Showing papers by "Wellcome Trust Centre for Human Genetics published in 2019"
Nasim Mavaddat1, Kyriaki Michailidou2, Kyriaki Michailidou1, Joe Dennis1 +307 more•Institutions (105)
TL;DR: This PRS, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset is developed and empirically validated and is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
653 citations
TL;DR: Evidence of a causal effect of the gut microbiome on metabolic traits is shown and the use of MR is supported as a means to elucidate causal relationships from microbiome-wide association findings.
Abstract: Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity1. However, the causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available2, then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Using bidirectional Mendelian randomization (MR) analyses to assess causality3, we found that the host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test (P = 9.8 × 10-5), whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D (P = 0.004). These data provide evidence of a causal effect of the gut microbiome on metabolic traits and support the use of MR as a means to elucidate causal relationships from microbiome-wide association findings.
631 citations
University of Oxford1, Broad Institute2, Utrecht University3, University of Exeter4, Wellcome Trust Centre for Human Genetics5, University of Liverpool6, University of Queensland7, Queen Mary University of London8, Harvard University9, University of Regensburg10, Icahn School of Medicine at Mount Sinai11
TL;DR: A genome‐wide association study meta‐analysis of body fat distribution, measured by waist‐to‐hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci found heritability and variant effects were generally stronger in women than men, and one‐third of all signals to be sexually dimorphic.
Abstract: More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.
580 citations
Vanderbilt University Medical Center1, Vanderbilt University2, University of Pennsylvania3, Queen Mary University of London4, National Institute for Health Research5, Veterans Health Administration6, Emory University7, VA Boston Healthcare System8, Imperial College London9, University of Ioannina10, University of Leicester11, University of Bordeaux12, University of Michigan13, University of Cambridge14, McMaster University15, University of Dundee16, COMSATS Institute of Information Technology17, University of Newcastle18, Lund University19, Leiden University Medical Center20, University Medical Center Groningen21, University of Edinburgh22, King's College London23, Guy's and St Thomas' NHS Foundation Trust24, University of Texas Health Science Center at Houston25, University of Liverpool26, Broad Institute27, Boston University28, University of London29, University of Bristol30, Washington University in St. Louis31, university of lille32, Wellcome Trust Centre for Human Genetics33, University of Eastern Finland34, Wellcome Trust Sanger Institute35, National Institutes of Health36, Population Health Research Institute37, Brigham and Women's Hospital38, University of Sassari39, Wellcome Trust40, University of Oxford41, Harokopio University42, University of Washington43, Harvard University44, VA Palo Alto Healthcare System45, Stanford University46
TL;DR: Analysis of blood pressure data from the Million Veteran Program trans-ethnic cohort identifies common and rare variants, and genetically predicted gene expression across multiple tissues associated with systolic, diastolic and pulse pressure in over 775,000 individuals.
Abstract: In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
310 citations
University of Leicester1, University of Melbourne2, Walter and Eliza Hall Institute of Medical Research3, Brigham and Women's Hospital4, GlaxoSmithKline5, Mahidol University6, University of Arizona7, University of Oxford8, University of British Columbia9, University of Cambridge10, Imperial College London11, Greifswald University Hospital12, University of Edinburgh13, University of Liverpool14, Sir Charles Gairdner Hospital15, Swiss Tropical and Public Health Institute16, Science for Life Laboratory17, University of Helsinki18, University of Tampere19, University of Bergen20, Johns Hopkins University21, Laval University22, University Medical Center Groningen23, Icahn School of Medicine at Mount Sinai24, Anschutz Medical Campus25, Peking University26, Uppsala University27, Wellcome Trust Centre for Human Genetics28, Merck & Co.29, University of Aberdeen30, University of Münster31, University of Nottingham32, University of Dundee33, Autonomous University of Barcelona34, VA Boston Healthcare System35, University of California, San Francisco36, Princeton University37, Turku University Hospital38, University of Split39, University of Basel40, University of Western Australia41, Wellcome Trust Sanger Institute42, St George's, University of London43, National Institute for Health Research44
TL;DR: In this paper, a genome-wide association study in 400,102 individuals of European ancestry was conducted to define 279 lung function signals, 139 of which are new and the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups.
Abstract: Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
295 citations
TL;DR: A trans-ancestry genome-wide association study of serum urate levels identifies 183 loci that improve the prediction of gout in an independent cohort of 334,880 individuals, and implicates the kidney and liver as key target organs and prioritize potential causal genes.
Abstract: Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
214 citations
TL;DR: This work indexed the entire global corpus of 447,833 bacterial and viral whole-genome sequence datasets using four orders of magnitude less storage than previous methods and produced a searchable data structure named BItsliced Genomic Signature Index (BIGSI).
Abstract: Exponentially increasing amounts of unprocessed bacterial and viral genomic sequence data are stored in the global archives. The ability to query these data for sequence search terms would facilitate both basic research and applications such as real-time genomic epidemiology and surveillance. However, this is not possible with current methods. To solve this problem, we combine knowledge of microbial population genomics with computational methods devised for web search to produce a searchable data structure named BItsliced Genomic Signature Index (BIGSI). We indexed the entire global corpus of 447,833 bacterial and viral whole-genome sequence datasets using four orders of magnitude less storage than previous methods. We applied our BIGSI search function to rapidly find resistance genes MCR-1, MCR-2, and MCR-3, determine the host-range of 2,827 plasmids, and quantify antibiotic resistance in archived datasets. Our index can grow incrementally as new (unprocessed or assembled) sequence datasets are deposited and can scale to millions of datasets. The global set of bacterial and viral sequences can be rapidly searched using a data structure inspired by web-search algorithms.
124 citations
TL;DR: The current study suggests that prevalence of LS in EC patients is approximately 3%, similar to that of colorectal cancer patients; therefore the data support the implementation of universal EC screening for LS.
122 citations
Imperial College London1, Swiss Tropical and Public Health Institute2, University of Basel3, University of London4, Karolinska Institutet5, Walter and Eliza Hall Institute of Medical Research6, University of Notre Dame7, University of Melbourne8, Pasteur Institute9, Radboud University Nijmegen10, Addis Ababa University11, PATH12, Wellcome Trust Centre for Human Genetics13, University of Oxford14, University of Health and Allied Sciences15, University of Paris16, University of the Sciences17, University of Ghana18, Centers for Disease Control and Prevention19, National Institute for Medical Research20, University of California, San Francisco21, Dar es Salaam University College of Education22, University of Edinburgh23, Mahidol University24
TL;DR: Results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.
Abstract: Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.
121 citations
TL;DR: The authors reveal the impact of BRCA2 depletion on the cell transcriptional program with activation of the innate immune response that is potentiated by PARP inhibitor treatments.
Abstract: Heterozygous germline mutations in BRCA2 predispose to breast and ovarian cancer. Contrary to non-cancerous cells, where BRCA2 deletion causes cell cycle arrest or cell death, tumors carrying BRCA2 inactivation continue to proliferate. Here we set out to investigate adaptation to loss of BRCA2 focusing on genome-wide transcriptome alterations. Human cells in which BRCA2 expression is inhibited for 4 or 28 days are subjected to RNA-seq analyses revealing a biphasic response to BRCA2 abrogation. The early, acute response consists of downregulation of genes involved in cell cycle progression, DNA replication and repair and is associated with cell cycle arrest in G1. Surprisingly, the late, chronic response consists predominantly of upregulation of interferon-stimulated genes (ISGs). Activation of the cGAS-STING-STAT pathway detected in these cells further substantiates the concept that BRCA2 abrogation triggers cell-intrinsic immune signaling. Importantly, we find that treatment with PARP inhibitors stimulates the interferon response in cells and tumors lacking BRCA2.
120 citations
TL;DR: The authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies, which generate a priority list of genes and pathways for translational research to reduce albuminuria.
Abstract: Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
TL;DR: Profiling of deregulated miRNAs in pancreatic cancer can correlate to diagnosis, indicate optimal treatment and predict response to therapy, and understanding the main effector genes in pancreatIC cancer along with downstream pathways can identify possible mi RNAs as therapeutic candidates.
Abstract: A severe lack of early diagnosis coupled with resistance to most available therapeutic options renders pancreatic cancer as a major clinical concern. The limited efficacy of current treatments necessitates the development of novel therapeutic strategies that are based on an understanding of the molecular mechanisms involved in pancreatic cancer progression. MicroRNAs (miRNAs) are non-coding small RNAs that regulate the expression of multiple proteins in the post-translation process and thus have promise as biomarkers, prognostic agents, and as advanced pancreatic therapies. Profiling of deregulated miRNAs in pancreatic cancer can correlate to diagnosis, indicate optimal treatment and predict response to therapy. Furthermore, understanding the main effector genes in pancreatic cancer along with downstream pathways can identify possible miRNAs as therapeutic candidates. Additionally, obstacles to the translation of miRNAs into the clinic are also considered. Distinct miRNA expression profiles can correlate to stages of malignant pancreatic disease, and hold potential as biomarkers, prognostic markers and clinical targets. However, a limited understanding and validation of the specific role of such miRNAs stunts clinical application. Target prediction using algorithms provides a wide range of possible targets, but these miRNAs still require validation through pre-clinical studies to determine the knock-on genetic effects.
Wellcome Trust Centre for Human Genetics1, University of Liverpool2, University of Virginia3, Washington University in St. Louis4, University of Manchester5, University Medical Center Groningen6, University of Bristol7, University of California, San Diego8, Icahn School of Medicine at Mount Sinai9, Mexican Social Security Institute10, University of Miami11, UCLA Medical Center12, Fred Hutchinson Cancer Research Center13, University of Washington14, QIMR Berghofer Medical Research Institute15, Karolinska Institutet16, Dalarna University17, University of Southern California18, Federation University Australia19, University of Leicester20, University of Melbourne21, Fu Jen Catholic University22, Erasmus University Medical Center23, Columbia University24, Uppsala University25, University of California, Los Angeles26, Loyola University Medical Center27, Broad Institute28, University of Queensland29, University of California, Irvine30, Jackson Memorial Hospital31, University of Düsseldorf32, Kaiser Permanente33, Stanford University34, University of North Carolina at Chapel Hill35, Osaka University36, University of Tokyo37, York University38
TL;DR: Trans-ethnic genome-wide meta-analyses for eGFR in 312,468 individuals are performed and novel loci and downstream putative causal genes are identified, offering insight into clinical outcomes and routes to CKD treatment development.
Abstract: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
TL;DR: The findings indicated that TGFβ plays a noncanonical role in coordinating immune responses against human tumors and suggest a potential role for CXCL13+CD103+CD8+ TILs in mediating B-cell recruitment and TLS formation in human tumors.
Abstract: The chemokine CXCL13 mediates recruitment of B cells to tumors and is essential for the formation of tertiary lymphoid structures (TLSs). TLSs are thought to support antitumor immunity and are associated with improved prognosis. However, it remains unknown whether TLSs are formed in response to the general inflammatory character of the tumor microenvironment, or rather, are induced by (neo)antigen-specific adaptive immunity. We here report on the finding that the TGFβ-dependent CD103+CD8+ tumor-infiltrating T-cell (TIL) subpopulation expressed and produced CXCL13. Accordingly, CD8+ T cells from peripheral blood activated in the presence of TGFβ upregulated CD103 and secreted CXCL13. Conversely, inhibition of TGFβ receptor signaling abrogated CXCL13 production. CXCL13+CD103+CD8+ TILs correlated with B-cell recruitment, TLSs, and neoantigen burden in six cohorts of human tumors. Altogether, our findings indicated that TGFβ plays a noncanonical role in coordinating immune responses against human tumors and suggest a potential role for CXCL13+CD103+CD8+ TILs in mediating B-cell recruitment and TLS formation in human tumors.
Radboud University Nijmegen1, Leiden University Medical Center2, Wellcome Trust Centre for Human Genetics3, University of Würzburg4, University of Bonn5, Peter MacCallum Cancer Centre6, University of Melbourne7, Saints Cyril and Methodius University of Skopje8, Leeds Teaching Hospitals NHS Trust9, Ohio State University10, Norwegian University of Science and Technology11, Haukeland University Hospital12, University Medical Center Groningen13, Dresden University of Technology14, Pomeranian Medical University15, McGill University16, University of Leeds17
TL;DR: NTHL1 is revealed as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.
TL;DR: A genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers of European ancestry provides an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P
TL;DR: It is demonstrated that VPS13A is a peripheral membrane protein, associated with mitochondria, the endoplasmic reticulum and lipid droplets, and required for lipid transfer required for mitochondria and lipid Droplet related processes.
Abstract: The VPS13A gene is associated with the neurodegenerative disorder Chorea Acanthocytosis. It is unknown what the consequences are of impaired function of VPS13A at the subcellular level. We demonstrate that VPS13A is a peripheral membrane protein, associated with mitochondria, the endoplasmic reticulum and lipid droplets. VPS13A is localized at sites where the endoplasmic reticulum and mitochondria are in close contact. VPS13A interacts with the ER residing protein VAP-A via its FFAT domain. Interaction with mitochondria is mediated via its C-terminal domain. In VPS13A-depleted cells, ER-mitochondria contact sites are decreased, mitochondria are fragmented and mitophagy is decreased. VPS13A also localizes to lipid droplets and affects lipid droplet motility. In VPS13A-depleted mammalian cells lipid droplet numbers are increased. Our data, together with recently published data from others, indicate that VPS13A is required for establishing membrane contact sites between various organelles to enable lipid transfer required for mitochondria and lipid droplet related processes.
TL;DR: Data show a correlation between αSyn cellular pathology and deficits in metabolic and cellular bioenergetics in the pathology of PD.
Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorder and a central role for α-synuclein (αSyn; SNCA) in disease aetiology has been proposed based on genetics and neuropathology. To better understand the pathological mechanisms of αSyn, we generated induced pluripotent stem cells (iPSCs) from healthy individuals and PD patients carrying the A53T SNCA mutation or a triplication of the SNCA locus and differentiated them into dopaminergic neurons (DAns). iPSC-derived DAn from PD patients carrying either mutation showed increased intracellular αSyn accumulation, and DAns from patients carrying the SNCA triplication displayed oligomeric αSyn pathology and elevated αSyn extracellular release. Transcriptomic analysis of purified DAns revealed perturbations in expression of genes linked to mitochondrial function, consistent with observed reduction in mitochondrial respiration, impairment in mitochondrial membrane potential, aberrant mitochondrial morphology and decreased levels of phosphorylated DRP1Ser616. Parkinson's iPSC-derived DAns showed increased endoplasmic reticulum stress and impairments in cholesterol and lipid homeostasis. Together, these data show a correlation between αSyn cellular pathology and deficits in metabolic and cellular bioenergetics in the pathology of PD.
TL;DR: This paper dissected the evolutionary history of colorectal cancer using multiregion sequencing and reconstructed the temporal sequence of events leading to CA-CRC using phylogenetic trees.
Abstract: Objective IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing. Design Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC. Results 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated ‘catastrophic’ CNA increase. Conclusions Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.
19 Feb 2019
TL;DR: A new molecular mechanism is uncovered, by which the CRC cells display differences in resistance to chemotherapy and metastatic potential, which is uncovers.
Abstract: Colorectal cancer (CRC) patients develop recurrence after chemotherapy owing to the survival of stem cell-like cells referred to as cancer stem-like cells (CSCs). The origin of CSCs is linked to the epithelial-mesenchymal transition (EMT) process. Currently, it remains poorly understood how EMT programmes enable CSCs residing in the tumour microenvironment to escape the effects of chemotherapy. This study identifies a key molecular pathway that is responsible for the formation of drug-resistant CSC populations. Using a modified yeast-2-hybrid system and 2D gel-based proteomics methods, we show that the E3-ubiquitin ligase FBXW7 directly binds and degrades the EMT-inducing transcription factor ZEB2 in a phosphorylation-dependent manner. Loss of FBXW7 induces an EMT that can be effectively reversed by knockdown of ZEB2. The FBXW7-ZEB2 axis regulates such important cancer cell features, as stemness/dedifferentiation, chemoresistance and cell migration in vitro, ex vivo and in animal models of metastasis. High expression of ZEB2 in cancer tissues defines the reduced ZEB2 expression in the cancer-associated stroma in patients and in murine intestinal organoids, demonstrating a tumour-stromal crosstalk that modulates a niche and EMT activation. Our study thus uncovers a new molecular mechanism, by which the CRC cells display differences in resistance to chemotherapy and metastatic potential.
TL;DR: It is shown that illumination of gold salt solutions with circularly polarized light induces the formation of NPs and their subsequent assembly into chiral nanostructures 10-15 nm in diameter, and the resulting nanocolloids showed circular dichroism (CD) spectra with opposite polarity after exposure to photons with left and right circular polarization.
Abstract: Photon-to-matter chirality transfer offers both simplicity and universality to chiral synthesis, but its efficiency is typically low for organic compounds. Besides the fundamental importance of thi...
National Institutes of Health1, University of Amsterdam2, University of Florence3, Imperial College London4, University of Michigan5, Stanford University6, Boston Children's Hospital7, Erasmus University Rotterdam8, University of São Paulo9, Yale University10, Brigham and Women's Hospital11, University of Oxford12, Churchill Hospital13, Wellcome Trust Centre for Human Genetics14
TL;DR: Novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a “likely pathogenic” classification, even without additional segregation or functional data, and proposed adaptations to ACMG/AMP guidelines are proposed.
Abstract: International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework. We compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts (up to 6179 cases) to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). We analysed the distribution of variants using a bespoke unsupervised clustering algorithm to identify gene regions in which variants are significantly clustered in cases. Analysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF ≥ 0.95 were identified in five established HCM genes. Applying this approach leads to an estimated 14–20% increase in cases with actionable HCM variants, i.e. variants classified as pathogenic/likely pathogenic that might be used for predictive testing in probands’ relatives. When found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a “likely pathogenic” classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consistent and unbiased approach to variant interpretation for Mendelian disease genetic testing. We propose adaptations to ACMG/AMP guidelines to incorporate such evidence in a quantitative and transparent manner.
TL;DR: In this paper, the authors used genomic inbreeding coefficients (FROH) for >1.4 million individuals and found that FROH is significantly associated with apparently deleterious changes in 32 out of 100 traits analysed.
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
Max Planck Society1, Ludwig Maximilian University of Munich2, University of Bonn3, University of Bristol4, University of California, San Diego5, Hungarian Academy of Sciences6, Institut de Physique du Globe de Paris7, Pasteur Institute8, Wellcome Trust Centre for Human Genetics9, University of Colorado Boulder10, University of Nebraska Medical Center11, University of Denver12, Maastricht University13, The Chinese University of Hong Kong14, University of Jyväskylä15, Karolinska Institutet16, University of Zurich17, Heidelberg University18, University of Oxford19, Aston University20, Fraunhofer Society21, Radboud University Nijmegen22, Tufts University23, University of Graz24, King's College London25, University of St Andrews26, University of Liverpool27
TL;DR: A genome-wide association study of reading-impaired and typically developing children of European ancestry and polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD.
Abstract: Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
University College London1, Wellcome Trust Sanger Institute2, University of Oxford3, Clinical Trial Service Unit4, King's College London5, Wellcome Trust Centre for Human Genetics6, University of London7, Uganda Virus Research Institute8, Karolinska Institutet9, Peking Union Medical College10, University of Essex11, National and Kapodistrian University of Athens12, Peking University13, University of Cambridge14
TL;DR: It is found that the major lipid loci are mostly transferrable between Europeans and Asians while there are notable exceptions for African populations.
Abstract: Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r = 0.23–0.28, p < 1.9 × 10−14). Overall, there is evidence of reproducibility for ~75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions. The majority of published GWAS was performed in European ancestry populations. Here, Kuchenbaecker et al., test to which extent lipid loci are shared and find that the major lipid loci are mostly transferrable between Europeans and Asians while there are notable exceptions for African populations.
TL;DR: A disease model of human myocardial fibrosis is presented and a heteropolar integrated model with fibrotic and healthy cardiac tissues coupled together is constructed with the utility of the system for the evaluation of antifibrotic compounds demonstrated.
Abstract: Myocardial fibrosis is a severe global health problem due to its prevalence in all forms of cardiac diseases and direct role in causing heart failure. The discovery of efficient antifibrotic compou...
TL;DR: Cryo-electron tomography (cryoET) subtomogram averaging has emerged as a structural biology method for sparse and heterogenerous sampls and can delineate different conformational states of macromolecular complexes.
TL;DR: The genetic structure of the modern Iberian population is analysed at fine scale, revealing historical population movements associated with the time of Muslim rule and the subsequent Reconquista.
Abstract: The Iberian Peninsula is linguistically diverse and has a complex demographic history, including a centuries-long period of Muslim rule. Here, we study the fine-scale genetic structure of its population, and the genetic impacts of historical events, leveraging powerful, haplotype-based statistical methods to analyse 1413 individuals from across Spain. We detect extensive fine-scale population structure at extremely fine scales (below 10 Km) in some regions, including Galicia. We identify a major east-west axis of genetic differentiation, and evidence of historical north to south population movement. We find regionally varying fractions of north-west African ancestry (0–11%) in modern-day Iberians, related to an admixture event involving European-like and north-west African-like source populations. We date this event to 860–1120 CE, implying greater genetic impacts in the early half of Muslim rule in Iberia. Together, our results indicate clear genetic impacts of population movements associated with both the Muslim conquest and the subsequent Reconquista.
Amgen1, University of Iceland2, Erasmus University Rotterdam3, Wellcome Trust Centre for Human Genetics4, Wellcome Trust Sanger Institute5, The Chinese University of Hong Kong6, Alice Ho Miu Ling Nethersole Hospital7, University of Ulsan8, Lund University9, Ton Duc Thang University10, Garvan Institute of Medical Research11, University of Technology, Sydney12, University of New South Wales13, Newcastle University14, Health Science University15
TL;DR: 12 loci in a GWAS for bone area derived from DXA scans are identified and it is shown that these loci associate with other bone-related phenotypes including osteoarthritis, height, bone mineral density and risk of hip fracture.
Abstract: Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 – 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10−42, β = −0.090) and confers risk of hip fracture (P = 1.0 × 10−8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density. Size and shape of bones are important for height and body shape. Here, Styrkarsdottir et al identify 12 loci in a GWAS for bone area derived from DXA scans and show that these loci associate with other bone-related phenotypes including osteoarthritis, height, bone mineral density and risk of hip fracture.
TL;DR: Cryogenic super-resolution optical fluctuation imaging (cryo-SOFI), a low-dose super- resolution imaging scheme based on the SOFI principle, is introduced, which presents a general solution to the problem of specimen devitrification in super- Resolution cryo-CLEM.
Abstract: Correlative light and electron cryo-microscopy (cryo-CLEM) combines information from the specific labeling of fluorescence cryo-microscopy (cryo-FM) with the high resolution in environmental context of electron cryo-microscopy (cryo-EM). Exploiting super-resolution methods for cryo-FM is advantageous, as it enables the identification of rare events within the environmental background of cryo-EM at a sensitivity and resolution beyond that of conventional methods. However, due to the need for relatively high laser intensities, current super-resolution cryo-CLEM methods require cryo-protectants or support films which can severely reduce image quality in cryo-EM and are not compatible with many samples, such as mammalian cells. Here, we introduce cryogenic super-resolution optical fluctuation imaging (cryo-SOFI), a low-dose super-resolution imaging scheme based on the SOFI principle. As cryo-SOFI does not require special sample preparation, it is fully compatible with conventional cryo-EM specimens, and importantly, it does not affect the quality of cryo-EM imaging. By applying cryo-SOFI to a variety of biological application examples, we demonstrate resolutions up to ∼135 nm, an improvement of up to three times compared with conventional cryo-FM, while maintaining the specimen in a vitrified state for subsequent cryo-EM. Cryo-SOFI presents a general solution to the problem of specimen devitrification in super-resolution cryo-CLEM. It does not require a complex optical setup and can easily be implemented in any existing cryo-FM system.