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| 4. |
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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- 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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| 9. |
- Zhou, Wei, et al.
(författare)
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Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease
- 2022
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Ingår i: Cell Genomics. - : Elsevier. - 2666-979X. ; 2:10
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Tidskriftsartikel (refereegranskat)abstract
- Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
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| 11. |
- 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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| 12. |
- 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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| 13. |
- 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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| 14. |
- 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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| 15. |
- Su, Zhan, et al.
(författare)
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Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)abstract
- Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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| 16. |
- 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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| 20. |
- 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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| 26. |
- 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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| 27. |
- Barrett, Jennifer H., et al.
(författare)
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Genome-wide association study identifies three new melanoma susceptibility loci
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1108-1113
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 x 10(-9)), an SNP in MX2 (rs45430, P = 2.9 x 10-9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 x 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 x 10(-7) under a fixed-effects model and P = 1.2 x 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.
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| 28. |
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| 30. |
- 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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| 31. |
- 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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| 33. |
- Lagergren, K., et al.
(författare)
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Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett's Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- Background The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett's oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute. This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS). Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only. Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.
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| 34. |
- MacGregor, Stuart, et al.
(författare)
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Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1114-1118
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Tidskriftsartikel (refereegranskat)abstract
- We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 x 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 x 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.
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| 35. |
- 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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| 36. |
- 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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| 37. |
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| 38. |
- Iles, Mark M., et al.
(författare)
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A variant in FTO shows association with melanoma risk not due to BMI
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:4, s. 428-432
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Tidskriftsartikel (refereegranskat)abstract
- We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 x 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanomasusceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
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| 39. |
- Levine, David M, et al.
(författare)
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A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:12
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Tidskriftsartikel (refereegranskat)abstract
- Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.
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| 40. |
- Purcell, Shaun M., et al.
(författare)
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Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 460:7256, s. 748-752
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
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| 41. |
- Suggitt, Andrew J., et al.
(författare)
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Extinction risk from climate change is reduced by microclimatic buffering
- 2018
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Ingår i: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 8:8, s. 713-
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Tidskriftsartikel (refereegranskat)abstract
- Protecting biodiversity against the impacts of climate change requires effective conservation strategies that safeguard species at risk of extinction(1). Microrefugia allowed populations to survive adverse climatic conditions in the past(2,3), but their potential to reduce extinction risk from anthropogenic warming is poorly understood(3-5), hindering our capacity to develop robust in situ measures to adapt conservation to climate change(6). Here, we show that microclimatic heterogeneity has strongly buffered species against regional extirpations linked to recent climate change. Using more than five million distribution records for 430 climate-threatened and range-declining species, population losses across England are found to be reduced in areas where topography generated greater variation in the microclimate. The buffering effect of topographic microclimates was strongest for those species adversely affected by warming and in areas that experienced the highest levels of warming: in such conditions, extirpation risk was reduced by 22% for plants and by 9% for insects. Our results indicate the critical role of topographic variation in creating microrefugia, and provide empirical evidence that microclimatic heterogeneity can substantially reduce extinction risk from climate change.
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| 42. |
- Axelson, Olav, 1937-, et al.
(författare)
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Regulatory toxicology and pharmacology.
- 2003
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Ingår i: International journal of occupational and environmental health. - 1077-3525 .- 2049-3967. ; 9, s. 386-389
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Tidskriftsartikel (refereegranskat)
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| 43. |
- Brown, Kevin M., et al.
(författare)
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Common sequence variants on 20q11.22 confer melanoma susceptibility
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:7, s. 838-840
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.
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| 44. |
- 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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| 45. |
- 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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| 46. |
- Kenny, Gavin G., et al.
(författare)
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A Late Paleocene age for Greenland’s Hiawatha impact structure
- 2022
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- The ~31-km-wide Hiawatha structure, located beneath Hiawatha Glacier in northwestern Greenland, has been proposed as an impact structure that may have formed after the Pleistocene inception of the Greenland Ice Sheet. To date the structure, we conducted 40Ar/39Ar analyses on glaciofluvial sand and U-Pb analyses on zircon separated from glaciofluvial pebbles of impact melt rock, all sampled immediately downstream of Hiawatha Glacier. Unshocked zircon in the impact melt rocks dates to ~1915 million years (Ma), consistent with felsic intrusions found in local bedrock. The 40Ar/39Ar data indicate Late Paleocene resetting and shocked zircon dates to 57.99 ± 0.54 Ma, which we interpret as the impact age. Consequently, the Hiawatha impact structure far predates Pleistocene glaciation and is unrelated to either the Paleocene-Eocene Thermal Maximum or flood basalt volcanism in east Greenland. However, it was contemporaneous with the Paleocene Carbon Isotope Maximum, although the impact’s exact paleoenvironmental and climatic significance awaits further investigation.
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| 47. |
- 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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| 48. |
- Thrift, Aaron P, et al.
(författare)
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Obesity and risk of esophageal adenocarcinoma and Barrett's esophagus : a Mendelian randomization study.
- 2014
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 106:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). However, the relationships may be affected by bias and confounding.METHODS: We used data from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided.RESULTS: The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m(2) increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses.CONCLUSIONS: People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.
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| 49. |
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| 50. |
- 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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