| 11. |
- Feitosa, Mary F., et al.
(author)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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In: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Journal article (peer-reviewed)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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| 12. |
- Flannick, Jason, et al.
(author)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
-
Journal article (peer-reviewed)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 13. |
- Fuchsberger, Christian, et al.
(author)
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The genetic architecture of type 2 diabetes
- 2016
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Journal article (peer-reviewed)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 14. |
- Jang, Kyung-Jin, et al.
(author)
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Reproducing human and cross-species drug toxicities using a Liver-Chip
- 2019
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In: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 11:517
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Journal article (peer-reviewed)abstract
- Nonclinical rodent and nonrodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans, contributing to drug failures in the clinic. Here, we applied microengineered Organs-on-Chips technology to design a rat, dog, and human Liver-Chip containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chip detected diverse phenotypes of liver toxicity, including hepatocellular injury, steatosis, cholestasis, and fibrosis, and species-specific toxicities when treated with tool compounds. A multispecies Liver-Chip may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.
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| 15. |
- Jepson, Paul D., et al.
(author)
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PCB pollution continues to impact populations of orcas and other dolphins in European waters
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Journal article (peer-reviewed)abstract
- Organochlorine (OC) pesticides and the more persistent polychlorinated biphenyls (PCBs) have well-established dose-dependent toxicities to birds, fish and mammals in experimental studies, but the actual impact of OC pollutants on European marine top predators remains unknown. Here we show that several cetacean species have very high mean blubber PCB concentrations likely to cause population declines and suppress population recovery. In a large pan-European meta-analysis of stranded (n = 929) or biopsied (n = 152) cetaceans, three out of four species:-striped dolphins (SDs), bottlenose dolphins (BNDs) and killer whales (KWs) had mean PCB levels that markedly exceeded all known marine mammal PCB toxicity thresholds. Some locations (e.g. western Mediterranean Sea, south-west Iberian Peninsula) are global PCB "hotspots" for marine mammals. Blubber PCB concentrations initially declined following a mid-1980s EU ban, but have since stabilised in UK harbour porpoises and SDs in the western Mediterranean Sea. Some small or declining populations of BNDs and KWs in the NE Atlantic were associated with low recruitment, consistent with PCB-induced reproductive toxicity. Despite regulations and mitigation measures to reduce PCB pollution, their biomagnification in marine food webs continues to cause severe impacts among cetacean top predators in European seas.
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| 16. |
- Kohler, Annegret, et al.
(author)
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Convergent losses of decay mechanisms and rapid turnover of symbiosis genes in mycorrhizal mutualists.
- 2015
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:4, s. 176-410
-
Journal article (peer-reviewed)abstract
- To elucidate the genetic bases of mycorrhizal lifestyle evolution, we sequenced new fungal genomes, including 13 ectomycorrhizal (ECM), orchid (ORM) and ericoid (ERM) species, and five saprotrophs, which we analyzed along with other fungal genomes. Ectomycorrhizal fungi have a reduced complement of genes encoding plant cell wall-degrading enzymes (PCWDEs), as compared to their ancestral wood decayers. Nevertheless, they have retained a unique array of PCWDEs, thus suggesting that they possess diverse abilities to decompose lignocellulose. Similar functional categories of nonorthologous genes are induced in symbiosis. Of induced genes, 7-38% are orphan genes, including genes that encode secreted effector-like proteins. Convergent evolution of the mycorrhizal habit in fungi occurred via the repeated evolution of a 'symbiosis toolkit', with reduced numbers of PCWDEs and lineage-specific suites of mycorrhiza-induced genes.
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| 17. |
- Manning, Alisa, et al.
(author)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
-
Journal article (peer-reviewed)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 18. |
- Martin, Sylvia, et al.
(author)
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Examining the relationships between impulsivity, aggression, and recidivism for prisoners with antisocial personality disorder
- 2019
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In: Aggression and Violent Behavior. - : Elsevier BV. - 1359-1789 .- 1873-6335. ; 49
-
Journal article (peer-reviewed)abstract
- Impulsivity impacts multiple life domains and is related to criminal and problematic behaviors. In forensic contexts, impulsivity and aggression are often associated with psychiatric issues. Personality disorders are related to worse prognosis, increased relapse, and damage to relationships. The aim of this study was to clarify the impact of psychopathy, impulsivity, and aggression on recidivism, and to investigate the relationships between these dimensions in prisoners with and without Antisocial Personality Disorder. The forensic sample included inmates with (n = 50) or without Antisocial Personality Disorder (n = 50). We measured psychopathic traits with the Triarchic Psychopathy Measure (TriPM), impulsivity with the Barratt Impulsiveness Scale (BIS-11), and aggression with the Impulsive/Premeditated Aggression Scale (IPAS). There were significant between-group differences regarding premeditated aggression and attentional impulsivity. For inmates with antisocial personality disorder, impulsive aggression was related to recidivism (number of times in jail). Their level of psychopathy was related to premeditated aggression and motor impulsivity. Impulsive aggression, like attentional impulsivity, was related to recidivism only for inmates with antisocial personality disorder. In conclusion, psychopathy is associated with recidivism; moreover, impulsivity and aggression are central to recidivism for these individuals.
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| 19. |
- Pirzkal, Norbert, et al.
(author)
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A Two-dimensional Spectroscopic Study of Emission-line Galaxies in the Faint Infrared Grism Survey (FIGS). I. Detection Method and Catalog
- 2018
-
In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 868:1
-
Journal article (peer-reviewed)abstract
- We present the results from the application of a two-dimensional emission line detection method, EMission-line two-Dimensional (EM2D), to the near-infrared G102 grism observations obtained with the Wide-Field Camera 3 (WFC3) as part of the Cycle 22 Hubble Space Telescope Treasury Program: the Faint Infrared Grism Survey (FIGS). Using the EM2D method, we have assembled a catalog of emission line galaxies (ELGs) with resolved star formation from each of the four FIGS fields. Not only can one better assess the global properties of ELGs, but the EM2D method allows for the analysis and improved study of the individual emission-line region within each galaxy. This paper includes a description of the methodology, advantages, and the first results of the EM2D method applied to ELGs in FIGS. The advantage of 2D emission line measurements includes significant improvement of galaxy redshift measurements, approaching the level of accuracy seen in high-spectral-resolution data, but with greater efficiency; and the ability to identify and measure the properties of multiple sites of star formation and over scales of similar to 1 kpc within individual galaxies out to z similar to 4. The EM2D method also significantly improves the reliability of high-redshift (z similar to 7) Ly alpha detections. Coupled with the wide field of view and high efficiency of space-based grism observations, EM2D provides a noteworthy improvement on the physical parameters that can be extracted from grism observations.
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| 20. |
- Pirzkal, Norbert, et al.
(author)
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FIGS-Faint Infrared Grism Survey : Description and Data Reduction
- 2017
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 846:1
-
Journal article (peer-reviewed)abstract
- The Faint Infrared Grism Survey (FIGS) is a deep Hubble Space Telescope (HST) WFC3/IR (Wide Field Camera 3 Infrared) slitless spectroscopic survey of four deep fields. Two fields are located in the Great Observatories Origins Deep Survey-North (GOODS-N) area and two fields are located in the Great Observatories Origins Deep Survey-South (GOODS-S) area. One of the southern fields selected is the Hubble Ultra Deep Field. Each of these four fields were observed using the WFC3/G102 grism (0.8 mu m-1.15 mu m continuous coverage) with a total exposure time of 40 orbits (approximate to 100 kilo-seconds) per field. This reaches a 3 sigma continuum depth of approximate to 26 AB magnitudes and probes emission lines to similar to 10(-17) erg s(-1) cm(-2). This paper details the four FIGS fields and the overall observational strategy of the project. A detailed description of the Simulation Based Extraction (SBE) method used to extract and combine over 10,000 spectra of over 2000 distinct sources brighter than m(F105W) = 26.5 mag is provided. High fidelity simulations of the observations is shown to significantly improve the background subtraction process, the spectral contamination estimates, and the final flux calibration. This allows for the combination of multiple spectra to produce a final high quality, deep, 1D spectra for each object in the survey.
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