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Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants., GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.

Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking. Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia. Results: We identified an interaction (βint = −0.036, 95% confidence interval, −0.040 to −0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect. Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.

‎In the present‎ ‎paper we introduce the notion Bochner integral for measurable sections and study some properties such integrals‎. ‎Given necessary and successfully condition for integrability of a‎ ‎measurable section‎. ‎Dominated convergence theorem and analogue of‎ ‎Hille's theorem are proved‎.

This work was carried out to shed light on the present status of the Burullus Lagoon's phytoplankton and the long-term changes that had resulted from phytoplankton abundance, community structure, dominant species and diversity indices. Phytoplankton dynamics were examined seasonally from summer 2013 to spring 2014 at twelve sampling stations represented by three basins (eastern, middle and western). Water was alkaline, well oxygenated and with an annual average salinity of 3.89 PSU. Nutrient concentrations were generally high. A total of 163 taxa from five classes were recorded; diatoms were the most diversified group. The three dominant classes: Chlorophyceae, Bacillariophyceae and Cyanobacteria had a progressively lower abundance from west to east, while species diversity showed the opposite trend. The results showed that Chlorophyceae was the dominant group in the three basins, followed by Bacillariophyceae in the eastern and western basins, while Cyanobacteria followed chlorophytes in the middle basin. Shannon-Wiener diversity index values were higher than those recorded during the previous years. Notable phytoplankton species recorded can be regarded as possible indicators for each basin. Providing evidence that phytoplankton abundance decreased from year to year and that a nuisance species such as Geitlerinema amphibium was evidently environmentally harmful, hence suggesting that a major improvement in water quality must be done.

The influence of the antioxidant spermine of the UV-induced formation of free radicals from tryptophan in frozen aqueous solutions was studied by electron paramagnetic resonance (EPR) instrumentation, and the stability of the radicals was investigated in the range 95–200 K. Without spermine, the tryptophan cation and neutral tryptophan radical were stabilized at 77 K; cations were formed by electron ejection from an excited singlet state, and neutral radicals by hydrogen donation from tryptophan in the triplet state. When present, spermine trapped the ejected photoelectrons; the rates of the two photoreactions of tryptophan were also influenced by spermine. Firstly, at low tryptophan concentrations, the yield of cations was reduced, due to diminished charge transfer from the excited singlet state to the solvation shell. Secondly, at high concentrations, minute additions of spermine enhanced intersystem crossing (which is quenched, in the absence of spermine, by dimerization) and, consequently, the yield of neutral radicals was increased. At 180 K, the electrons trapped by spermine were released and reacted with molecular oxygen to form the superoxide radical; at 190 K, the tryptophan radicals were thermally annealed.

The influence of the antioxidant spermine on the photophysical processes and photodegradation of tryptophan at neutral pH was studied by fluorescence and absorption spectroscopy. Spermine, which is a polyamine, binds cooperatively to tryptophan with a binding constant of 1.2 × 10−3 mM−3.7 at 20 °C. It is suggested that, when the charged spermine molecules bind to tryptophan, the rotation of the zwitterion around the CαCβ bond is blocked and only one rotamer form of tryptophan is present. The hindered rotation gives rise to the following spectroscopic changes. (i) Minor changes are observed in the absorption spectrum, since the two most frequent rotamers have different spectra. (ii) The quantum yield of the S1 band increases by a factor of 2.6, as is also the case when the amino group is deprotonated. ( iii) The yield of photodegradation increases from zero to 0.08 for excitation at 280 nm, which is equal to the yield of photoionization under similar conditions.

Fluorescence, phosphorescence and electron paramagnetic resonance techniques were used to investigate the effect of the antioxidant spermine on the initial photophysical reactions of tryptophan (Trp) in aqueous salt solutions at 77 K. At low concentrations of Trp (3.5 X 10(-5) M) a ground state complex was formed between one Trp and two spermine molecules (a 1:2 complex). Complexed Trp was photodegraded at a rate 65% lower than the free molecule due to a change in the charge-transfer character of the excited 1La state. At high concentrations of Trp (3.5 X 10(-3) M) the phosphorescence was almost completely quenched due to hydrogen-bond formation between two neighbouring Trp molecules. A strong complex was formed between this Trp dimer and one spermine molecule on addition of spermine (a 2:1 complex). Spermine enhanced intersystem crossing in one of the two Trp molecules in the 2:1 complex and phosphorescence was observed. From this triplet state the tryptophyl radical was formed with high efficiency by hydrogen-atom transfer. The yield of radical formation from the triplet state in the 2:1 complex was much larger than from the excited singlet state in the 1:2 complex.

A software program has been implemented to meet the requirements of an acknowledge enabled and Handshake protocol for reading, transmitting and saving of data from a SPEX Datamate controller to a VAX computer at real time scanning. The logic of the program can easily be applied to similar analytical instrumentation and computers. It stands forward as powerful method for data acquisition and processing and provides the basis for further calculations and plotting routines.