| 1. |
- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 2. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 3. |
- Hess, Paul, et al.
(författare)
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ISSC Technical Committee III.1 - Ultimate Strength
- 2022
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Ingår i: Proceedings of The 21st International Ship and Offshore Structures Congress (ISSC 2022). ; 1, s. 395-499
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Konferensbidrag (refereegranskat)abstract
- Concern for the collapse behaviour of ships and offshore structures and their structural components under ultimate conditions. Uncertainties in strength assessment shall be highlighted. Attention shall be given to the influence of response to load combinations including accidents; fabrication imperfections; life-cycle effects; and user approach. Consideration shall be given to the practical application of methods.
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| 4. |
- Laisk, Triin, et al.
(författare)
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The genetic architecture of sporadic and multiple consecutive miscarriage.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P=3.2 × 10-8, odds ratio (OR)=1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF=6.4%, P=1.3 × 10-8, OR=1.7; rs143445068, MAF=0.8%, P=5.2 × 10-9, OR=3.4; rs183453668, MAF=0.5%, P=2.8 × 10-8, OR=3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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| 5. |
- Argirion, Ilona, et al.
(författare)
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Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
- 2023
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association For Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 32:5, s. 687-696
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epstein-Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL).Methods: Anti-EBV IgG and IgA antibody responses target-ing 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case-control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their associ-ation with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies repre-senting the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models.Results: IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glyco-protein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types.Conclusions: Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis.Impact: Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer.
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| 6. |
- Crewe, C., et al.
(författare)
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Deficient Caveolin-1 Synthesis in Adipocytes Stimulates Systemic Insulin-Independent Glucose Uptake via Extracellular Vesicles
- 2022
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797. ; 71:12, s. 2496-2512
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Tidskriftsartikel (refereegranskat)abstract
- Caveolin-1 (cav1) is an important structural and signaling component of plasma membrane invaginations called caveolae and is abundant in adipocytes. As previ-ously reported, adipocyte-specific ablation of the cav1 gene (ad-cav1 knockout [KO] mouse) does not result in elimination of the protein, as cav1 protein traffics to adi-pocytes from neighboring endothelial cells. However, this mouse is a functional KO because adipocyte caveo-lar structures are depleted. Compared with controls, ad-cav1KO mice on a high-fat diet (HFD) display improved whole-body glucose clearance despite complete loss of glucose-stimulated insulin secretion, blunted insulin-stimulated AKT activation in metabolic tissues, and partial lipodystrophy. The cause is increased insulin-independent glucose uptake by white adipose tissue (AT) and reduced hepatic gluconeogenesis. Further-more, HFD-fed ad-cav1KO mice display significant AT inflammation, fibrosis, mitochondrial dysfunction, and dysregulated lipid metabolism. The glucose clearance phenotype of the ad-cav1KO mice is at least partially mediated by AT small extracellular vesicles (AT-sEVs). Injection of control mice with AT-sEVs from ad-cav1KO mice phenocopies ad-cav1KO characteristics. Interest-ingly, AT-sEVs from ad-cav1KO mice propagate the phenotype of the AT to the liver. These data indicate that ad-cav1 is essential for healthy adaptation of the AT to overnutrition and prevents aberrant propagation of neg-ative phenotypes to other organs by EVs.
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| 7. |
- de Zwarte, Sonja M. C., et al.
(författare)
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Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder
- 2022
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Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 414-430
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Tidskriftsartikel (refereegranskat)abstract
- First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
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| 8. |
- Golden, Gregory J, et al.
(författare)
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Endothelial Heparan Sulfate Mediates Hepatic Neutrophil Trafficking and Injury during Staphylococcus aureus Sepsis
- 2021
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Ingår i: mBio. - 2161-2129. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Hepatic failure is an important risk factor for poor outcome in septic patients. Using a chemical tagging workflow and high-resolution mass spectrometry, we demonstrate that rapid proteome remodeling of the vascular surfaces precedes hepatic damage in a murine model of Staphylococcus aureus sepsis. These early changes include vascular deposition of neutrophil-derived proteins, shedding of vascular receptors, and altered levels of heparin/heparan sulfate-binding factors. Modification of endothelial heparan sulfate, a major component of the vascular glycocalyx, diminishes neutrophil trafficking to the liver and reduces hepatic coagulopathy and organ damage during the systemic inflammatory response to infection. Modifying endothelial heparan sulfate likewise reduces neutrophil trafficking in sterile hepatic injury, reflecting a more general role of heparan sulfate contribution to the modulation of leukocyte behavior during inflammation. IMPORTANCE Vascular glycocalyx remodeling is critical to sepsis pathology, but the glycocalyx components that contribute to this process remain poorly characterized. This article shows that during Staphylococcus aureus sepsis, the liver vascular glycocalyx undergoes dramatic changes in protein composition associated with neutrophilic activity and heparin/heparan sulfate binding, all before organ damage is detectable by standard circulating liver damage markers or histology. Targeted manipulation of endothelial heparan sulfate modulates S. aureus sepsis-induced hepatotoxicity by controlling the magnitude of neutrophilic infiltration into the liver in both nonsterile and sterile injury. These data identify an important vascular glycocalyx component that impacts hepatic failure during nonsterile and sterile injury.
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| 9. |
- Kaminski, Thomas, et al.
(författare)
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Assessing the constraint of atmospheric CO2 and NO2 measurements from space on city-scale fossil fuel CO2 emissions in a data assimilation system
- 2022
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Ingår i: Frontiers in Remote Sensing. - : Frontiers Media SA. - 2673-6187. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- The European Copernicus programme plans to install a constellation of multiple polar orbiting satellites (Copernicus Anthropogenic CO2 Monitoring Mission, CO2M mission) for observing atmospheric CO2 content with the aim to estimate fossil fuel CO2 emissions. We explore the impact of potential CO2M observations of column-averaged CO2 (XCO2), nitrogen dioxide (NO2), and aerosols in a 200 × 200 km2 domain around Berlin. For the quantification of anticipated XCO2 random and systematic errors we developed and applied new error parameterisation formulae based on artificial neural networks. For the interpretation of these data, we further established a CCFFDAS modelling chain from parameters of emission models to XCO2 and NO2 observations to simulate the 24 h periods preceeding simulated CO2M overpasses over the study area. For one overpass in winter and one in summer, we present a number of assessments of observation impact in terms of the posterior uncertainty in fossil fuel emissions on scales ranging from 2 to 200 km. This means the assessments include temporal and spatial scales typically not covered by inventories. The assessments differentiate the fossil fuel CO2 emissions into two sectors, an energy generation sector (power plants) and the complement, which we call “other sector.” We find that combined measurements of XCO2 and aerosols provide a powerful constraint on emissions from larger power plants; the uncertainty in fossil fuel emissions from the largest three power plants in the domain was reduced by 60%–90% after assimilating the observations. Likewise, these measurements achieve an uncertainty reduction for the other sector that increases when aggregated to larger spatial scales. When aggregated over Berlin the uncertainty reduction for the other sector varies between 28% and 48%. Our assessments show a considerable contribution of aerosol observations onboard CO2M to the constraint of the XCO2 measurements on emissions from all power plants and for the other sector on all spatial scales. NO2 measurements onboard CO2M provide a powerful additional constraint on the emissions from power plants and from the other sector. We further apply a Jacobian representation of the CCFFDAS modelling chain to decompose a simulated CO2 column in terms of spatial emission impact. This analysis reveals the complex structure of the footprint of an observed CO2 column, which indicates the limits of simple mass balances approaches for interpretation of such observations.
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| 10. |
- Kaminski, Thomas, et al.
(författare)
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Assessing the Impact of Atmospheric CO2 and NO2 Measurements From Space on Estimating City-Scale Fossil Fuel CO2 Emissions in a Data Assimilation System
- 2022
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Ingår i: Frontiers in Remote Sensing. - : Frontiers Media SA. - 2673-6187. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- The European Copernicus programme plans to install a constellation of multiple polar orbiting satellites (Copernicus Anthropogenic CO2 Monitoring Mission, CO2M mission) for observing atmospheric CO2 content with the aim to estimate fossil fuel CO2 emissions. We explore the impact of potential CO2M observations of column-averaged CO2 (XCO2), nitrogen dioxide (NO2), and aerosols in a 200 × 200 km2 domain around Berlin. For the quantification of anticipated XCO2 random and systematic errors we developed and applied new error parameterisation formulae based on artificial neural networks. For the interpretation of these data, we further established a CCFFDAS modelling chain from parameters of emission models to XCO2 and NO2 observations to simulate the 24 h periods preceeding simulated CO2M overpasses over the study area. For one overpass in winter and one in summer, we present a number of assessments of observation impact in terms of the posterior uncertainty in fossil fuel emissions on scales ranging from 2 to 200 km. This means the assessments include temporal and spatial scales typically not covered by inventories. The assessments differentiate the fossil fuel CO2 emissions into two sectors, an energy generation sector (power plants) and the complement, which we call “other sector.” We find that combined measurements of XCO2 and aerosols provide a powerful constraint on emissions from larger power plants; the uncertainty in fossil fuel emissions from the largest three power plants in the domain was reduced by 60%–90% after assimilating the observations. Likewise, these measurements achieve an uncertainty reduction for the other sector that increases when aggregated to larger spatial scales. When aggregated over Berlin the uncertainty reduction for the other sector varies between 28% and 48%. Our assessments show a considerable contribution of aerosol observations onboard CO2M to the constraint of the XCO2 measurements on emissions from all power plants and for the other sector on all spatial scales. NO2 measurements onboard CO2M provide a powerful additional constraint on the emissions from power plants and from the other sector. We further apply a Jacobian representation of the CCFFDAS modelling chain to decompose a simulated CO2 column in terms of spatial emission impact. This analysis reveals the complex structure of the footprint of an observed CO2 column, which indicates the limits of simple mass balances approaches for interpretation of such observations.
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