| 1. |
- Noguchi, S, et al.
(författare)
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FANTOM5 CAGE profiles of human and mouse samples
- 2017
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Ingår i: Scientific data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4, s. 170112-
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Tidskriftsartikel (refereegranskat)abstract
- In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
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| 2. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 4. |
- Spracklen, Cassandra N., et al.
(författare)
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Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology
- 2019
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Ingår i: American Journal of Human Genetics. - : CELL PRESS. - 0002-9297 .- 1537-6605. ; 105:1, s. 15-28
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Tidskriftsartikel (refereegranskat)abstract
- Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 x 10(-4)) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
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| 5. |
- Din, Lennox, et al.
(författare)
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Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes
- 2019
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Ingår i: Genetic Epidemiology. - : WILEY. - 0741-0395 .- 1098-2272. ; 43:7, s. 844-863
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p =.0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.
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| 8. |
- Hveem, T. S., et al.
(författare)
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Changes in Chromatin Structure in Curettage Specimens Identifies High-Risk Patients in Endometrial Cancer
- 2017
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Ingår i: Cancer Epidemiology Biomarkers & Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 26:1, s. 61-67
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most endometrial carcinoma patients are diagnosed at an early stage with a good prognosis. However, a relatively low fraction with lethal disease constitutes a substantial number of patients due to the high incidence rate. Preoperative identification of patients with high risk and low risk for poor outcome is necessary to tailor treatment. Nucleotyping refers to characterization of cell nuclei by image cytometry, including the assessment of chromatin structure by nuclear texture analysis. This method is a strong prognostic marker in many cancers but has not been evaluated in preoperative curettage specimens from endometrial carcinoma. Methods: The prognostic impact of changes in chromatin structure quantified with Nucleotyping was evaluated in preoperative curettage specimens from 791 endometrial carcinoma patients prospectively included in the MoMaTEC multicenter trial. Results: Nucleotyping was an independent prognostic marker of disease-specific survival in preoperative curettage specimens among patients with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I-II disease (HR = 2.9; 95% CI, 1.2-6.5; P - 0.013) and significantly associated with age, FIGO stage, histologic type, histologic grade, myometrial infiltration, lymph node status, curettage histology type, and DNA ploidy. Conclusions: Nucleotyping in preoperative curettage specimens is an independent prognostic marker for disease-specific survival, with potential to supplement existing parameters for risk stratification to tailor treatment. Impact: This is the first study to evaluate the prognostic impact of Nucleotyping in curettage specimens from endometrial carcinoma and shows that this may be a clinically useful prognostic marker in endometrial cancer. External validation is warranted. (C) 2016 AACR.
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| 9. |
- Moshontz, Hannah, et al.
(författare)
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The Psychological Science Accelerator: Advancing Psychology Through a Distributed Collaborative Network
- 2018
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Ingår i: Advances in Methods and Practices in Psychological Science. - : SAGE Publications. - 2515-2459 .- 2515-2467. ; 1:4, s. 501-515
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Tidskriftsartikel (refereegranskat)abstract
- Concerns about the veracity of psychological research have been growing. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions or replicate prior research in large, diverse samples. The PSA’s mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time limited), efficient (in that structures and principles are reused for different projects), decentralized, diverse (in both subjects and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside the network). The PSA and other approaches to crowdsourced psychological science will advance understanding of mental processes and behaviors by enabling rigorous research and systematic examination of its generalizability.
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| 10. |
- Njolstad, T. S., et al.
(författare)
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DNA ploidy in curettage specimens identifies high-risk patients and lymph node metastasis in endometrial cancer
- 2015
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 112:10, s. 1656-1664
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Tidskriftsartikel (refereegranskat)abstract
- Background: Preoperative risk stratification is essential in tailoring endometrial cancer treatment, and biomarkers predicting lymph node metastasis and aggressive disease are aspired in clinical practice. DNA ploidy assessment in hysterectomy specimens is a well-established prognostic marker. DNA ploidy assessment in preoperative curettage specimens is less studied, and in particular in relation to the occurrence of lymph node metastasis. Methods: Curettage image cytometry DNA ploidy in relation to established clinicopathological variables and outcome was investigated in 785 endometrial carcinoma patients prospectively included in the MoMaTEC multicentre trial. Results: Diploid curettage status was found in 72.0%, whereas 28.0% were non-diploid. Non-diploid status significantly correlated with traditional aggressive postoperative clinicopathological features, and was an independent predictor of lymph node metastasis among FIGO stage I-III patients in multivariate analysis (OR 1.94, P = 0.033). Non-diploid status was related to shorter disease-specific survival (5-year DSS of 74.4% vs 88.8% for diploid curettage, P<0.001). When stratifying by FIGO stage and lymph node status, the prognostic effect remained. However, in multivariate regression analysis, preoperative histological risk classification was a stronger predictor of DSS than DNA ploidy. Conclusions: Non-diploid curettage is significantly associated with aggressive clinicopathological phenotype, lymph node metastasis, and poor survival in endometrial cancer. The prognostic effect was also observed among subgroups with (presumably) less aggressive traits, such as low FIGO stage and negative lymph node status. Our results indicate curettage DNA ploidy as a possible supplement to existing parameters used to tailor surgical treatment. ELER VM, 1991, CANCER, V67, P3093
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| 11. |
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| 12. |
- McMaster, ML, et al.
(författare)
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Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 4182-
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Tidskriftsartikel (refereegranskat)abstract
- Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10−54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10−19). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.
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| 16. |
- Johansson, Daniel, 1975, et al.
(författare)
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Multi-model comparison of the economic and energy implications for China and India in an international climate regime
- 2015
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Ingår i: Mitigation and Adaptation Strategies for Global Change. - : Springer Science and Business Media LLC. - 1381-2386 .- 1573-1596. ; 20:8, s. 1335-1359
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a modeling comparison on how stabilization of global climate change at about 2 °C above the pre-industrial level could affect economic and energy systems development in China and India. Seven General Equilibrium (CGE) and energy system models on either the global or national scale are soft-linked and harmonized with respect to population and economic assumptions. We simulate a climate regime, based on long-term convergence of per capita carbon dioxide (CO2) emissions, starting from the emission pledges presented in the Copenhagen Accord to the United Nations Framework Convention on Climate Change and allowing full emissions trading between countries. Under the climate regime, Indian emission allowances are allowed to grow more than the Chinese allowances, due to the per capita convergence rule and the higher population growth in India. Economic and energy implications not only differ among the two countries, but also across model types. Decreased energy intensity is the most important abatement approach in the CGE models, while decreased carbon intensity is most important in the energy system models. The reduction in carbon intensity is mostly achieved through deployment of carbon capture and storage, renewable energy sources and nuclear energy. The economic impacts are generally higher in China than in India, due to higher 2010–2050 cumulative abatement in China and the fact that India can offset more of its abatement cost though international emission trading.
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| 17. |
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| 18. |
- Saju, Jolly M., et al.
(författare)
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Heat Shock Factor 5 Is Essential for Spermatogenesis in Zebrafish
- 2018
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Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 25:12, s. 3252-3261
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Tidskriftsartikel (refereegranskat)abstract
- Heat shock factors (Hsfs) are transcription factors that regulate responses to heat shock and other environmental stimuli. Four heat shock factors (Hsf1-4) have been characterized from vertebrates to date. In addition to stress response, they also play important roles in development and gametogenesis. Here, we study the fifth member of heat shock factor family, Hsf5, using zebrafish as a model organism. Mutant hsf5(-/-) males, generated by CRISPR/Cas9 technique, were infertile with drastically reduced sperm count, increased sperm head size, and abnormal tail architecture, whereas females remained fertile. We show that Hsf5 is required for progression through meiotic prophase 1 during spermatogenesis as suggested by the accumulation of cells in the leptotene and zygotene-pachytene stages and increased apoptosis in post-meiotic cells. hsf5(-/-) mutants show gonadal misregulation of a substantial number of genes with roles in cell cycle, apoptosis, protein modifications, and signal transduction, indicating an important role of Hsf5 in early stages of spermatogenesis.
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