| 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. |
- Freitag, Daniel F., et al.
(författare)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 4. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 5. |
- Cornish, Alex J., et al.
(författare)
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The genomic landscape of 2,023 colorectal cancers
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 633:8028, s. 127-136
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2–9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichiacolipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11–13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.
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| 6. |
- Li, Wanxin, et al.
(författare)
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Exploring the Complex Relationship between Gut Microbiota and Risk of Colorectal Neoplasia Using Bidirectional Mendelian Randomization Analysis
- 2023
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association For Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 32:6, s. 809-817
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Tidskriftsartikel (refereegranskat)abstract
- Background: Human gut microbiome has complex relation-ships with the host, contributing to metabolism, immunity, and carcinogenesis.Methods: Summary-level data for gut microbiota and metabo-lites were obtained from MiBioGen, FINRISK and human meta-bolome consortia. Summary-level data for colorectal cancer were derived from a genome-wide association study meta-analysis. In forward Mendelian randomization (MR), we employed genetic instrumental variables (IV) for 24 gut microbiota taxa and six bacterial metabolites to examine their causal relationship with colorectal cancer. We also used a lenient threshold for nine apriori gut microbiota taxa as secondary analyses. In reverse MR, we explored association between genetic liability to colorectal neoplasia and abundance of microbiota studied above using 95, 19, and 7 IVs for colorectal cancer, adenoma, and polyps, respectively.Results: Forward MR did not find evidence indicating causal relationship between any of the gut microbiota taxa or six bacterial metabolites tested and colorectal cancer risk. However, reverse MR supported genetic liability to colorectal adenomas was causally related with increased abundance of two taxa: Gammaproteobacteria (b = 0.027, which represents a 0.027 increase in log-transformed relative abundance values of Gam-maproteobacteria for per one-unit increase in log OR of adenoma risk; P = 7.06x10-8), Enterobacteriaceae (b = 0.023, P = 1.29x10-5).Conclusions: We find genetic liability to colorectal neoplasia may be associated with abundance of certain microbiota taxa. It is more likely that subset of colorectal cancer genetic liability variants changes gut biology by influencing both gut microbiota and colo-rectal cancer risk.Impact: This study highlights the need of future complemen-tary studies to explore causal mechanisms linking both host genetic variation with gut microbiome and colorectal cancer susceptibility.
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| 7. |
- 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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| 8. |
- Schmidt, Amand F., et al.
(författare)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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| 9. |
- 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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| 10. |
- Thompson, Deborah J, et al.
(författare)
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Genetic predisposition to mosaic Y chromosome loss in blood
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 575, s. 652-657
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Tidskriftsartikel (refereegranskat)abstract
- Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
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