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Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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Enfermedad , Frecuencia de los Genes , Fenotipo , Humanos , Persona de Mediana Edad , Enfermedad/genética , Estonia , Finlandia , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Metaanálisis como Asunto , Reino Unido , Población Blanca/genéticaRESUMEN
Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes1. Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery.
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Estudio de Asociación del Genoma Completo , Proteínas , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Polimorfismo de Nucleótido Simple/genética , Proteínas/genética , Secuenciación del ExomaRESUMEN
INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. HIGHLIGHTS: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.
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MOTIVATION: Mendelian randomization is an epidemiological technique that uses genetic variants as instrumental variables to estimate the causal effect of a risk factor on an outcome. We consider a scenario in which causal estimates based on each variant in turn differ more strongly than expected by chance alone, but the variants can be divided into distinct clusters, such that all variants in the cluster have similar causal estimates. This scenario is likely to occur when there are several distinct causal mechanisms by which a risk factor influences an outcome with different magnitudes of causal effect. We have developed an algorithm MR-Clust that finds such clusters of variants, and so can identify variants that reflect distinct causal mechanisms. Two features of our clustering algorithm are that it accounts for differential uncertainty in the causal estimates, and it includes 'null' and 'junk' clusters, to provide protection against the detection of spurious clusters. RESULTS: Our algorithm correctly detected the number of clusters in a simulation analysis, outperforming methods that either do not account for uncertainty or do not include null and junk clusters. In an applied example considering the effect of blood pressure on coronary artery disease risk, the method detected four clusters of genetic variants. A post hoc hypothesis-generating search suggested that variants in the cluster with a negative effect of blood pressure on coronary artery disease risk were more strongly related to trunk fat percentage and other adiposity measures than variants not in this cluster. AVAILABILITY AND IMPLEMENTATION: MR-Clust can be downloaded from https://github.com/cnfoley/mrclust. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Análisis de la Aleatorización Mendeliana , Causalidad , Análisis por Conglomerados , Simulación por Computador , Factores de RiesgoRESUMEN
An observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of the risk factor will have a causal impact on the outcome (correlation is not causation). If genetic variants associated with the risk factor are also associated with the outcome, then this increases the plausibility that the risk factor is a causal determinant of the outcome. However, if the genetic variants in the analysis do not have a specific biological link to the risk factor, then causal claims can be spurious. We review the Mendelian randomization paradigm for making causal inferences using genetic variants. We consider monogenic analysis, in which genetic variants are taken from a single gene region, and polygenic analysis, which includes variants from multiple regions. We focus on answering two questions: When can Mendelian randomization be used to make reliable causal inferences, and when can it be used to make relevant causal inferences?
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Estudio de Asociación del Genoma Completo , Causalidad , Humanos , Análisis de la Aleatorización Mendeliana , Factores de RiesgoRESUMEN
While comorbidity between coronary heart disease (CHD) and depression is evident, it is unclear whether the two diseases have shared underlying mechanisms. We performed a range of analyses in 367,703 unrelated middle-aged participants of European ancestry from UK Biobank, a population-based cohort study, to assess whether comorbidity is primarily due to genetic or environmental factors, and to test whether cardiovascular risk factors and CHD are likely to be causally related to depression using Mendelian randomization. We showed family history of heart disease was associated with a 20% increase in depression risk (95% confidence interval [CI] 16-24%, p < 0.0001), but a genetic risk score that is strongly associated with CHD risk was not associated with depression. An increase of 1 standard deviation in the CHD genetic risk score was associated with 71% higher CHD risk, but 1% higher depression risk (95% CI 0-3%; p = 0.11). Mendelian randomization analyses suggested that triglycerides, interleukin-6 (IL-6), and C-reactive protein (CRP) are likely causal risk factors for depression. The odds ratio for depression per standard deviation increase in genetically-predicted triglycerides was 1.18 (95% CI 1.09-1.27; p = 2 × 10-5); per unit increase in genetically-predicted log-transformed IL-6 was 0.74 (95% CI 0.62-0.89; p = 0.0012); and per unit increase in genetically-predicted log-transformed CRP was 1.18 (95% CI 1.07-1.29; p = 0.0009). Our analyses suggest that comorbidity between depression and CHD arises largely from shared environmental factors. IL-6, CRP and triglycerides are likely to be causally linked with depression, so could be targets for treatment and prevention of depression.
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Enfermedad Coronaria , Depresión , Adulto , Anciano , Proteína C-Reactiva/análisis , Estudios de Cohortes , Enfermedad Coronaria/sangre , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/genética , Depresión/sangre , Depresión/epidemiología , Depresión/genética , Femenino , Humanos , Interleucina-6/sangre , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Triglicéridos/sangre , Reino Unido/epidemiologíaRESUMEN
A two-step multicomponent reaction oxidation protocol is reported herein, which affords novel tunable fluorescent tetracyclic indolizines. The procedure involves a novel 4-center-3-component reaction, which proceeds via a sequential Knoevenagel condensation, [4+1] cycloaddition, and imine condensation to afford imino-indolizines. Products then undergo cyclization and are oxidized in situ to afford fluorescent tetracycles, which are readily tunable through modification of diversity elements.
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Indolizinas , Colorantes , Ciclización , Reacción de Cicloadición , Estructura MolecularRESUMEN
This article describes the action of iodine(III) reagents [diacetoxyiodobenzene, PhI(OAc)2, and iodosobenzene, (PhIO)n] in conjunction with TMSBr which act as functional bromine equivalents in unique oxidations of saturated, carbamate protected N-heterocycles. Interestingly, during this work, treatment of the same carbamates with molecular bromine alone afforded similar products, which were sequestered by the solvent methanol.
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BACKGROUND: Obsessive-compulsive disorder (OCD) is prevalent and without adequate treatment usually follows a chronic course. "High-intensity" cognitive-behaviour therapy (CBT) from a specialist therapist is current "best practice." However, access is difficult because of limited numbers of therapists and because of the disabling effects of OCD symptoms. There is a potential role for "low-intensity" interventions as part of a stepped care model. Low-intensity interventions (written or web-based materials with limited therapist support) can be provided remotely, which has the potential to increase access. However, current evidence concerning low-intensity interventions is insufficient. We aimed to determine the clinical effectiveness of 2 forms of low-intensity CBT prior to high-intensity CBT, in adults meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for OCD. METHODS AND FINDINGS: This study was approved by the National Research Ethics Service Committee North West-Lancaster (reference number 11/NW/0276). All participants provided informed consent to take part in the trial. We conducted a 3-arm, multicentre randomised controlled trial in primary- and secondary-care United Kingdom mental health services. All patients were on a waiting list for therapist-led CBT (treatment as usual). Four hundred and seventy-three eligible patients were recruited and randomised. Patients had a median age of 33 years, and 60% were female. The majority were experiencing severe OCD. Patients received 1 of 2 low-intensity interventions: computerised CBT (cCBT; web-based CBT materials and limited telephone support) through "OCFighter" or guided self-help (written CBT materials with limited telephone or face-to-face support). Primary comparisons concerned OCD symptoms, measured using the Yale-Brown Obsessive Compulsive Scale-Observer-Rated (Y-BOCS-OR) at 3, 6, and 12 months. Secondary outcomes included health-related quality of life, depression, anxiety, and functioning. At 3 months, guided self-help demonstrated modest benefits over the waiting list in reducing OCD symptoms (adjusted mean difference = -1.91, 95% CI -3.27 to -0.55). These effects did not reach a prespecified level of "clinically significant benefit." cCBT did not demonstrate significant benefit (adjusted mean difference = -0.71, 95% CI -2.12 to 0.70). At 12 months, neither guided self-help nor cCBT led to differences in OCD symptoms. Early access to low-intensity interventions led to significant reductions in uptake of high-intensity CBT over 12 months; 86% of the patients allocated to the waiting list for high-intensity CBT started treatment by the end of the trial, compared to 62% in supported cCBT and 57% in guided self-help. These reductions did not compromise longer-term patient outcomes. Data suggested small differences in satisfaction at 3 months, with patients more satisfied with guided self-help than supported cCBT. A significant issue in the interpretation of the results concerns the level of access to high-intensity CBT before the primary outcome assessment. CONCLUSIONS: We have demonstrated that providing low-intensity interventions does not lead to clinically significant benefits but may reduce uptake of therapist-led CBT. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) Registry ISRCTN73535163.
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Terapia Cognitivo-Conductual/métodos , Trastorno Obsesivo Compulsivo/terapia , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Reino Unido , Listas de Espera , Adulto JovenRESUMEN
Herein, a two-step MCR-oxidation methodology accessing decorated 2° α-ketoamides and α-ketotetrazoles is described via a catalytic copper(i)-mediated C-N oxidation/acidic hydrolysis of Ugi-three-component and Ugi-azide reaction products. The ability to install diversity from aldehyde and isocyanide synthons allows rapid complexity generation. Of note, (1) 2° α-ketoamides are traditionally difficult to access and more so reminiscent of the endogenous peptide bonds. (2) The route to α-keto-tetrazoles is significantly shorter than that in previous reports.
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A concise one-pot three-component reaction that affords fluorescent indolizines, benzo[d]pyrrolo[2,1-b]thiazoles, and pyrrolo[1,2-a]pyrazines is reported. The methodology involves the formation of a heterocyclic 1-aza-1,3-diene derived from a Knoevenagel condensation between an aldehyde and 2-methyl-ene-cyano aza-heterocycles, followed by [4 + 1] cycloaddition of acetyl cyanide behaving as a non-classical isocyanide replacement.
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The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC) and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent mechanisms (including constitutively active AR splice variants) highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA-binding protein 2 (GATA2) as a regulator of AR signaling and an actionable therapeutic target in PC. We demonstrate that GATA2 directly promotes expression of both full-length and splice-variant AR, resulting in a strong positive correlation between GATA2 and AR expression in both PC cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both full-length and splice-variant AR. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a first-in-field approach to target AR expression and function and improve outcomes in CRPC.
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Factor de Transcripción GATA2/fisiología , Coactivadores de Receptor Nuclear/metabolismo , Receptores Androgénicos/metabolismo , Proliferación Celular , Cromatina/metabolismo , Elementos de Facilitación Genéticos , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Pronóstico , Receptores Androgénicos/fisiología , Transducción de Señal , Transcripción Genética/fisiologíaRESUMEN
Modern food technology has given rise to numerous alternative protein sources in response to a growing human population and the negative environmental impacts of current food systems. To aid in achieving global food security, one such form of alternative protein being investigated is cultivated meat, which applies the principles of mechanical and tissue engineering to produce animal proteins and meat products from animal cells. Herein, nonmodified and methacrylated whey protein formed hydrogels with methacrylated alginate as potential tissue engineering scaffolds for cultivated meat. Whey protein is a byproduct of dairy processing and was selected because it is an approved food additive and cytocompatible and has shown efficacy in other biomaterial applications. Whey protein and alginate scaffolds were formed via visible light cross-linking in aqueous solutions under ambient conditions. The characteristics of the precursor solution and the physical-mechanical properties of the scaffolds were quantified; while gelation occurred within the homo- and copolymer hydrogels, the integrity of the network was significantly altered with varying components. Qualitatively, the scaffolds exhibited a three-dimensional (3D) interconnected porous network. Whey protein isolate (WPI)-based scaffolds were noncytotoxic and supported in vitro myoblast adhesion and proliferation. The data presented support the hypothesis that the composition of the hydrogel plays a significant role in the scaffold's performance.
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Carne in Vitro , Andamios del Tejido , Animales , Humanos , Proteína de Suero de Leche , Hidrogeles , AlginatosRESUMEN
The circulating proteome offers insights into the biological pathways that underlie disease. Here, we test relationships between 1,468 Olink protein levels and the incidence of 23 age-related diseases and mortality in the UK Biobank (n = 47,600). We report 3,209 associations between 963 protein levels and 21 incident outcomes. Next, protein-based scores (ProteinScores) are developed using penalized Cox regression. When applied to test sets, six ProteinScores improve the area under the curve estimates for the 10-year onset of incident outcomes beyond age, sex and a comprehensive set of 24 lifestyle factors, clinically relevant biomarkers and physical measures. Furthermore, the ProteinScore for type 2 diabetes outperforms a polygenic risk score and HbA1c-a clinical marker used to monitor and diagnose type 2 diabetes. The performance of scores using metabolomic and proteomic features is also compared. These data characterize early proteomic contributions to major age-related diseases, demonstrating the value of the plasma proteome for risk stratification.
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Proteínas Sanguíneas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores/sangre , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/análisis , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Incidencia , Proteómica , Biobanco del Reino Unido , Reino Unido/epidemiologíaRESUMEN
Alzheimer's disease (AD) involves pathological processing of amyloid precursor protein (APP) into amyloid-ß and microtubule associated protein Tau (MAPT) into hyperphosphorylated Tau tangles leading to neurodegeneration. Only 5% of AD cases are familial making it difficult to predict who will develop the disease thereby hindering our ability to treat the causes of the disease. A large population who almost certainly will, are those with Down syndrome (DS), who have a 90% lifetime incidence of AD. DS is caused by trisomy of chromosome 21 resulting in three copies of APP and other AD-associated genes, like dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) overexpression. This implies that DYRK1a inhibitors may have therapeutic potential for DS and AD, however It is not clear how overexpression of each of these genes contributes to the pathology of each disease as well as how effective a DYRK1A inhibitor would be at suppressing any of these. To address this knowledge gap, we used Drosophila models with human Tau, human amyloid-ß or fly DYRK1A (minibrain (mnb)) neuronal overexpression resulting in photoreceptor neuron degeneration, premature death, decreased locomotion, sleep and memory loss. DYRK1A small molecule Type 1 kinase inhibitors (DYR219 and DYR533) were effective at suppressing these disease relevant phenotypes confirming their therapeutic potential.
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Enfermedad de Alzheimer , Síndrome de Down , Síndromes de Neurotoxicidad , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Modelos Animales de Enfermedad , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/genética , Síndrome de Down/metabolismo , Drosophila , Humanos , Fosforilación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Tirosina/metabolismo , Proteínas tau/metabolismo , Quinasas DyrKRESUMEN
Genetic associations with macroscopic brain structure can provide insights into brain function and disease. However, specific associations with measures of local brain folding are largely under-explored. Here, we conducted large-scale genome- and exome-wide associations of regional cortical sulcal measures derived from magnetic resonance imaging scans of 40,169 individuals in UK Biobank. We discovered 388 regional brain folding associations across 77 genetic loci, with genes in associated loci enriched for expression in the cerebral cortex, neuronal development processes, and differential regulation during early brain development. We integrated brain eQTLs to refine genes for various loci, implicated several genes involved in neurodevelopmental disorders, and highlighted global genetic correlations with neuropsychiatric phenotypes. We provide an interactive 3D visualisation of our summary associations, emphasising added resolution of regional analyses. Our results offer new insights into the genetic architecture of brain folding and provide a resource for future studies of sulcal morphology in health and disease.
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Bancos de Muestras Biológicas , Encéfalo , Encéfalo/diagnóstico por imagen , Corteza Cerebral/anatomía & histología , Estudio de Asociación del Genoma Completo , Humanos , Imagen por Resonancia Magnética , Reino UnidoRESUMEN
The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer's Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI preprocessing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features - i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia. The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features - Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) - were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/prevención & control , Biomarcadores , Encéfalo/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/métodos , Síntomas Prodrómicos , Flujo de TrabajoRESUMEN
A 5-endo trig oxidative radical cyclization of benzylamine-derived Ugi three-component reaction products rapidly affords imidazolidinones with three diversity elements. This adaptation of our previously described multicomponent reaction-oxidation methodology further showcases manipulation of the diversity elements in multicomponent reaction products via oxidative radical cyclizations, which generates highly decorated privileged heterocycles.