| 1. |
- Berndt, Sonja, I, et al.
(författare)
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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
- 2022
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Ingår i: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:12, s. 2835-2844
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Tidskriftsartikel (refereegranskat)abstract
- Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
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| 2. |
- Kaufman, Darrell, et al.
(författare)
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A global database of Holocene paleotemperature records
- 2020
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- A comprehensive database of paleoclimate records is needed to place recent warming into the longer-term context of natural climate variability. We present a global compilation of quality-controlled, published, temperature-sensitive proxy records extending back 12,000 years through the Holocene. Data were compiled from 679 sites where time series cover at least 4000 years, are resolved at sub-millennial scale (median spacing of 400 years or finer) and have at least one age control point every 3000 years, with cut-off values slackened in data-sparse regions. The data derive from lake sediment (51%), marine sediment (31%), peat (11%), glacier ice (3%), and other natural archives. The database contains 1319 records, including 157 from the Southern Hemisphere. The multi-proxy database comprises paleotemperature time series based on ecological assemblages, as well as biophysical and geochemical indicators that reflect mean annual or seasonal temperatures, as encoded in the database. This database can be used to reconstruct the spatiotemporal evolution of Holocene temperature at global to regional scales, and is publicly available in Linked Paleo Data (LiPD) format.
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| 3. |
- Sumaila, U. Rashid, et al.
(författare)
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WTO must ban harmful fisheries subsidies
- 2021
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Ahearn, Thomas U., et al.
(författare)
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Common variants in breast cancer risk loci predispose to distinct tumor subtypes
- 2022
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Ingår i: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.ConclusionThis report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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| 5. |
- Alimena, Juliette, et al.
(författare)
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Searching for long-lived particles beyond the Standard Model at the Large Hadron Collider
- 2020
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Ingår i: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 47:9
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Tidskriftsartikel (refereegranskat)abstract
- Particles beyond the Standard Model (SM) can generically have lifetimes that are long compared to SM particles at the weak scale. When produced at experiments such as the Large Hadron Collider (LHC) at CERN, these long-lived particles (LLPs) can decay far from the interaction vertex of the primary proton-proton collision. Such LLP signatures are distinct from those of promptly decaying particles that are targeted by the majority of searches for new physics at the LHC, often requiring customized techniques to identify, for example, significantly displaced decay vertices, tracks with atypical properties, and short track segments. Given their non-standard nature, a comprehensive overview of LLP signatures at the LHC is beneficial to ensure that possible avenues of the discovery of new physics are not overlooked. Here we report on the joint work of a community of theorists and experimentalists with the ATLAS, CMS, and LHCb experiments-as well as those working on dedicated experiments such as MoEDAL, milliQan, MATHUSLA, CODEX-b, and FASER-to survey the current state of LLP searches at the LHC, and to chart a path for the development of LLP searches into the future, both in the upcoming Run 3 and at the high-luminosity LHC. The work is organized around the current and future potential capabilities of LHC experiments to generally discover new LLPs, and takes a signature-based approach to surveying classes of models that give rise to LLPs rather than emphasizing any particular theory motivation. We develop a set of simplified models; assess the coverage of current searches; document known, often unexpected backgrounds; explore the capabilities of proposed detector upgrades; provide recommendations for the presentation of search results; and look towards the newest frontiers, namely high-multiplicity 'dark showers', highlighting opportunities for expanding the LHC reach for these signals.
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| 6. |
- Broekman, Maarten J. E., et al.
(författare)
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Evaluating expert-based habitat suitability information of terrestrial mammals with GPS-tracking data
- 2022
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 31:8, s. 1526-1541
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Macroecological studies that require habitat suitability data for many species often derive this information from expert opinion. However, expert-based information is inherently subjective and thus prone to errors. The increasing availability of GPS tracking data offers opportunities to evaluate and supplement expert-based information with detailed empirical evidence. Here, we compared expert-based habitat suitability information from the International Union for Conservation of Nature (IUCN) with habitat suitability information derived from GPS-tracking data of 1,498 individuals from 49 mammal species.Location: Worldwide.Time period: 1998-2021.Major taxa studied: Forty-nine terrestrial mammal species.Methods: Using GPS data, we estimated two measures of habitat suitability for each individual animal: proportional habitat use (proportion of GPS locations within a habitat type), and selection ratio (habitat use relative to its availability). For each individual we then evaluated whether the GPS-based habitat suitability measures were in agreement with the IUCN data. To that end, we calculated the probability that the ranking of empirical habitat suitability measures was in agreement with IUCN's classification into suitable, marginal and unsuitable habitat types.Results: IUCN habitat suitability data were in accordance with the GPS data (> 95% probability of agreement) for 33 out of 49 species based on proportional habitat use estimates and for 25 out of 49 species based on selection ratios. In addition, 37 and 34 species had a > 50% probability of agreement based on proportional habitat use and selection ratios, respectively.Main conclusions: We show how GPS-tracking data can be used to evaluate IUCN habitat suitability data. Our findings indicate that for the majority of species included in this study, it is appropriate to use IUCN habitat suitability data in macroecological studies. Furthermore, we show that GPS-tracking data can be used to identify and prioritize species and habitat types for re-evaluation of IUCN habitat suitability data.
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| 7. |
- Middha, Pooja K., et al.
(författare)
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A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry
- 2023
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Ingår i: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411 .- 1465-542X. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Genome-wide studies of gene-environment interactions (GxE) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide GxE analysis of similar to 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 x 10(-5) prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). Conclusions Overall, the contribution of GxE interactions to the heritability of breast cancer is very small. At the population level, multiplicative GxE interactions do not make an important contribution to risk prediction in breast cancer.
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| 8. |
- Moore, Amy, et al.
(författare)
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Genetically Determined Height and Risk of Non-hodgkin Lymphoma
- 2020
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Ingår i: Frontiers in Oncology. - : FRONTIERS MEDIA SA. - 2234-943X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.
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| 9. |
- Sims, John R., et al.
(författare)
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Donanemab in Early Symptomatic Alzheimer Disease : The TRAILBLAZER-ALZ 2 Randomized Clinical Trial
- 2023
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Ingår i: JAMA. - 0098-7484. ; 330:6, s. 512-527
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Tidskriftsartikel (refereegranskat)abstract
- Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of.04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P <.001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P <.001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P <.001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P <.001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration: ClinicalTrials.gov Identifier: NCT04437511.
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| 10. |
- Wang, Xiaoliang, et al.
(författare)
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Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women
- 2022
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 x 10(-8) as genome-wide significant, and p-values < 1 x 10(-5) as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 x 10(5). The strongest evidence was found for rs4674019 (p-value = 2.27 x 10(-7)), which showed genome-wide significant interaction (p-value = 3.8 x 10(-8)) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.
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