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- Ramdas, S., et al.
(författare)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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- Korenblik, R., et al.
(författare)
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Dragon 1 Protocol Manuscript : Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy
- 2022
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Ingår i: Cardiovascular and Interventional Radiology. - : Springer. - 0174-1551 .- 1432-086X. ; 45, s. 1391-1398
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Tidskriftsartikel (refereegranskat)abstract
- Study Purpose The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. Methods The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. Results Not applicable. Conclusion DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR.
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- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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- 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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- Chang, C. -W, et al.
(författare)
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The mediating role of perceived social support in the relationship between perceived stigma and depression among individuals diagnosed with substance use disorders
- 2022
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Ingår i: Journal of Psychiatric and Mental Health Nursing. - : John Wiley & Sons. - 1351-0126 .- 1365-2850. ; 29:2, s. 307-316
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Tidskriftsartikel (refereegranskat)abstract
- What is known on the subject?: Individuals diagnosed with substance use disorders may perceive stigma and suffer from mental health problems. Perceived stigma is related to poor mental health among individuals diagnosed with substance use disorders. The social support deterioration deterrence model proposes that stressors (e.g. perceived stigma) negatively affect mental health via reduced perceived social support. To the best of the present authors’ knowledge, the model has never been tested in the context of perceived stigma among individuals diagnosed with substance use disorders. What the paper adds to existing knowledge?: The paper used structural equation modelling to show that the social support deterioration deterrence model could explain the relationship between perceived stigma and depression among individuals diagnosed with substance use disorders. Perceived support from family and perceived support from friends are mediators in the association between perceived stigma and depression among individuals diagnosed with substance use disorders. What are the implications for practice?: Psychosocial interventions to increase perceived support from family and friends would be helpful in addressing perceived stigma effects on mental health. Abstract: Introduction Although the relationship between perceived stigma and mental health outcomes is documented in the existing literature, very few studies have investigated the mechanism linking perceived stigma and mental health outcomes among individuals diagnosed with substance use disorders. To the best of the present authors’ knowledge, the social support deterioration deterrence model has never been tested in the context of perceived stigma among individuals diagnosed with substance use disorders. Aim/Question Guided by the social support deterioration deterrence model, the present study investigated the mediating role of perceived support from three types of social network members (i.e. significant others, family members, and friends) in the association between perceived stigma and depression in individuals diagnosed with substance use disorders. Method The study employed a cross-sectional survey design comprising 300 participants diagnosed with substance use disorders in Taiwan. Results Results of a structural equation modelling analysis indicated that perceived stigma was significantly associated with depression. The relationship between perceived stigma and depression was partially mediated by perceived family support and perceived friend support. Discussion Consistent with the prediction of the social support deterioration deterrence model, the negative effect of perceived stigma on depression for individuals diagnosed with substance use disorders is through the mediating effect of social support. Implications for practices Based on the present study's results, psychosocial interventions to increase perceived support from family and friends would be helpful in addressing negative effects of perceived stigma on mental health among individuals diagnosed with substance use disorders.
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