Meta-analysis of Correlated Traits via Summary Statistics from GWASs with an Application in Hypertension

Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple—even distinct—traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 × 10⁻⁸) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 × 10⁻⁷) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes.     

A 2,6,9-hetero-trisubstituted purine inhibitor exhibits potent biological effects against multiple myeloma cells

A focused library of hetero-trisubstituted purines was developed for improving the cell penetrating and biological efficacy of a series of anti-Stat3 protein inhibitors. From this SAR study, lead agent 22e was identified as being a promising inhibitor of MM tumour cells (IC₅₀’s <5 μM). Surprisingly, biophysical and biochemical characterization proved that 22e was not a Stat3 inhibitor. Initial screening against the kinome, prompted by the purine scaffold’s history for targeting ATP binding pockets, suggests possible targeting of the JAK family kinases, as well for ABL1 (nonphosphorylated F317L) and AAK1.     

Die Mitochondrien vonChlamydomonas reinhardii

Zusammenfassung Dreidimensionale, maßstabgetreue Modelle, die nach elektronenmikroskopischen Bildern von Serienschnitten konstruiert wurden, zeigen, daß in den Zellen vonChlamydomonas reinhardii nur ein geringer Teil der Mitochondrien eine einfache rundliche oder ellipsoidale Form hat. Die meisten Mitochondrien sind langgestreekt und weisen charakteristische Einschnürungen und Verzweigungen auf. Die Einschnürungen sind mitunter so schmal, daß es nicht sicher ist, ob der innere Teil der Mitochondrienhülle noch einen einzigen Innenraum umschließt oder ob das betreffende Mitochondrium 2 getrennte Räume enthält. Durch ihre Verzweigungen können die Mitochondrien Gesamtlängen erreichen, die weit größer sind als die jeweiligen Zelldurchmesser. Die verästelte Form der Mitochondrien kann dazu führen, daß Mitochondrienanschnitte, die in einem Einzelschnitt sogar an entgegengesetzten Zellpolen auftreten, tatsächlich Teile ein- und desselben Mitochondriums sind. Die wirkliche Zahl der Mitochondrien pro Zelle ist infolge dieser besonderen Gestaltung erheblich geringer als man sie aufgrund der Beobachtung von Einzelbildern schätzen würde. Sie betrug in 2 durch Serienschnitte vollständig erfaßten Zellen (+Gameten) 9 bzw. 14 Mitochondrien. Es wird diskutiert, ob bei einer streptomycinbedürftigen Mutante vonChlamydomonas reinhardii die Zuordnung des sd-Gens zum Mitochondrien-Genom in Einklang mit den hier gewonnenen Ergebnissen steht.

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The mitochondria ofChlamydomonas reinhardii

Summary Three-dimensional scale models constructed on the basis of serial section electron microscopy showed that only a little fraction of the mitochondria in the cells ofChlamydomonas reinhardii has a simple spherical or elliptical shape. Most of the mitochondria are elongated, and show characteristical constrictions and branchings. Sometimes the constrictions are so narrow, that it seems not sure whether the inner part of the envelope of a mitochondrion surrounds one single space or whether there are two separate spaces within the mitochondrion concerned. By their branchings the mitochondria can reach overall-lengths much longer than the diameter of the cell. The branched shape of the mitochondria may lead to the result, that profiles of mitochondria occurring in a single section even at opposite poles of the cell are in fact parts of the same mitochondrion. Caused by this exceptional shape, the actual number of mitochondria per cell is considerably smaller than one would estimate from the observation of single electron micrographs. We counted 9 and 14 mitochondria resp. in 2 cells (+ gametes), both completely included in a series of consecutive sections. It is discussed, whether in a streptomycindependent mutant ofChlamydomonas reinhardii the association of the sd-gene with the mitochondrion-genome is in agreement with the results obtained in this study.

     

Isolation of cloned Syrian hamster insulinoma cell lines with limited capacity for insulin production.

Cell lines derived from a Syrian hamster insulinoma have been cloned in agar and maintained continuously in culture in vitro for 1 1/2 years. The cell lines have average doubling times of 48 h, they have modal chromosome numbers between 38 and 39, and they retain the ability to form tumors when injected into Syrian hamsters. The cells do not produce immunoreactive insulin when grown in vitro (less than 0.5 ng/mg protein), but do produce immunoreactive insulin when grown in vivo as tumors (mean value from six determinations = 7.1 +/- 1.5 ng/mg protein).     

Induction of structural chromosome aberrations and sister chromatid exchanges in human lymphocytes in vitro by aristolochic acid

The medicinal use of Aristolochia clematitis has been known for some time. The main active agent of this medicinal plant is aristolochic acid, a nitrophenanthrenecarbonic acid. Very recently, however, the Federal Health Office withdrew the licence for all drugs containing aristolochic acid, because of the well-founded suspicion that aristolochic acid may be a very potent carcinogen. We investigated the induction of structural chromosome aberrations and sister chromatid exchanges (SCEs) by aristolochic acid in human lymphocytes in vitro. Cells were treated with the agent tested throughout culture time and during the G0 phase of the cell cycle. We tested concentrations over a range of 1 to 20 micrograms/ml. Both treatment conditions resulted in an increased aberration frequency. The induction of gaps and breaks as well as the induction of SCEs showed a dose-dependent increase. The number of SCEs per metaphase was enhanced by a factor of 2 to 3. If conventional cytogenetic methods had been applied in time, one would have recognized the mutagenic risk of aristolochic acid earlier.     

Über die Zahl der Kopien eines außerkaryotischen Gens bei Chlamydomonas reinhardii

The streptomycin sensitive (ss-) revertants of the streptomycin dependent mutant sd₃ segregate on streptomycin medium again sd-cells. This sd-segregation decreases continuously with increasing time of cultivation until zero-level is reached. The revertant R 20 differ from the other revertants mainly that the rate of segregation remaining almost at the same high level a long time. But the results of clonings showed that also in R 20 the number of cells able to segregate sd-cells decreases. After 6 months, only 20% of the cells still possessed this ability. Former investigations showed that the ss-revertants still had sd-informations. These informations segregate in the following cell-divisions and produce again sd-colonies on the streptomycin medium. The rate of segregation was changing with the different clones. This proves the non-oriented distribution of the sd- and ss-gene copies at the mitotic division. The clonings demonstrate also the existence of much more than 2 copies. According to Sager and Ramanis the genes of the chloroplast exist at the most in 2 copies. If the statement should be true in principle for all vegetative cells, then the sd-information cannot be in the chloroplast. It must be located in the mitochondria.     

Ultrastructural localization of amiloride-sensitive sodium channels and Na+,K(+)-ATPase in the rat's olfactory epithelial surface

Several studies have indicated that olfactory responses are impeded byamiloride. Therefore, it was of interest to see whether, and if so which,olfactory epithelial cellular compartments have amiloride- sensitivestructures. Using ultrastructural methods that involved rapid freezing,freeze-substitution and low temperature embedding of olfactory epithelia,this study shows that, in the rat, this tissue is immunoreactive toantibodies against amiloride sensitive Na(+)- channels. However, microvilliof olfactory supporting cells, as opposed to receptor cilia, contained mostof the immunoreactive sites. Apices from which the microvilli sprout andreceptor cell dendritic knobs had much less if any of theamiloride-antibody binding sites. Using a direct ligand-bindingcytochemical method, this study also confirms earlier ones that showed thatolfactory receptor cell cilia have Na+, K(+)-ATPase. It is proposed thatsupporting cell microvilli and the receptor cilia themselves havemechanisms, different but likely complementary, that participate inregulating the salt concentration around the receptor cell cilia. In thisway, both structures help to provide the ambient mucous environment forreceptor cells to function properly. This regulation of the saltconcentration of an ambient fluid environment is a function that theolfactory epithelium shares with cells of transporting epithelia, such asthose of kidney.     

Persistent High IgG Phase I Antibody Levels against Coxiella burnetii among Veterinarians Compared to Patients Previously Diagnosed with Acute Q Fever after Three Years of Follow-Up

Background

Little is known about the development of chronic Q fever in occupational risk groups. The aim of this study was to perform long-term follow-up of Coxiella burnetii seropositive veterinarians and investigate the course of IgG phase I and phase II antibodies against C. burnetii antigens and to compare this course with that in patients previously diagnosed with acute Q fever.

Methods

Veterinarians with IgG phase I ≥1:256 (immunofluorescence assay) that participated in a previous seroprevalence study were asked to provide a second blood sample three years later. IgG antibody profiles were compared to a group of acute Q fever patients who had IgG phase I ≥1:256 twelve months after diagnosis.

Results

IgG phase I was detected in all veterinarians (n = 76) and in 85% of Q fever patients (n = 98) after three years (p<0.001). IgG phase I ≥1:1,024, indicating possible chronic Q fever, was found in 36% of veterinarians and 12% of patients (OR 3.95, 95% CI: 1.84–8.49).

Conclusions

IgG phase I persists among veterinarians presumably because of continuous exposure to C. burnetii during their work. Serological and clinical follow-up of occupationally exposed risk groups should be considered.