| 1. |
|
|
| 2. |
- Antoniou, Antonis C., et al.
(författare)
-
Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers
- 2011
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:16, s. 3304-3321
-
Tidskriftsartikel (refereegranskat)abstract
- Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
|
|
| 3. |
- Manzoni, Claudia, et al.
(författare)
-
Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
- 2024
-
Ingår i: American Journal of Human Genetics. - 0002-9297. ; 111:7, s. 1316-1329
-
Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
|
|
| 4. |
- Palmer, Nicholette D, et al.
(författare)
-
A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
-
Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
-
Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
|
|
| 5. |
- van Rheenen, Wouter, et al.
(författare)
-
Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
-
Tidskriftsartikel (refereegranskat)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
|
|
| 6. |
- Kehoe, Laura, et al.
(författare)
-
Make EU trade with Brazil sustainable
- 2019
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 7. |
|
|
| 8. |
- Fazey, Ioan, et al.
(författare)
-
Transforming knowledge systems for life on Earth : Visions of future systems and how to get there
- 2020
-
Ingår i: Energy Research & Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 70
-
Tidskriftsartikel (refereegranskat)abstract
- Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.
|
|
| 9. |
|
|
| 10. |
- Machiela, Mitchell J., et al.
(författare)
-
Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
-
Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
|
|
| 11. |
|
|
| 12. |
- Owens, Kay, et al.
(författare)
-
Cultural horizons for mathematics
- 2011
-
Ingår i: Mathematics Education Research Journal. - : Springer Science and Business Media LLC. - 1033-2170 .- 2211-050X. ; 23:2, s. 253-274
-
Tidskriftsartikel (refereegranskat)abstract
- As a result of a number of government reports, there have been numerous systemic changes in Indigenous education in Australia revolving around the importance of partnerships with the community. A forum with our local Dubbo community established the importance of working together and developed a model which placed the child in an ecological perspective that particularly noted the role of Elders and the place of the child in the family. However, there was also the issue of curriculum and mathematics education to be addressed. It was recognised that a colonised curriculum reduces the vision of what might be the potential for Indigenous mathematics education. This paper reports on the sharing that developed between our local community and some researchers and teachers from Sweden, Papua New Guinea and New Zealand. It has implications for recognising the impact of testing regimes, the teaching space, understanding the ways children learn, the curriculum, and teacher education. As a result of these discussions, a critical pedagogy that considers culture and place is presented as an ecocultural perspective on mathematics education. This perspective was seen as critical for the curriculum and learning experiences of Indigenous children.
|
|
| 13. |
|
|
| 14. |
- Sampson, Joshua N., et al.
(författare)
-
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
-
Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
|
|
| 15. |
- Sawcer, Stephen, et al.
(författare)
-
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
|
|
| 16. |
|
|
| 17. |
- Zheng, Hou-Feng, et al.
(författare)
-
Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
-
Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
|
|
| 18. |
- Ali, Zaheer, et al.
(författare)
-
Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization
- 2019
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 39:7, s. 1402-1418
-
Tidskriftsartikel (refereegranskat)abstract
- Objective—Pathological neovascularization is crucial for progression and morbidity of serious diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. While mechanisms of ongoing pathological neovascularization have been extensively studied, the initiating pathological vascular remodeling (PVR) events, which precede neovascularization remains poorly understood. Here, we identify novel molecular and cellular mechanisms of preneovascular PVR, by using the adult choriocapillaris as a model.Approach and Results—Using hypoxia or forced overexpression of VEGF (vascular endothelial growth factor) in the subretinal space to induce PVR in zebrafish and rats respectively, and by analyzing choriocapillaris membranes adjacent to choroidal neovascular lesions from age-related macular degeneration patients, we show that the choriocapillaris undergo robust induction of vascular intussusception and permeability at preneovascular stages of PVR. This PVR response included endothelial cell proliferation, formation of endothelial luminal processes, extensive vesiculation and thickening of the endothelium, degradation of collagen fibers, and splitting of existing extravascular columns. RNA-sequencing established a role for endothelial tight junction disruption, cytoskeletal remodeling, vesicle- and cilium biogenesis in this process. Mechanistically, using genetic gain- and loss-of-function zebrafish models and analysis of primary human choriocapillaris endothelial cells, we determined that HIF (hypoxia-induced factor)-1α-VEGF-A-VEGFR2 signaling was important for hypoxia-induced PVR.Conclusions—Our findings reveal that PVR involving intussusception and splitting of extravascular columns, endothelial proliferation, vesiculation, fenestration, and thickening is induced before neovascularization, suggesting that identifying and targeting these processes may prevent development of advanced neovascular disease in the future.Visual Overview—An online visual overview is available for this article.
|
|
| 19. |
- Antoniou, A. C., et al.
(författare)
-
Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers : Implications for risk prediction
- 2010
-
Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 70:23, s. 9742-9754
-
Tidskriftsartikel (refereegranskat)abstract
- The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10-11 - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.
|
|
| 20. |
- Balgård, Sture (ed.), et al.
(författare)
-
STUDIER AV ARKITEKTONISK GESTALT : OFFETLIG OCH PRIVAT
- 1990
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- This work contains sketches and pictures of a selection of buildings and housing enviroments, made by students at the Department of Architectural Conservation at the Royal University Collage of Fine Arts in september to October 1990.
|
|
| 21. |
- Benzinou, Michael, et al.
(författare)
-
Common nonsynonymous variants in PCSK1 confer risk of obesity.
- 2008
-
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:8, s. 943-5
-
Tidskriftsartikel (refereegranskat)abstract
- Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.
|
|
| 22. |
- Berthon, Beatrice, et al.
(författare)
-
PETSTEP : generation of synthetic PET lesions for fast evaluation of segmentation methods
- 2015
-
Ingår i: Physica medica (Testo stampato). - : Elsevier BV. - 1120-1797 .- 1724-191X. ; 31:8, s. 969-980
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: This work describes PETSTEP (PET Simulator of Tracers via Emission Projection): a faster and more accessible alternative to Monte Carlo (MC) simulation generating realistic PET images, for studies assessing image features and segmentation techniques.Methods: PETSTEP was implemented within Matlab as open source software. It allows generating threedimensional PET images from PET/CT data or synthetic CT and PET maps, with user-drawn lesions and user-set acquisition and reconstruction parameters. PETSTEP was used to reproduce images of the NEMA body phantom acquired on a GE Discovery 690 PET/CT scanner, and simulated with MC for the GE Discovery LS scanner, and to generate realistic Head and Neck scans. Finally the sensitivity (S) and Positive Predictive Value (PPV) of three automatic segmentation methods were compared when applied to the scanner-acquired and PETSTEP-simulated NEMA images.Results: PETSTEP produced 3D phantom and clinical images within 4 and 6 min respectively on a single core 2.7 GHz computer. PETSTEP images of the NEMA phantom had mean intensities within 2% of the scanner-acquired image for both background and largest insert, and 16% larger background Full Width at Half Maximum. Similar results were obtained when comparing PETSTEP images to MC simulated data. The S and PPV obtained with simulated phantom images were statistically significantly lower than for the original images, but led to the same conclusions with respect to the evaluated segmentation methods.Conclusions: PETSTEP allows fast simulation of synthetic images reproducing scanner-acquired PET data and shows great promise for the evaluation of PET segmentation methods.
|
|
| 23. |
|
|
| 24. |
- Crona, Beatrice I., et al.
(författare)
-
Learning in support of governance : Theories, methods, and a framework to assess how bridging organizations contribute to adaptive resource governance
- 2012
-
Ingår i: Ecology and Society. - 1708-3087. ; 17:1, s. 32-
-
Tidskriftsartikel (refereegranskat)abstract
- Humanity faces increasingly intractable environmental problems characterized by high uncertainty, complexity, and swift change. Natural resource governance must therefore involve continuous production and use of new knowledge to adapt to highly complex, rapidly changing social-ecological systems to ensure long-term sustainable development. Bridging and boundary organizations have been proposed as potentially powerful means of achieving these aims by promoting cooperation among actors from the science, policy, and management sectors. However, despite substantial investments of time, capital, and human resources, little agreement exists about definitions and measures of knowledge production and how this is achieved in bridging organizations and there is only meager understanding of how knowledge production and its use are shaped by social interactions, socio-political environments, and power relations. New concepts, methods, and metrics for conceptualizing and measuring learning in support of natural resource governance and testing the conditions under which it can be achieved are therefore badly needed. This paper presents an attempt at a holistic framework to address this, drawing on theory, methods, and metrics from three research areas: knowledge utilization, boundary organizations, and stakeholder theory. Taken together, these provide a solid conceptual and methodological toolkit for conducting cross-case comparisons aimed at understanding the social environmental conditions under which learning in such organizations does and does not occur. We use empirical data to show how the framework can be applied and discuss some of the practical considerations and important challenges that emerge. We close with a general discussion and an agenda for future research to promote discussion around the topic of how to erect systematic comparisons of learning in support of adaptive natural resource governance as it occurs in bridging organizations.
|
|
| 25. |
- Crona, Beatrice, et al.
(författare)
-
Network Determinants of Knowledge Utilization : preliminary Lessons from a Boundary Organization
- 2011
-
Ingår i: Science communication. - : SAGE Publications. - 1075-5470 .- 1552-8545. ; 33:4, s. 448-471
-
Tidskriftsartikel (refereegranskat)abstract
- This study examines the socio-organizational model of science-policy knowledge transfer. Using social network analysis, the authors study how interactions between researchers-policy makers affect utilization of research by policy makers in a boundary organization designed to mediate between research and policy communities. Two types of social interactions with independent effects on utilization are identified. Policy makers with more direct contacts with researchers are more likely to utilize research. Policy makers interacting more with other policy makers regarding research are also more likely to utilize it. This indicates the importance of policy makers’ embeddedness in social networks and the importance of external reputation of boundary organizations for successful knowledge transfer.
|
|
| 26. |
- Ding, Yuan C, et al.
(författare)
-
A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
- 2012
-
Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 21:8, s. 1362-1370
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
|
|
| 27. |
|
|
| 28. |
- Eckel-Passow, Jeanette E., et al.
(författare)
-
Using germline variants to estimate glioma and subtype risks
- 2019
-
Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 21:4, s. 451-461
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Twenty-five single nucleotide polymorphisms (SNPs) are associated with adult diffuse glioma risk. We hypothesized that the inclusion of these 25 SNPs with age at diagnosis and sex could estimate risk of glioma as well as identify glioma subtypes.Methods: Case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for histologic and molecular subtypes. Case-case design and logistic regression were used to develop models to predict isocitrate dehydrogenase (IDH) mutation status. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray.Results: Patients in the highest 5% of the risk score had more than a 14-fold increase in relative risk of developing an IDH mutant glioma. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile. For both IDH mutant 1p/19q non-codeleted glioma and IDH mutant 1p/19q codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation concordance index of 0.85.Conclusions: These results suggest that germline genotyping can provide new tools for the initial management of newly discovered brain lesions. Given the low lifetime risk of glioma, risk scores will not be useful for population screening; however, they may be useful in certain clinically defined high-risk groups.
|
|
| 29. |
- Eckel-Passow, Jeanette, et al.
(författare)
-
USING GERMLINE VARIANTS TO PREDICT GLIOMA RISK AND IDENTIFY GLIOMA SUBTYPE PRE-OPERATIVELY
- 2018
-
Ingår i: Neuro-Oncology. - : OXFORD UNIV PRESS INC. - 1522-8517 .- 1523-5866. ; 20, s. 82-82
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- To date, 25 single nucleotide polymorphisms (SNPs) have been shown to be associated with overall glioma risk or with risk of specific subtypes of glioma. We hypothesized that the inclusion of these 25 SNPs with patient age at diagnosis and sex could predict risk of glioma as well as predict IDH mutation status. Thus, case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for molecular subtypes. Case-case design and logistic regression were used to develop models to predict IDH mutation status. Each model included all 25 glioma risk SNPs, patient age at diagnosis and sex. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray. We observed that patients in the highest 5% of the risk score had more than a 14-fold increased relative risk of developing an IDH-mutant glioma, compared to patients with median risk score. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile categories. For both IDH-mutated 1p/19q non-codeleted glioma and IDH-mutated 1p/19q-codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation c-index of 0.85. These results suggest that germline genotyping has the potential to provide a new tool for clinicians for the initial management of newly-discovered brain lesions. Specifically, given the low lifetime risk of glioma, SNP-based risk scores should not be useful for general population screening. However, with further research these risk scores may be useful in certain clinically-defined high-risk groups.
|
|
| 30. |
- Folke, Carl, et al.
(författare)
-
Transnational corporations and the challenge of biosphere stewardship
- 2019
-
Ingår i: Nature Ecology & Evolution. - : Springer Science and Business Media LLC. - 2397-334X. ; 3:10, s. 1396-1403
-
Tidskriftsartikel (refereegranskat)abstract
- Sustainability within planetary boundaries requires concerted action by individuals, governments, civil society and private actors. For the private sector, there is concern that the power exercised by transnational corporations generates, and is even central to, global environmental change. Here, we ask under which conditions transnational corporations could either hinder or promote a global shift towards sustainability. We show that a handful of transnational corporations have become a major force shaping the global intertwined system of people and planet. Transnational corporations in agriculture, forestry, seafood, cement, minerals and fossil energy cause environmental impacts and possess the ability to influence critical functions of the biosphere. We review evidence of current practices and identify six observed features of change towards 'corporate biosphere stewardship', with significant potential for upscaling. Actions by transnational corporations, if combined with effective public policies and improved governmental regulations, could substantially accelerate sustainability efforts.
|
|
| 31. |
- Frank, Beatrice M., et al.
(författare)
-
A review of ecological models for brown trout : towards a new demogenetic model
- 2011
-
Ingår i: Ecology of Freshwater Fish. - : Wiley-Blackwell. - 0906-6691 .- 1600-0633. ; 20:2, s. 167-198
-
Tidskriftsartikel (refereegranskat)abstract
- Ecological models for stream fish range in scale from individual fish to entire populations. They have been used to assess habitat quality and to predict the demographic and genetic responses to management or disturbance. In this paper, we conduct the first comprehensive review and synthesis of the vast body of modelling literature on the brown trout, Salmo trutta L., with the aim of developing the framework for a demogenetic model, i.e., a model integrating both population dynamics and genetics. We use a bibliometric literature review to identify two main categories of models: population ecology (including population dynamics and population genetics) and population distribution (including habitat–hydraulic and spatial distribution). We assess how these models have previously been applied to stream fish, particularly brown trout, and how recent models have begun to integrate them to address two key management and conservation questions: (i) How can we predict fish population responses to management intervention? and (ii) How is the genetic structure of fish populations influenced by landscape characteristics? Because salmonid populations tend to show watershed scale variation in both demographic and genetic traits, we propose that models combining demographic, genetic and spatial data are promising tools for improving their management and conservation. We conclude with a framework for an individual-based, spatially explicit demogenetic model that we will apply to stream-dwelling brown trout populations in the near future.
|
|
| 32. |
- Graversgaard, Morten, et al.
(författare)
-
Opportunities and barriers for water co-governance : A critical analysis of seven cases of diffuse water pollution from agriculture in Europe, Australia and North America
- 2018
-
Ingår i: Sustainability. - : MDPI. - 2071-1050. ; 10:5
-
Tidskriftsartikel (refereegranskat)abstract
- Diffuse Water Pollution from Agriculture (DWPA) and its governance has received increased attention as a policy concern across the globe. Mitigation of DWPA is a complex problem that requires a mix of policy instruments and a multi-agency, broad societal response. In this paper, opportunities and barriers for developing co-governance, defined as collaborative societal involvement in the functions of government, and its suitability for mitigation of DWPA are reviewed using seven case studies in Europe (Poland, Denmark, Sweden, The Netherlands and UK), Australia (Murray-Darling Basin) and North America (State of Minnesota). An analytical framework for assessing opportunities and barriers of co-governance was developed and applied in this review. Results indicated that five key issues constitute both opportunities and barriers, and include: (i) pressure for change; (ii) connected governance structures and allocation of resources and funding; (iii) leadership and establishment of partnerships through capacity building; (iv) use and co-production of knowledge; and (v) time commitment to develop water co-governance
|
|
| 33. |
- Jacobs, Kevin B, et al.
(författare)
-
Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
-
Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
-
Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
|
|
| 34. |
- Kirchhoff, Tomas, et al.
(författare)
-
Breast cancer risk and 6q22.33 : combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
- 2012
-
Ingår i: PLOS ONE. - : Public library of science. - 1932-6203. ; 7:6
-
Tidskriftsartikel (refereegranskat)abstract
- Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
|
|
| 35. |
- Klein, Alison P., et al.
(författare)
-
Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
- 2018
-
Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 x 10(-8)). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PAN-DoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 x 10(-14)), rs2941471 at 8q21.11 (HNF4G, P = 6.60 x 10(-10)), rs4795218 at 17q12 (HNF1B, P = 1.32 x 10(-8)), and rs1517037 at 18q21.32 (GRP, P = 3.28 x 10(-8)). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
|
|
| 36. |
- Le Guen, Yann, et al.
(författare)
-
Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- 2023
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
-
Tidskriftsartikel (refereegranskat)abstract
- Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
|
|
| 37. |
- Liu, Yanhong, et al.
(författare)
-
Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 genes involved in the double-strand break repair pathway predict glioblastoma survival
- 2010
-
Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 28:14, s. 2467-2474
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Glioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment. PATIENTS AND METHODS: Among 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genome-wide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; or= 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs. RESULTS: We identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients >or= 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years). CONCLUSION: Polymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.
|
|
| 38. |
- Machiela, Mitchell J, et al.
(författare)
-
Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
-
Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
|
|
| 39. |
- Melin, Beatrice S., et al.
(författare)
-
Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors
- 2017
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:5, s. 789-794
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 x 10(-9), odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 x 10(-10), OR = 1.24), 16p13.3 (rs2562152; P = 1.93 x 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 x 10(-11), OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 x 10(-10), OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 x 10(-9), OR = 1.19), 1q44 (rs12076373; P = 2.63 x 10(-10), OR = 1.23), 2q33.3 (rs7572263; P = 2.18 x 10(-10), OR = 1.20), 3p14.1 (rs11706832; P = 7.66 x 10(-9), OR = 1.15), 10q24.33 (rs11598018; P = 3.39 x 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 x 10(-10), OR = 1.16), 14q12 (rs10131032; P = 5.07 x 10(-11), OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 x 10(-9), OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.
|
|
| 40. |
- Osorio, A., et al.
(författare)
-
Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2 (CIMBA)
- 2009
-
Ingår i: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 101:12, s. 2048-2054
-
Tidskriftsartikel (refereegranskat)abstract
- Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.
|
|
| 41. |
|
|
| 42. |
- Ostrom, Quinn T., et al.
(författare)
-
Age‐specific genome‐wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'‐like features associated with younger age
- 2018
-
Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 143:10, s. 2359-2366
-
Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age‐at‐diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age‐at‐diagnosis has been explored, genome‐wide association studies (GWAS) have not previously been stratified by age. Potential age‐specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18–53, 54–64, 65+) datasets were analyzed using age‐stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta‐analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54–63 = 1.50x10−9, OR54–63 = 1.28, 95%CI54–63 = 1.18–1.39; p64+ = 2.14x10−11, OR64+ = 1.32, 95%CI64+ = 1.21–1.43] and rs11979158 [p54–63 = 6.13x10−8, OR54–63 = 1.35, 95%CI54–63 = 1.21–1.50; p64+ = 2.18x10−10, OR64+ = 1.42, 95%CI64+ = 1.27–1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18–53 (p18–53 = 9.30 × 10−11, OR18–53 = 1.76, 95%CI18–53 = 1.49–2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of ‘LGG’‐like tumor characteristics in GBM samples in those 18–53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54–63] and 0.8% [64+] (p = 0.0005). Age‐specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18–53 suggests that more younger individuals may present initially with ‘secondary glioblastoma.’
|
|
| 43. |
- Ostrom, Quinn T., et al.
(författare)
-
Evaluating glioma risk associated with extent of European admixture in African-Americans and Latinos
- 2018
-
Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 78:13
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Glioma incidence is highest in non-Hispanic Whites, where it occurs ~2x as frequently compared with other race/ethnicity groups. Glioma GWAS to date have included European ancestry populations only, and it is unknown whether variants identified by these analyses are associated with glioma in non- European ancestry populations. African Americans and Hispanics are admixed populations with varying proportions of European ancestry. While global ancestry may be similar within admixed groups, the proportion of European ancestry at each allele can vary across the genome. As glioma is more common in European ancestry populations, the presence of increased local European ancestry in these admixed populations could be used to identify glioma risk loci. Here we assessed whether excess European ancestry at established risk loci (Melin et al, Nature Genetics, 2017) was associated with glioma risk in non-European ancestry populations. Global ancestry was estimated using fastStructure, and local ancestry was estimated using RFMix. Both methods used 1,000 genomes project reference populations (African: YRI; European: CEU; East Asian: CHB/JPT; and Native American: CLM/PEL/MXL). We evaluated differences in local European ancestry between cases and controls using logistic regression conditioned on global European ancestry within 500kb of 25 previously identified risk variants among individuals with ≥50% African ancestry, and ≥30% Native American ancestry for all gliomas, and for grade IV glioblastoma (GBM) and grade II-III non-GBM. There were 347 individuals (184 cases and 163 controls) with ≥50% global African ancestry, and 277 individuals (153 cases and 124 controls) with ≥30% global American ancestry. There was no significant difference in proportion of global European ancestry between cases and controls with ≥50% global African ancestry (cases: 18.2%, controls: 17.7%, p=0.6834), and no significant difference in proportion of global European ancestry between cases and controls with ≥30% global American ancestry (cases: 51.1%, controls: 49.0%, p=0.2123). Among individuals with >50% African ancestry, we observed a nominally significant association between all glioma and increased local European ancestry at 7p11.2 (EGFR, pmin=0.0070) and between GBM and increased local European ancestry at 22q13.1 (CSNK1E, pmin=0.0098), both near SNPs previously associated with glioblastoma in majority European-ancestry populations. The dataset used for this analysis represents the largest collection of genotyped non-European glioma cases. These results suggest that glioma risk in African Americans may be associated with an increased local European ancestry variants at glioma risk loci previously identified in majority European ancestry populations (7p11.2 and 22q13.1).
|
|
| 44. |
- Ostrom, Quinn T., et al.
(författare)
-
Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics
- 2020
-
Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:3, s. 739-748
-
Tidskriftsartikel (refereegranskat)abstract
- Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with >= 40% AA (AFR(>= 0.4)), and >= 15% NAA (AMR(>= 0.15)), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 x 10(-4); 11p11.12, p = 7.0 x 10-4) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR(>= 0.4). In addition, we identified a peak at rs1620291 (p = 4.36 x 10(-6)) in 7q21.3. Among AMR(>= 0.15), we found an association between increased EA in one region (12q24.21, p = 8.38 x 10(-4)), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 x 10(-4)). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies. What's new? Glioma is rare in non-White populations, and most glioma genome-wide association studies have included only primarily European ancestry populations. Here, the authors assess whether variation in European ancestry is associated with glioma risk in populations with a combination of European, African and Native American ancestry. Based on African American and Hispanic cases from two large glioma case-control studies, this analysis shows that increased European ancestry in admixed populations may be associated with increased glioma risk. The associations between glioma and two chromosomal regions previously identified in European ancestry populations, and four novel regions, may guide future studies.
|
|
| 45. |
- Ostrom, Quinn T., et al.
(författare)
-
Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21
- 2018
-
Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.
|
|
| 46. |
- Parker, John, et al.
(författare)
-
On being all things to all people : Boundary organizations and the contemporary research university
- 2012
-
Ingår i: Social Studies of Science. - : SAGE Publications. - 0306-3127 .- 1460-3659. ; 42:2, s. 262-289
-
Tidskriftsartikel (refereegranskat)abstract
- This article examines the challenges and tensions that inhere in university-based boundary organizations. We begin by reconceptualizing the theory of boundary organizations, bringing it into greater alignment with the realities of the current university environment. Using in-depth interviews, documentary analysis and ethnographic field work, this framework is applied to a university-based boundary organization attempting to reconcile the needs of water policymakers, university administrators, university departments, and funding agencies. These stakeholders place diverse, conflicting demands on the boundary organization. Those demands create four sets of enduring tensions requiring ongoing management by the boundary organization. However, the ability to manage these tensions is structured by constituents' relative levels of power, legitimacy, and saliency. We show the importance of adaptive boundary management for managing these enduring tensions, while also concluding that the demands of some stakeholders may be incommensurable. The article closes with a number of concrete suggestions for enhancing the efficacy of university-based boundary organizations.
|
|
| 47. |
- Perry, John R. B., et al.
(författare)
-
Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes
- 2010
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:3, s. 535-544
-
Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
|
|
| 48. |
- Rajaraman, Preetha, et al.
(författare)
-
Genome-wide association study of glioma and meta-analysis
- 2012
-
Ingår i: Human Genetics. - : SPRINGER. - 0340-6717 .- 1432-1203. ; 131:12, s. 1877-1888
-
Tidskriftsartikel (refereegranskat)abstract
- Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.
|
|
| 49. |
|
|
| 50. |
- Robertson, Lindsay B, et al.
(författare)
-
Survey of familial glioma and role of germline p16INK4A/p14ARF and p53 mutation
- 2010
-
Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 9:3, s. 413-421
-
Tidskriftsartikel (refereegranskat)abstract
- There is increasing recognition of familial propensity to glioma as a distinct clinical entity beyond a few rare syndromes; however its genetic basis is poorly understood. The role of p16(INK4A)/p14(ARF) and p53 mutations in sporadic glioma provides a strong rationale for investigating germline mutations in these genes as a cause of familial glioma. To survey the familial glioma phenotype and examine the contribution of germline mutation in p16(INK4A)/p14(ARF) and p53 to the disease we have analyzed a series of 101 index familial cases collected through the GLIOGENE Consortium (http://braintumor.epigenetic.org/). There was little evidence for within family correlations for tumour histology, suggesting generic susceptibility to glial tumors. We did not detect any functional mutations in p16(INK4A) or p14(ARF). One index case with glioblastoma multiforme (GBM) diagnosed at age 54 and had a family history comprised of a paternal aunt with GBM at age 55, carried the p53 R158H mutation, which is predicted to be functional and has previously been implicated as a cause of Li-Fraumeni syndrome. Our findings provide no evidence that p16(INK4A)/p14(ARF) and p53 mutations contribute significantly to familial glioma.
|
|
