| 1. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 2. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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| 3. |
- Huyghe, Jeroen R, et al.
(författare)
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Genetic architectures of proximal and distal colorectal cancer are partly distinct
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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| 4. |
- Thomas, Minta, et al.
(författare)
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Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
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| 5. |
- Wang, Anqi, et al.
(författare)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Tidskriftsartikel (refereegranskat)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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| 6. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Aad, G., et al.
(författare)
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A search for heavy Higgs bosons decaying into vector bosons in same-sign two-lepton final states in pp collisions at √s=13 TeV with the ATLAS detector
- 2023
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Ingår i: Journal of High Energy Physics (JHEP). - : Springer Nature. - 1126-6708 .- 1029-8479. ; 2023:7
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Tidskriftsartikel (refereegranskat)abstract
- A search for heavy Higgs bosons produced in association with a vector boson and decaying into a pair of vector bosons is performed in final states with two leptons (electrons or muons) of the same electric charge, missing transverse momentum and jets. A data sample of proton–proton collisions at a centre-of-mass energy of 13 TeV recorded with the ATLAS detector at the Large Hadron Collider between 2015 and 2018 is used. The data correspond to a total integrated luminosity of 139 fb−1. The observed data are in agreement with Standard Model background expectations. The results are interpreted using higher-dimensional operators in an effective field theory. Upper limits on the production cross-section are calculated at 95% confidence level as a function of the heavy Higgs boson’s mass and coupling strengths to vector bosons. Limits are set in the Higgs boson mass range from 300 to 1500 GeV, and depend on the assumed couplings. The highest excluded mass for a heavy Higgs boson with the coupling combinations explored is 900 GeV. Limits on coupling strengths are also provided.
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| 8. |
- Aad, G, et al.
(författare)
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Alignment of the ATLAS Inner Detector in Run 2
- 2020
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 80:12
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Tidskriftsartikel (refereegranskat)abstract
- The performance of the ATLAS Inner Detector alignment has been studied using pp collision data at s=13TeV collected by the ATLAS experiment during Run 2 (2015–2018) of the Large Hadron Collider (LHC). The goal of the detector alignment is to determine the detector geometry as accurately as possible and correct for time-dependent movements. The Inner Detector alignment is based on the minimization of track-hit residuals in a sequence of hierarchical levels, from global mechanical assembly structures to local sensors. Subsequent levels have increasing numbers of degrees of freedom; in total there are almost 750,000. The alignment determines detector geometry on both short and long timescales, where short timescales describe movements within an LHC fill. The performance and possible track parameter biases originating from systematic detector deformations are evaluated. Momentum biases are studied using resonances decaying to muons or to electrons. The residual sagitta bias and momentum scale bias after alignment are reduced to less than ∼0.1TeV-1 and 0.9 × 10 - 3, respectively. Impact parameter biases are also evaluated using tracks within jets. © 2020, The Author(s).
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| 9. |
- Aad, G., et al.
(författare)
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Anomaly detection search for new resonances decaying into a Higgs boson and a generic new particle X in hadronic final states using √s=13 TeV pp collisions with the ATLAS detector
- 2023
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Ingår i: Physical Review D. - : AMER PHYSICAL SOC. - 2470-0010 .- 2470-0029. ; 108:5
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Tidskriftsartikel (refereegranskat)abstract
- A search is presented for a heavy resonance Y decaying into a Standard Model Higgs boson H and a new particle X in a fully hadronic final state. The full Large Hadron Collider run 2 dataset of proton-proton collisions at √s=13 TeV collected by the ATLAS detector from 2015 to 2018 is used and corresponds to an integrated luminosity of 139 fb−1. The search targets the high Y-mass region, where the H and X have a significant Lorentz boost in the laboratory frame. A novel application of anomaly detection is used to define a general signal region, where events are selected solely because of their incompatibility with a learned background-only model. It is constructed using a jet-level tagger for signal-model-independent selection of the boosted X particle, representing the first application of fully unsupervised machine learning to an ATLAS analysis. Two additional signal regions are implemented to target a benchmark X decay into two quarks, covering topologies where the X is reconstructed as either a single large-radius jet or two small-radius jets. The analysis selects Higgs boson decays into , and a dedicated neural-network-based tagger provides sensitivity to the boosted heavy-flavor topology. No significant excess of data over the expected background is observed, and the results are presented as upper limits on the production cross section for signals with mY between 1.5 and 6 TeV and mX between 65 and 3000 GeV.
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| 10. |
- Aad, G, et al.
(författare)
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ATLAS data quality operations and performance for 2015-2018 data-taking
- 2020
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Ingår i: Journal of Instrumentation. - : Institute of Physics Publishing (IOPP). - 1748-0221. ; 15:4
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Tidskriftsartikel (refereegranskat)abstract
- The ATLAS detector at the Large Hadron Collider reads out particle collision data from over 100 million electronic channels at a rate of approximately 100 kHz, with a recording rate for physics events of approximately 1 kHz. Before being certified for physics analysis at computer centres worldwide, the data must be scrutinised to ensure they are clean from any hardware or software related issues that may compromise their integrity. Prompt identification of these issues permits fast action to investigate, correct and potentially prevent future such problems that could render the data unusable. This is achieved through the monitoring of detector-level quantities and reconstructed collision event characteristics at key stages of the data processing chain. This paper presents the monitoring and assessment procedures in place at ATLAS during 2015-2018 data-taking. Through the continuous improvement of operational procedures, ATLAS achieved a high data quality efficiency, with 95.6% of the recorded proton-proton collision data collected at s=13 TeV certified for physics analysis.
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