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| 5. |
- Bryant, J. M., et al.
(författare)
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Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium
- 2016
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 354:6313, s. 751-757
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Tidskriftsartikel (refereegranskat)abstract
- Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.
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| 6. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 9. |
- Herrick, A. L., et al.
(författare)
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Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study
- 2018
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 77:4, s. 563-570
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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| 11. |
- Wadsworth, R., et al.
(författare)
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Spin-gap Isomer in 96Cd
- 2012
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6596 .- 1742-6588. ; 381:1
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Tidskriftsartikel (refereegranskat)abstract
- Evidence has been obtained for the existence of the long predicted 16+ spin-gap isomer in 96Cd. The decay of the isomer was identified and studied following the use of an 850 MeV/u beam of 124Xe impinging on a Be target and the fragment recoil separator at the GSI Laboratory. Gamma decays from the fragments were detected using the RISING gamma ray array, in its stopped beam configuration, plus a silicon active stopper. The data obtained have been compared with shell model predictions, which indicate that the isoscalar neutron-proton interaction plays a key role in the formation of the isomer.
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| 12. |
- Aguar-Bartolome, P., et al.
(författare)
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New determination of the eta transition form factor in the Dalitz decay eta -> e(+) e(-) gamma with the Crystal Ball/TAPS detectors at the Mainz Microtron
- 2014
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 89:4
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Tidskriftsartikel (refereegranskat)abstract
- The Dalitz decay eta -> e(+) e(-) gamma has been measured in the gamma p -> eta p reaction with the Crystal Ball and TAPS multiphoton spectrometers, together with the photon-tagging facility at the Mainz Microtron MAMI. The experimental statistic used in this work is one order of magnitude greater than in any previous measurement of eta -> e(+) e(-) gamma. The value obtained for the slope parameter Lambda(-2) of the eta transition form factor, Lambda(-2) = (1.95 +/- 0.15(stat) +/- 0.10(syst)) GeV-2, is in good agreement with recent measurements conducted in eta -> e(+) e(-) gamma and eta -> mu(+) mu(-) gamma decays, as well as with recent form-factor calculations. The uncertainty obtained in the value of Lambda(-2) is lower compared to results from previous measurements of the eta -> e(+) e(-) gamma decay.
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| 13. |
- Aronson, M.F.J., et al.
(författare)
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A global analysis of the impacts of urbanization on bird and plant diversity reveals key anthropogenic drivers
- 2014
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Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 281:1780, s. 20133330-
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Tidskriftsartikel (refereegranskat)abstract
- Urbanization contributes to the loss of the world's biodiversity and the homogenization of its biota. However, comparative studies of urban biodiversity leading to robust generalities of the status and drivers of biodiversity in cities at the global scale are lacking. Here, we compiled the largest global dataset to date of two diverse taxa in cities: birds (54 cities) and plants (110 cities). We found that the majority of urban bird and plant species are native in the world's cities. Few plants and birds are cosmopolitan, the most common being Columba livia and Poa annua. The density of bird and plant species (the number of species per km2) has declined substantially: only 8% of native bird and 25% of native plant species are currently present compared with estimates of non-urban density of species. The current density of species in cities and the loss in density of species was best explained by anthropogenic features (landcover, city age) rather than by non-anthropogenic factors (geography, climate, topography). As urbanization continues to expand, efforts directed towards the conservation of intact vegetation within urban landscapes could support higher concentrations of both bird and plant species. Despite declines in the density of species, cities still retain endemic native species, thus providing opportunities for regional and global biodiversity conservation, restoration and education.
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| 14. |
- Bruce, A. M., et al.
(författare)
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Beta Decay of 102Y Produced in Projectile Fission of 238U
- 2012
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6596 .- 1742-6588. ; 381
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Tidskriftsartikel (refereegranskat)abstract
- The population of 102Zr following the β decay of 102Y produced in the projectile fission of 238U at the GSI facility in Darmstadt, Germany has been studied. 102Y is known to ß decay into 102Zr via two states, one of high spin and the other low spin. These states preferentially populate different levels in the 102Zr daughter. In this paper the intensities of transitions in 102Zr observed are compared with those from the decay of the low-spin level studied at the TRISTAN facility at Brookhaven National Laboratory and of the high-spin level studied at the JOSEF separator at the Kernforschungsanlage Jülich.
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| 15. |
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| 16. |
- Duffy, DL, et al.
(författare)
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Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 299-
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Tidskriftsartikel (refereegranskat)abstract
- The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
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| 17. |
- Mlecnik, B, et al.
(författare)
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Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.
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| 18. |
- Myers, L. S., et al.
(författare)
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Compton scattering from C-12 using tagged photons in the energy range 65-115 MeV
- 2014
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 89:3
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Tidskriftsartikel (refereegranskat)abstract
- Elastic scattering of photons from C-12 has been investigated using quasimonoenergetic tagged photons with energies in the range 65-115 MeV at laboratory angles of 60 degrees, 120 degrees, and 150 degrees. at the Tagged-Photon Facility at the MAX IV Laboratory in Lund, Sweden. A phenomenological model was employed to provide an estimate of the sensitivity of the C-12(gamma,gamma)C-12 cross section to the bound- nucleon polarizabilities.
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| 19. |
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| 20. |
- Aguar-Bartolome, P., et al.
(författare)
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Measurement of the gamma p -> K-0 Sigma(+) reaction with the Crystal Ball/TAPS detectors at the Mainz Microtron
- 2013
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 88:4
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Tidskriftsartikel (refereegranskat)abstract
- The gamma p -> K-0 Sigma(+) reaction has been measured from threshold to E-gamma = 1.45 GeV (W-CM = 1.9 GeV) using the Crystal Ball and TAPS multiphoton spectrometers together with the photon tagging facility at the Mainz Microtron MAMI. In the present experiment, this reaction was searched for in the 3 pi(0)p final state, by assuming K-S(0) -> pi(0)pi(0) and Sigma(+) -> pi(0)p. The experimental results include total and differential cross sections as well as the polarization of the recoil hyperon. The new data significantly improve empirical knowledge about the gamma p -> K-0 Sigma(+) reaction in the measured energy range. The results are compared to previous measurements and model predictions. It is demonstrated that adding the present gamma p -> K-0 Sigma(+) results to existing data allowed a better description of this reaction with various models.
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| 22. |
- Creighton, S, et al.
(författare)
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Predictive, pre-natal and diagnostic genetic testing for Huntington's disease : the experience in Canada from 1987 to 2000.
- 2003
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Ingår i: Clinical Genetics. - 0009-9163 .- 1399-0004. ; 63:6, s. 462-75
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Tidskriftsartikel (refereegranskat)abstract
- Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.
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| 23. |
- Kashevarov, V. L., et al.
(författare)
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Experimental study of the gamma p -> pi (0)pi(0) p reaction with the Crystal Ball/TAPS detector system at the Mainz Microtron
- 2012
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 85:6
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Tidskriftsartikel (refereegranskat)abstract
- The gamma p -> pi(0)pi(0) p reaction has been measured from threshold to 1.4 GeV using the Crystal Ball and TAPS photon spectrometers together with the photon tagging facility at the Mainz Microtron. The experimental results include total and differential cross sections as well as specific angular distributions, which were used to extract partial-wave amplitudes. In particular, the energy region below the D-13(1520) resonance was studied.
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| 24. |
- Mlecnik, B, et al.
(författare)
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Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I–III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I–III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10–4.55) p = 0.0269) of the patient’s gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.
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| 25. |
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| 27. |
- Thorleifsson, Gudmar, et al.
(författare)
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Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:10, s. 906-909
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[ A], odds ratio (OR) = 1.36, P = 5.0 x 10(-10)). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.
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| 38. |
- Chen, Hongjie, et al.
(författare)
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Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals
- 2021
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Ingår i: Human Genetics and Genomics Advances. - : Cell Press. - 2666-2477. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
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| 39. |
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| 40. |
- Feng, Helian, et al.
(författare)
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Cross-cancer cross-tissue Transcriptome-wide Association Study (TWAS) of 11 cancers identifies 56 novel genes
- 2020
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Ingår i: Genetic Epidemiology. - : John Wiley & Sons. - 0741-0395 .- 1098-2272. ; 44:5, s. 481-481
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Though heterogeneous, multiple tumor types share hallmark mechanisms. Thus, identifying genes associated with multiple cancer types may shed light on general oncogenic mechanisms and identify genes missed in single‐cancer analyses. TWAS have been successful in testing whether genetically‐predicted tissue‐specific gene expression is associated with cancer risk. Although cross‐cancer genome‐wide association studies (GWAS) analyses have been performed previously, no cross‐cancer TWAS has been conducted to date. Here, we implement a pipeline to perform cross‐cancer, cross‐tissue TWAS analysis. We use newly‐developed multi‐trait TWAS test statistics to integrate the TWAS results for association between 11 separated cancers and predicted gene expression in 43 GTEx tissues, including a “sum” test and a “variance components” test, analogous to fixed‐ and random‐effects meta‐analyses. We then integrated the results across different tissues using the Aggregated Cauchy Association Test (ACAT) combined test.A total of 403 genes were significantly associated with at least one cancer type for at least one tissue; 96 additional genes were identified when combining test results across cancers; and 35 additional genes when further combining test results across tissue. Among these significant genes, 70 were not near previously‐published GWAS index variants. 14 of the 70 novel genes were identified from the single‐cancer single‐tissue test; an additional 43 were identified with the cross‐cancer test; and another 13 were identified when further combined across tissues. The newly identified genes, including RBBP8 and TP53BP , are involved in chromatin structure, tumorigenesis, apoptosis, transcriptional regulation, DNA repair, immune system, oxidative damage and cell‐cycle, proliferation, progression, shape, structure, and migration.
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| 41. |
- Frisén, Lars, 1939, et al.
(författare)
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Sarcoid-like disorder of the intracranial optic nerve.
- 1977
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - 0022-3050. ; 40:7, s. 702-7
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Tidskriftsartikel (refereegranskat)abstract
- Two cases with a sarcoid-like disorder apparently restricted to the intracranial optic nerve and the adjacent dura mater are described, doublilng the number of reported cases. In both instances there were unilateral visual loss and unusual radiographic changes in the optic canal area. Biopsy samples showed localised infiltration of tissues with non-caseating tubercles containing epithelioid and multinucleated giant cells.
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| 42. |
- Lindström, Sara, et al.
(författare)
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Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions
- 2023
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 115:6, s. 712-732
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.METHODS: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.RESULTS: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.CONCLUSIONS: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.
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| 43. |
- Mateos, Marion K., et al.
(författare)
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Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p < 5 × 10−8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 × 10−6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10−7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10−7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.
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| 44. |
- 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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| 45. |
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| 46. |
- Zhang, YD, et al.
(författare)
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Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 3353-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
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| 47. |
- Almqvist, E, et al.
(författare)
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Risk reversals in predictive testing for Huntington disease.
- 1997
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 61:4, s. 945-52
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Tidskriftsartikel (refereegranskat)abstract
- The first predictive testing for Huntington disease (HD) was based on analysis of linked polymorphic DNA markers to estimate the likelihood of inheriting the mutation for HD. Limits to accuracy included recombination between the DNA markers and the mutation, pedigree structure, and whether DNA samples were available from family members. With direct tests for the HD mutation, we have assessed the accuracy of results obtained by linkage approaches when requested to do so by the test individuals. For six such individuals, there was significant disparity between the tests. Three went from a decreased risk to an increased risk, while in another three the risk was decreased. Knowledge of the potential reasons for these changes in results and impact of these risk reversals on both patients and the counseling team can assist in the development of strategies for the prevention and, where necessary, management of a risk reversal in any predictive testing program.
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| 48. |
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| 49. |
- Ek, Weronica E, et al.
(författare)
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Germline genetic contributions to risk for esophageal adenocarcinoma, barrett's esophagus, and gastroesophageal reflux
- 2013
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 105:22, s. 1711-1718
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Tidskriftsartikel (refereegranskat)abstract
- Background Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA. Methods We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h2 g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were twosided, except in the case of variance-explained estimation where one-sided tests were used. Results We estimated a statistically significant genetic variance explained for BE (h2 g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10-9) and for EA (h2 g = 25 %; SE = 5%; one-sided P = 2 × 10-7). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10-6), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD. Conclusions We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases. © The Author 2013.
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| 50. |
- Ek, Weronica E, et al.
(författare)
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Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma
- 2016
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 138:5, s. 1146-1152
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Tidskriftsartikel (refereegranskat)abstract
- The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p=0.002) and in males (p=0.003), but not in females separately (p=0.3). This association was found in tobacco smokers (p=0.003) and in BE patients without reflux (p=0.004), but not in nonsmokers (p=0.2) or those with reflux (p=0.036). SNPs within JMJD1C were associated with risk of EAC in females (p=0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.
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