Genetic risk prediction and neurobiological understanding of alcoholism

We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value single-nucleotide length polymorphisms (SNPs) in the top candidate genes discovered by CFG (n = 135 genes, 713 SNPs) was used to generate a genetic risk prediction score (GRPS), which showed a trend towards significance (P = 0.053) in separating alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n = 11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P = 0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P = 0.00012) and one with alcohol abuse (a less severe form of alcoholism; P = 0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P = 0.000013) and the alcohol abuse cohort (P = 0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape

Арап элифбесинде нешир этильген къырымтатар грамматикаларнынъ тенъештирме талили

Статья посвящена сопоставительному анализу имени существительного и глагола в арабографических грамматиках крымскотатарского языка.Стаття присвячена порівняльному аналізу іменника і дієслова в арабографічних граматиках кримськотатарської мови.The article annotation is devoted to the comparative analysis of the noun and the verb in arabographis grammars of the Crimean Tatar language

Таксононімія логічних девіацій у нормативно-правових актах

Розглянуто особливості логічних девіацій у текстах нормативно-правових актів, які є складовою частиною офіційно-ділового стилю української літературної мови. Запропоновано власний підхід до класифікації виявлених у текстах чинних кодексів логічно аномальних уживань.The features of the logical deviations in the texts of laws which belong to the official style of Ukrainian literary language is under consideration. The taxonomy for the notion above in Ukrainian laws is proposed

Convergent Functional Genomics of Schizophrenia: From Comprehensive Understanding to Genetic Risk Prediction

poster abstractWe have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study (GWAS) data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein coupled receptor signaling and cAMP- mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data is consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European-American (EA) and one African-American (AA), increasing overlap, reproducibility and consistency of findings from SNPs to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Lastly, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics, and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology

The impacts of climate change on the winter water cycle of the western Himalaya

Some 180 million people depend on the Indus River as a key water resource, fed largely by precipitation falling over the western Himalaya. However, the projected response of western Himalayan precipitation to climate change is currently not well constrained: CMIP5 GCMs project a reduced frequency and vorticity of synoptic-scale systems impacting the area, but such systems would exist in a considerably moister atmosphere. In this study, a convection-permitting (4 km horizontal resolution) setup of the Weather Research and Forecasting (WRF) model is used to examine 40 cases of these synoptic-scale systems, known as western disturbances (WDs), as they interact with the western Himalaya. In addition to a present-day control run, three experiments are performed by perturbing the boundary and initial conditions to reflect pre-industrial, RCP4.5 and RCP8.5 background climates respectively. It is found that in spite of the weakening intensity of WDs, net precipitation associated with them in future climate scenarios increases significantly; conversely there is no net change in precipitation between the pre-industrial and control experiments despite a significant conversion of snowfall in the pre-industrial experiment to rainfall in the control experiment, consistent with the changes seen in historical observations. This shift from snowfall to rainfall has profound consequences on water resource management in the Indus Valley, where irrigation is dependent on spring meltwater. Flux decomposition shows that the increase in future precipitation follows directly from the projected moistening of the tropical atmosphere (which increases the moisture flux incident on the western Himalaya by 28%) overpowering the weakened dynamics (which decreases it by 20%). Changes to extreme rainfall events are also examined: it is found that such events may increase significantly in frequency in both future scenarios examined. Two-hour maxima rainfall events that currently occur in 1-in-8 WDs are projected to increase tenfold in frequency in the RCP8.5 scenario; more prolonged (one-week maxima) events are projected to increase fiftyfold

A streamlined CRISPR/Cas9 approach for fast genome editing in Toxoplasma gondii and Besnoitia besnoiti

Toxoplasma gondii (T. gondii) and Besnoitia besnoiti (B. besnoiti) are closely related coccidian parasites belonging to the phylum Apicomplexa, which comprises many other important pathogens of humans and livestock. T. gondii is considered a model organism for studying the cell biology of Apicomplexa mainly due to the ease of propagation in diverse host cells and the availability of a wide range of genetic tools. Conversely, B. besnoiti in vitro culture systems currently exist only for the acute phase of infection, and genetic manipulation has proven much more challenging. In recent years, the targeted editing of chromosomal DNA by the programmable CRISPR-associated (Cas)9 enzyme has greatly improved the scope and accuracy of genetic manipulation in T. gondii and related parasites but is still lagging in B. besnoiti. The CRISPR/Cas9 technology enables the introduction of single point and insertion/deletion mutations, precise integration of in-frame epitope tags, and deletions of genes at reduced time and cost compared to previous methods. Current protocols for CRISPR-mediated genome editing in T. gondii rely on either constitutive or transient expression of Cas9 as well as target specific sgRNAs encoded separately or together on transfected plasmid vectors. Constitutively expressed Cas9 carries the risk of toxicity, whilst the transient approach is laborious and error-prone. Here we present a protocol for plasmid vector-independent genome-editing using chemically synthesized and modified sgRNAs. This protocol allows for rapid, efficient, and cost-effective generation of mutant cell lines of T. gondii and B. besnoiti