged recrudescent viremia. Altogether, our data implicates translocating microbes as amplifiers of immunodeficiency virus replication that effectively undermine the host’s capacity to contain infection.</p></div
Longitudinal levels of SIV RNA and bacterial rDNA in plasma.
<p>Eight MHC-identical cynomolgus macaques became infected following intrarectal inoculation with SIVmac239. (<b>A</b>) The number of SIV RNA copies/ml of plasma was enumerated using qRT-PCR. Values are Log<sub>10</sub>-transformed and plotted longitudinally. (<b>B</b>) 16S sequencing data was used to correct raw 16S rDNA qPCR data by removing the proportion of 16S rDNA copies that corresponded to taxa detected in matched water controls. Corrected 16S rDNA copy data was Log<sub>10</sub>-transformed and plotted longitudinally. By Bonferroni-corrected one-way ANOVA, plasma levels of 16S rDNA did not change significantly between -42 and 0 DPI. Plasma levels of 16S rDNA increased significantly (P<0.0005) from both -42 to 8 DPI and 0 to 8 DPI. In both plots, the vertical checkered box positioned between 14 and 18 DPI corresponds to the acute-phase peak of SIV replication as detected by our sampling resolution.</p
Chemically inducing microbial translocation stimulates multiple host inflammatory processes and increases plasma viremia and levels of bacterial rDNA.
<p>(<b>A</b>) Log<sub>10</sub>-transformed plasma SIV load. (<b>B</b>) Linear plasma 16S rDNA load. The bacteria-specific host response was assessed by monitoring plasma levels of (<b>C</b>) EndoCAb and (<b>D</b>) sCD14. Plasma IFABP levels (<b>E</b>) were used to monitor changes to the integrity of the gastrointestinal epithelium. Generalized inflammation was monitored using plama levels of (<b>F</b>) MCP-1. In all panels, 5 black vertical lines indicate the 5-day period of once-daily treatment with dextran sulfate sodium (DSS).</p
Plasma markers of intestinal breach and host response to microbial translocation.
<p>(<b>A</b>) Longitudinal proportion (%) of plasma genera detected in contemporaneous stool. Each line corresponds to a single animal. Bonferroni-corrected one-way ANOVA was used to calculate statistical significance. (<b>B</b>) Longitudinal plasma levels of IFABP, a marker of enterocyte loss and generalized damage to the intestinal epithelium. The host response to microbial translocation was measured using plasma levels of (<b>C</b>) EndoCAb, and (<b>D</b>) sCD14. By linear regression analysis, plasma levels of sCD14 at (<b>E</b>) 8 DPI, and (<b>F</b>) 21 DPI correlated positively with chronic-phase set-point viral loads. Acute inflammation was measured using plasma levels of (<b>G</b>) MCP-1, and (<b>H</b>) SAA1. For B, C, D, G, and H, differences between 0–8 DPI were evaluated for statistical significance by two-tailed Wilcoxon signed rank testing.</p
Taxonomic characterization of translocating microbial products.
<p>(<b>A</b>) Longitudinal relative abundance (%) of major phyla detected in blood plasma. (<b>B</b>) Number of unique bacterial genera for which genomic DNA was detected in blood plasma throughout the period of observation. Each line corresponds to a single animal. (<b>C</b>) Longitudinal relative abundance (%) of major genera detected in blood plasma. For (A and C), vertical bars within a given cluster (time-point) correspond to each individual animal, and colored segments correspond to the proportion of specific taxa. Owing to sample limitations, relative abundance of microbial taxa could not be determined for all animals at all time-points.</p