163 research outputs found
Association Signals Unveiled by a Comprehensive Gene Set Enrichment Analysis of Dental Caries Genome-Wide Association Studies
Gene set-based analysis of genome-wide association study (GWAS) data has recently emerged as a useful approach to examine the joint effects of multiple risk loci in complex human diseases or phenotypes. Dental caries is a common, chronic, and complex disease leading to a decrease in quality of life worldwide. In this study, we applied the approaches of gene set enrichment analysis to a major dental caries GWAS dataset, which consists of 537 cases and 605 controls. Using four complementary gene set analysis methods, we analyzed 1331 Gene Ontology (GO) terms collected from the Molecular Signatures Database (MSigDB). Setting false discovery rate (FDR) threshold as 0.05, we identified 13 significantly associated GO terms. Additionally, 17 terms were further included as marginally associated because they were top ranked by each method, although their FDR is higher than 0.05. In total, we identified 30 promising GO terms, including 'Sphingoid metabolic process,' 'Ubiquitin protein ligase activity,' 'Regulation of cytokine secretion,' and 'Ceramide metabolic process.' These GO terms encompass broad functions that potentially interact and contribute to the oral immune response related to caries development, which have not been reported in the standard single marker based analysis. Collectively, our gene set enrichment analysis provided complementary insights into the molecular mechanisms and polygenic interactions in dental caries, revealing promising association signals that could not be detected through single marker analysis of GWAS data. © 2013 Wang et al
Network-Assisted Investigation of Combined Causal Signals from Genome-Wide Association Studies in Schizophrenia
With the recent success of genome-wide association studies (GWAS), a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each single GWAS dataset and then implemented a discovery-evaluation strategy to identify module genes with consistent association signals. We validated the module genes in an independent dataset, and also examined them through meta-analysis of the related SNPs using multiple GWAS datasets. As a result, we identified 205 module genes with a joint effect significantly associated with schizophrenia; these module genes included a number of well-studied candidate genes such as DISC1, GNA12, GNA13, GNAI1, GPR17, and GRIN2B. Further functional analysis suggested these genes are involved in neuronal related processes. Additionally, meta-analysis found that 18 SNPs in 9 module genes had PmetaHLA-DQA1 located in the MHC region on chromosome 6, which was reported in previous studies using the largest cohort of schizophrenia patients to date. These results demonstrated our bi-directional network-based strategy is efficient for identifying disease-associated genes with modest signals in GWAS datasets. This approach can be applied to any other complex diseases/traits where multiple GWAS datasets are available
RNA-Seq analysis implicates dysregulation of the immune system in schizophrenia
Background While genome-wide association studies identified some promising candidates for schizophrenia, the majority of risk genes remained unknown. We were interested in testing whether integration gene expression and other functional information could facilitate the identification of susceptibility genes and related biological pathways.
Results We conducted high throughput sequencing analyses to evaluate mRNA expression in blood samples isolated from 3 schizophrenia patients and 3 healthy controls. We also conducted pooled sequencing of 10 schizophrenic patients and matched controls. Differentially expressed genes were identified by t-test. In the individually sequenced dataset, we identified 198 genes differentially expressed between cases and controls, of them 19 had been verified by the pooled sequencing dataset and 21 reached nominal significance in gene-based association analyses of a genome wide association dataset. Pathway analysis of these differentially expressed genes revealed that they were highly enriched in the immune related pathways. Two genes, S100A8 and TYROBP, had consistent changes in expression in both individual and pooled sequencing datasets and were nominally significant in gene-based association analysis.
Conclusions Integration of gene expression and pathway analyses with genome-wide association may be an efficient approach to identify risk genes for schizophrenia
EXPRES IV: Two Additional Planets Orbiting Coronae Borealis Reveal Uncommon System Architecture
Thousands of exoplanet detections have been made over the last twenty-five
years using Doppler observations, transit photometry, direct imaging, and
astrometry. Each of these methods is sensitive to different ranges of orbital
separations and planetary radii (or masses). This makes it difficult to fully
characterize exoplanet architectures and to place our solar system in context
with the wealth of discoveries that have been made. Here, we use the EXtreme
PREcision Spectrograph (EXPRES) to reveal planets in previously undetectable
regions of the mass-period parameter space for the star Coronae
Borealis. We add two new planets to the previously known system with one hot
Jupiter in a 39-day orbit and a warm super-Neptune in a 102-day orbit. The new
detections include a temperate Neptune planet ( M)
in a 281.4-day orbit and a hot super-Earth ( M) in a
12.95-day orbit. This result shows that details of planetary system
architectures have been hiding just below our previous detection limits; this
signals an exciting era for the next generation of extreme precision
spectrographs.Comment: Accepted to AJ; 20 pages, 13 figures, 5 Table
Measured Spin-Orbit Alignment of Ultra-Short Period Super-Earth 55 Cancri e
A planet's orbital alignment places important constraints on how a planet
formed and consequently evolved. The dominant formation pathway of ultra-short
period planets ( day) is particularly mysterious as such planets most
likely formed further out, and it is not well understood what drove their
migration inwards to their current positions. Measuring the orbital alignment
is difficult for smaller super-Earth/sub-Neptune planets, which give rise to
smaller amplitude signals. Here we present radial velocities across two
transits of 55 Cancri e, an ultra-short period Super-Earth, observed with the
Extreme Precision Spectrograph (EXPRES). Using the classical
Rossiter-McLaughlin (RM) method, we measure 55 Cnc e's sky-projected stellar
spin-orbit alignment (i.e., the projected angle between the planet's orbital
axis and its host star's spin axis) to be with an unprojected angle of . The best-fit RM model to the EXPRES data has a radial velocity
semi-amplitude of just . The spin-orbit
alignment of 55 Cnc e favors dynamically gentle migration theories for
ultra-short period planets, namely tidal dissipation through low-eccentricity
planet-planet interactions and/or planetary obliquity tides.Comment: 12 pages, 4 figures, published in Nature Astronom
EXPRES I. HD~3651 an Ideal RV Benchmark
The next generation of exoplanet-hunting spectrographs should deliver up to
an order of magnitude improvement in radial velocity precision over the
standard 1 m/s state of the art. This advance is critical for enabling the
detection of Earth-mass planets around Sun-like stars. New calibration
techniques such as laser frequency combs and stabilized etalons ensure that the
instrumental stability is well characterized. However, additional sources of
error include stellar noise, undetected short-period planets, and telluric
contamination. To understand and ultimately mitigate error sources, the
contributing terms in the error budget must be isolated to the greatest extent
possible. Here, we introduce a new high cadence radial velocity program, the
EXPRES 100 Earths program, which aims to identify rocky planets around bright,
nearby G and K dwarfs. We also present a benchmark case: the 62-d orbit of a
Saturn-mass planet orbiting the chromospherically quiet star, HD 3651. The
combination of high eccentricity (0.6) and a moderately long orbital period,
ensures significant dynamical clearing of any inner planets. Our Keplerian
model for this planetary orbit has a residual RMS of 58 cm/s over a
month time baseline. By eliminating significant contributors to the radial
velocity error budget, HD 3651 serves as a standard for evaluating the long
term precision of extreme precision radial velocity (EPRV) programs.Comment: 11 pages, 6 figures, accepted for publication in Astronomical Journa
Refining the Stellar Parameters of Ceti: a Pole-on Solar Analog
To accurately characterize the planets a star may be hosting, stellar
parameters must first be well-determined. Ceti is a nearby solar analog
and often a target for exoplanet searches. Uncertainties in the observed
rotational velocities have made constraining Ceti's inclination
difficult. For planet candidates from radial velocity (RV) observations, this
leads to substantial uncertainties in the planetary masses, as only the minimum
mass () can be constrained with RV. In this paper, we used new
long-baseline optical interferometric data from the CHARA Array with the MIRC-X
beam combiner and extreme precision spectroscopic data from the Lowell
Discovery Telescope with EXPRES to improve constraints on the stellar
parameters of Ceti. Additional archival data were obtained from a
Tennessee State University Automatic Photometric Telescope and the Mount Wilson
Observatory HK project. These new and archival data sets led to improved
stellar parameter determinations, including a limb-darkened angular diameter of
mas and rotation period of days. By combining
parameters from our data sets, we obtained an estimate for the stellar
inclination of . This nearly-pole-on orientation has implications
for the previously-reported exoplanets. An analysis of the system dynamics
suggests that the planetary architecture described by Feng et al. (2017) may
not retain long-term stability for low orbital inclinations. Additionally, the
inclination of Ceti reveals a misalignment between the inclinations of
the stellar rotation axis and the previously-measured debris disk rotation axis
().Comment: 14 pages, 3 figures, 4 tables, 1 appendix, accepted for publication
to A
Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor
Purpose: Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Methods: Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. Results: In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in Cmaxand AUC of panobinostat, respectively. No substantial change in Tmaxor half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Conclusions: Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary
- …