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2.
Genome Biol ; 22(1): 32, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441155

RESUMO

GWAS summary statistics are fundamental for a variety of research applications yet no common storage format has been widely adopted. Existing tabular formats ambiguously or incompletely store information about genetic variants and associations, lack essential metadata and are typically not indexed yielding poor query performance and increasing the possibility of errors in data interpretation and post-GWAS analyses. To address these issues, we adapted the variant call format to store GWAS summary statistics (GWAS-VCF) and developed open-source tools to use this format in downstream analyses. We provide open access to over 10,000 complete GWAS summary datasets converted to this format ( https://gwas.mrcieu.ac.uk ).

3.
PLoS Genet ; 17(1): e1009224, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417599

RESUMO

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer's Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer's disease, 6 genes with Parkinson's disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.

4.
Hum Mol Genet ; 30(1): 119-134, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33450751

RESUMO

DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illumina Infinium HumanMethylation450 BeadChip. Change over time was widespread, observed at over one-half (53%) of CpGs. In most cases, DNAm was decreasing (36% of CpGs). Inter-individual variation in linear trajectories was similarly widespread (27% of CpGs). Evidence for non-linear change and inter-individual variation in non-linear trajectories was somewhat less common (11 and 8% of CpGs, respectively). Very little inter-individual variation in change was explained by sex differences (0.4% of CpGs) even though sex-specific DNAm was observed at 5% of CpGs. DNAm trajectories were distributed non-randomly across the genome. For example, CpGs with decreasing DNAm were enriched in gene bodies and enhancers and were annotated to genes enriched in immune-developmental functions. In contrast, CpGs with increasing DNAm were enriched in promoter regions and annotated to genes enriched in neurodevelopmental functions. These findings depict a methylome undergoing widespread and often non-linear change throughout childhood. They support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33288654

RESUMO

The advent of large-scale, phenotypically rich, and readily accessible data provides an unprecedented opportunity for epidemiologists, statistical geneticists, bioinformaticians, and also behavioral and social scientists to investigate the causes and consequences of disease. Computational tools and resources are an integral component of such endeavors, which will become increasingly important as these data continue to grow exponentially. In this review, we have provided an overview of computational software and databases that have been developed to assist with analyses in causal inference. This includes online tools that can be used to help generate hypotheses, publicly accessible resources that store summary-level information for millions of genetic markers, and computational approaches that can be used to leverage this wealth of data to study causal relationships.

6.
Bioinformatics ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33165574

RESUMO

MOTIVATION: The wealth of data resources on human phenotypes, risk factors, molecular traits and therapeutic interventions presents new opportunities for population health sciences. These opportunities are paralleled by a growing need for data integration, curation and mining to increase research efficiency, reduce mis-inference and ensure reproducible research. RESULTS: We developed EpiGraphDB (https://epigraphdb.org/), a graph database containing an array of different biomedical and epidemiological relationships and an analytical platform to support their use in human population health data science. In addition, we present three case studies that illustrate the value of this platform. The first uses EpiGraphDB to evaluate potential pleiotropic relationships, addressing mis-inference in systematic causal analysis. In the second case study, we illustrate how protein-protein interaction data offer opportunities to identify new drug targets. The final case study integrates causal inference using Mendelian randomization with relationships mined from the biomedical literature to "triangulate" evidence from different sources. AVAILABILITY: The EpiGraphDB platform is openly available at https://epigraphdb.org. Code for replicating case study results is available at https://github.com/MRCIEU/epigraphdb as Jupyter notebooks using the API, and https://mrcieu.github.io/epigraphdb-r using the R package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

7.
Arthritis Rheumatol ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33079445

RESUMO

OBJECTIVE: To ascertain the role of platelet glycoprotein Ib alpha chain (GPIbα) plasma protein levels in cardiovascular, autoimmune and autoinflammatory diseases and whether its effects are mediated by platelet count. METHODS: We performed a two-sample Mendelian randomization (MR) study, using both cis and trans-acting protein expression quantitative trait loci (pQTL) near GP1BA and BRAP genes as instruments. To assess if platelet count mediated the effect, we then performed a two-step MR study. Putative associations (GPIbα/ platelet count/ disease) detected by MR analyses were subsequently assessed using multiple-trait-colocalization analyses. RESULTS: After correcting for multiple testing (P ≤ 2×10-3 ), GPIbα, instrumented by either cis-pQTL or trans-pQTL, was causally implicated with increased risk of juvenile idiopathic arthritis (JIA - oligoarticular and rheumatoid factor negative subtypes). These effects of GPIbα appear to be mediated by platelet count and are supported by strong evidence of colocalization (probability of all three traits sharing a common causal variant ≥ 0.80). GPIbα instrumented by cis-pQTL did not appear to affect cardiovascular risk, although the GPIbα trans-pQTL associates with increased risk of cardiovascular diseases and autoimmune diseases but decreased risk of autoinflammatory diseases, suggesting this trans- instrument acts through other pathways. CONCLUSION: The role of platelets in thrombosis is well-established, however our findings provided some novel genetic evidence that platelets may be causally implicated in the development of JIA, and GPIba as a putative therapeutic target for these JIA subtypes.

8.
Brief Bioinform ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33094325

RESUMO

Sequencing technologies have led to the identification of many variants in the human genome which could act as disease-drivers. As a consequence, a variety of bioinformatics tools have been proposed for predicting which variants may drive disease, and which may be causatively neutral. After briefly reviewing generic tools, we focus on a subset of these methods specifically geared toward predicting which variants in the human cancer genome may act as enablers of unregulated cell proliferation. We consider the resultant view of the cancer genome indicated by these predictors and discuss ways in which these types of prediction tools may be progressed by further research.

9.
Nat Genet ; 52(10): 1122-1131, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32895551

RESUMO

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.


Assuntos
Proteínas Sanguíneas/genética , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Proteoma/genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
10.
Bioinformatics ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32810207

RESUMO

The field of literature based discovery is growing in step with the volume of literature being produced. From modern natural language processing algorithms to high quality entity tagging, the methods and their impact are developing rapidly. One annotation object that arises from these approaches, the subject-predicate-object triple, is proving to be very useful in representing knowledge. We have implemented efficient search methods and an application programming interface (API), to create fast and convenient functions to utilize triples extracted from the biomedical literature by SemMedDB. By refining these data we have identified a set of triples that focus on the mechanistic aspects of the literature, and provide simple methods to explore both enriched triples from single queries, and overlapping triples across two query lists. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

11.
Eur J Cardiothorac Surg ; 58(6): 1130-1136, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810233

RESUMO

OBJECTIVES: Interest in the clinical usefulness of machine learning for risk prediction has bloomed recently. Cardiac surgery patients are at high risk of complications and therefore presurgical risk assessment is of crucial relevance. We aimed to compare the performance of machine learning algorithms over traditional logistic regression (LR) model to predict in-hospital mortality following cardiac surgery. METHODS: A single-centre data set of prospectively collected information from patients undergoing adult cardiac surgery from 1996 to 2017 was split into 70% training set and 30% testing set. Prediction models were developed using neural network, random forest, naive Bayes and retrained LR based on features included in the EuroSCORE. Discrimination was assessed using area under the receiver operating characteristic curve, and calibration analysis was undertaken using the calibration belt method. Model calibration drift was assessed by comparing Goodness of fit χ2 statistics observed in 2 equal bins from the testing sample ordered by procedure date. RESULTS: A total of 28 761 cardiac procedures were performed during the study period. The in-hospital mortality rate was 2.7%. Retrained LR [area under the receiver operating characteristic curve 0.80; 95% confidence interval (CI) 0.77-0.83] and random forest model (0.80; 95% CI 0.76-0.83) showed the best discrimination. All models showed significant miscalibration. Retrained LR proved to have the weakest calibration drift. CONCLUSIONS: Our findings do not support the hypothesis that machine learning methods provide advantage over LR model in predicting operative mortality after cardiac surgery.

12.
Artigo em Inglês | MEDLINE | ID: mdl-32733862

RESUMO

Salt restriction was recommended in clinical practice guideline for chronic kidney disease (CKD) treatment, but its effect on kidney outcomes remains conflicting. We aimed to test the causal effect of salt intake, using estimated 24-h sodium excretion from spot urinary sodium/urinary creatinine (UNa/UCr) ratio as a surrogate, on renal function using two-sample Mendelian randomization (MR). Genetic instruments for UNa/UCr were derived from a recent genome-wide association study of 218,450 European-descent individuals in the UK Biobank. Kidney outcomes were creatinine-based estimated glomerular filtration rate (eGFRcrea) (N = 567,460) and CKD (eGFRcrea < 60 ml/min/1.73 m2, N cases = 41,395, N controls = 439,303) from the CKDGen consortium. Cystatin C-based eGFR (eGFRcys) and eGFRcrea single-nucleotide polymorphisms associated with blood urea nitrogen (BUN) were used for sensitivity analyses. MR revealed a causal effect of UNa/UCr on higher eGFRcrea [ß = 0.14, unit change in log ml/min/1.73 m2 per UNa/UCr ratio; 95% confidence interval (CI) = 0.07 - 0.20, P = 2.15 × 10-5] and a protective effect against CKD risk (odds ratio = 0.24, 95% CI = 0.14 to 0.41, P = 1.20 × 10-7). The MR findings were confirmed by MR-Egger regression, weighted median MR, and mode estimate MR, with less evidence of existence of horizontal pleiotropy. Consistent positive causal effect of UNa/UCr on eGFRcys was also detected. On the other hand, bidirectional MR suggested inconclusive results of CKD, eGFRcrea, eGFRcrea (BUN associated), and eGFRcys on UNa/UCr. The average 24-h sodium excretion was estimated to be approximately 2.6 g per day for women and 3.7 g per day for men. This study provides evidence that sodium excretion, well above the recommendation of <2 g per day of sodium intake, might not have a harmful effect on kidney function. Clinical trials are warranted to evaluate the sodium restriction target on kidney function.

13.
Am J Hum Genet ; 106(6): 885-892, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32413284

RESUMO

Leveraging high-dimensional molecular datasets can help us develop mechanistic insight into associations between genetic variants and complex traits. In this study, we integrated human proteome data derived from brain tissue to evaluate whether targeted proteins putatively mediate the effects of genetic variants on seven neurological phenotypes (Alzheimer disease, amyotrophic lateral sclerosis, depression, insomnia, intelligence, neuroticism, and schizophrenia). Applying the principles of Mendelian randomization (MR) systematically across the genome highlighted 43 effects between genetically predicted proteins derived from the dorsolateral prefrontal cortex and these outcomes. Furthermore, genetic colocalization provided evidence that the same causal variant at 12 of these loci was responsible for variation in both protein and neurological phenotype. This included genes such as DCC, which encodes the netrin-1 receptor and has an important role in the development of the nervous system (p = 4.29 × 10-11 with neuroticism), as well as SARM1, which has been previously implicated in axonal degeneration (p = 1.76 × 10-08 with amyotrophic lateral sclerosis). We additionally conducted a phenome-wide MR study for each of these 12 genes to assess potential pleiotropic effects on 700 complex traits and diseases. Our findings suggest that genes such as SNX32, which was initially associated with increased risk of Alzheimer disease, may potentially influence other complex traits in the opposite direction. In contrast, genes such as CTSH (which was also associated with Alzheimer disease) and SARM1 may make worthwhile therapeutic targets because they did not have genetically predicted effects on any of the other phenotypes after correcting for multiple testing.


Assuntos
Encéfalo/metabolismo , Variação Genética/genética , Doenças do Sistema Nervoso/genética , Fenômica , Proteoma/genética , Proteômica , Doença de Alzheimer/genética , Esclerose Amiotrófica Lateral/genética , Proteínas do Domínio Armadillo/genética , Proteínas de Transporte/genética , Catepsina H/genética , Proteínas do Citoesqueleto/genética , Depressão/genética , Estudo de Associação Genômica Ampla , Humanos , Inteligência/genética , Doenças do Sistema Nervoso/metabolismo , Neuroticismo , Proteínas Nucleares/genética , Fenótipo , Proteoma/metabolismo , Esquizofrenia/genética , Distúrbios do Início e da Manutenção do Sono/genética , Nexinas de Classificação/genética
14.
Bioinformatics ; 36(12): 3637-3644, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32282885

RESUMO

MOTIVATION: Next-generation sequencing technologies have accelerated the discovery of single nucleotide variants in the human genome, stimulating the development of predictors for classifying which of these variants are likely functional in disease, and which neutral. Recently, we proposed CScape, a method for discriminating between cancer driver mutations and presumed benign variants. For the neutral class, this method relied on benign germline variants found in the 1000 Genomes Project database. Discrimination could, therefore, be influenced by the distinction of germline versus somatic, rather than neutral versus disease driver. This motivates this article in which we consider predictive discrimination between recurrent and rare somatic single point mutations based solely on using cancer data, and the distinction between these two somatic classes and germline single point mutations. RESULTS: For somatic point mutations in coding and non-coding regions of the genome, we propose CScape-somatic, an integrative classifier for predictively discriminating between recurrent and rare variants in the human cancer genome. In this study, we use purely cancer genome data and investigate the distinction between minimal occurrence and significantly recurrent somatic single point mutations in the human cancer genome. We show that this type of predictive distinction can give novel insight, and may deliver more meaningful prediction in both coding and non-coding regions of the cancer genome. Tested on somatic mutations, CScape-somatic outperforms alternative methods, reaching 74% balanced accuracy in coding regions and 69% in non-coding regions, whereas even higher accuracy may be achieved using thresholds to isolate high-confidence predictions. AVAILABILITY AND IMPLEMENTATION: Predictions and software are available at http://CScape-somatic.biocompute.org.uk/. CONTACT: mark.f.rogers.phd@gmail.com or C.Campbell@bristol.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

15.
J Am Heart Assoc ; 9(5): e013131, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32114887

RESUMO

Background We aimed at investigating the association of circulating fatty acids with coronary heart disease (CHD) and stroke risk. Methods and Results We conducted an individual-participant data meta-analysis of 5 UK-based cohorts and 1 matched case-control study. Fatty acids (ie, omega-3 docosahexaenoic acid, omega-6 linoleic acid, monounsaturated and saturated fatty acids) were measured at baseline using an automated high-throughput serum nuclear magnetic resonance metabolomics platform. Data from 3022 incident CHD cases (13 104 controls) and 1606 incident stroke cases (13 369 controls) were included. Logistic regression was used to model the relation between fatty acids and odds of CHD and stroke, adjusting for demographic and lifestyle variables only (ie, minimally adjusted model) or with further adjustment for other fatty acids (ie, fully adjusted model). Although circulating docosahexaenoic acid, but not linoleic acid, was related to lower CHD risk in the fully adjusted model (odds ratio, 0.85; 95% CI, 0.76-0.95 per standard unit of docosahexaenoic acid), there was evidence of high between-study heterogeneity and effect modification by study design. Stroke risk was consistently lower with increasing circulating linoleic acid (odds ratio for fully adjusted model, 0.82; 95% CI, 0.75-0.90). Circulating monounsaturated fatty acids were associated with higher CHD risk across all models and with stroke risk in the fully adjusted model (odds ratio, 1.22; 95% CI, 1.03-1.44). Saturated fatty acids were not related to increased CHD risk in the fully adjusted model (odds ratio, 0.94; 95% CI, 0.82-1.09), or stroke risk. Conclusions We found consistent evidence that linoleic acid was associated with decreased risk of stroke and that monounsaturated fatty acids were associated with increased risk of CHD. The different pattern between CHD and stroke in terms of fatty acids risk profile suggests future studies should be cautious about using composite events. Different study designs are needed to assess which, if any, of the associations observed is causal.

16.
Nat Commun ; 11(1): 1010, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32081875

RESUMO

In Mendelian randomization (MR) analysis, variants that exert horizontal pleiotropy are typically treated as a nuisance. However, they could be valuable in identifying alternative pathways to the traits under investigation. Here, we develop MR-TRYX, a framework that exploits horizontal pleiotropy to discover putative risk factors for disease. We begin by detecting outliers in a single exposure-outcome MR analysis, hypothesising they are due to horizontal pleiotropy. We search across hundreds of complete GWAS summary datasets to systematically identify other (candidate) traits that associate with the outliers. We develop a multi-trait pleiotropy model of the heterogeneity in the exposure-outcome analysis due to pathways through candidate traits. Through detailed investigation of several causal relationships, many pleiotropic pathways are uncovered with already established causal effects, validating the approach, but also alternative putative causal pathways. Adjustment for pleiotropic pathways reduces the heterogeneity across the analyses.


Assuntos
Pleiotropia Genética , Análise da Randomização Mendeliana , Modelos Genéticos , Causalidade , Simulação por Computador , Bases de Dados Genéticas , Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
17.
Am J Hum Genet ; 106(3): 315-326, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084330

RESUMO

Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV1) in UK Biobank (n = 321,047) by using two-sample Mendelian randomization (MR) and then replicated this investigation in the SpiroMeta Consortium (n = 79,055). Second, we used two-step MR to investigate whether DNA methylation mediates the effect of smoking on FEV1. Lastly, we evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression by using a multiple-trait colocalization ("moloc") framework. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p < 1.2 × 10-4). Replication analysis supported a causal effect at three CpGs (cg21201401 [LIME1 and ZGPAT], cg19758448 [PGAP3], and cg12616487 [EML3 and AHNAK] [p < 0.0028]). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites might influence lung function via effects on smoking. By using "moloc", we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. These findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results.


Assuntos
Metilação de DNA , Pulmão/fisiologia , Análise da Randomização Mendeliana/métodos , Fumar , Ilhas de CpG , Volume Expiratório Forçado , Pleiotropia Genética , Humanos
18.
PLoS One ; 15(1): e0227728, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999706

RESUMO

BACKGROUND: High blood pressure is a major risk factor for cardiovascular disease and is influenced by both environmental and genetic factors. Epigenetic processes including DNA methylation potentially mediate the relationship between genetic factors, the environment and cardiovascular disease. Despite an increased risk of hypertension and cardiovascular disease in individuals of South Asians compared to Europeans, it is not clear whether associations between blood pressure and DNA methylation differ between these groups. METHODS: We performed an epigenome-wide association study and differentially methylated region (DMR) analysis to identify DNA methylation sites and regions that were associated with systolic blood pressure, diastolic blood pressure and hypertension. We analyzed samples from 364 European and 348 South Asian men (first generation migrants to the UK) from the Southall And Brent REvisited cohort, measuring DNA methylation from blood using the Illumina Infinium® HumanMethylation450 BeadChip. RESULTS: One CpG site was found to be associated with DBP in trans-ancestry analyses (i.e. both ethnic groups combined), while in Europeans alone seven CpG sites were associated with DBP. No associations were identified between DNA methylation and either SBP or hypertension. Comparison of effect sizes between South Asian and European EWAS for DBP, SBP and hypertension revealed little concordance between analyses. DMR analysis identified several regions with known relationships with CVD and its risk factors. CONCLUSION: This study identified differentially methylated sites and regions associated with blood pressure and revealed ethnic differences in these associations. These findings may point to molecular pathways which may explain the elevated cardiovascular disease risk experienced by those of South Asian ancestry when compared to Europeans.


Assuntos
Pressão Sanguínea/genética , Ilhas de CpG/genética , Metilação de DNA , Epigenoma/genética , Hipertensão/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Emigrantes e Imigrantes , Epigênese Genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido/epidemiologia
19.
Nat Commun ; 11(1): 185, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924771

RESUMO

Developing insight into tissue-specific transcriptional mechanisms can help improve our understanding of how genetic variants exert their effects on complex traits and disease. In this study, we apply the principles of Mendelian randomization to systematically evaluate transcriptome-wide associations between gene expression (across 48 different tissue types) and 395 complex traits. Our findings indicate that variants which influence gene expression levels in multiple tissues are more likely to influence multiple complex traits. Moreover, detailed investigations of our results highlight tissue-specific associations, drug validation opportunities, insight into the likely causal pathways for trait-associated variants and also implicate putative associations at loci yet to be implicated in disease susceptibility. Similar evaluations can be conducted at http://mrcieu.mrsoftware.org/Tissue_MR_atlas/.


Assuntos
Análise da Randomização Mendeliana , Fenômica , Transcriptoma , Aromatase/genética , Fibrilina-2/genética , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Proteínas Ribossômicas/genética , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/metabolismo
20.
J Neurol Neurosurg Psychiatry ; 91(3): 305-313, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31937585

RESUMO

OBJECTIVE: After aneurysmal subarachnoid haemorrhage (aSAH), extracellular haemoglobin (Hb) in the subarachnoid space is bound by haptoglobin, neutralising Hb toxicity and helping its clearance. Two exons in the HP gene (encoding haptoglobin) exhibit copy number variation (CNV), giving rise to HP1 and HP2 alleles, which influence haptoglobin expression level and possibly haptoglobin function. We hypothesised that the HP CNV associates with long-term outcome beyond the first year after aSAH. METHODS: The HP CNV was typed using quantitative PCR in 1299 aSAH survivors in the Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study, a retrospective multicentre cohort study with a median follow-up of 18 months. To investigate mediation of the HP CNV effect by haptoglobin expression level, as opposed to functional differences, we used rs2000999, a single nucleotide polymorphism associated with haptoglobin expression independent of the HP CNV. Outcome was assessed using modified Rankin and Glasgow Outcome Scores. SAH volume was dichotomised on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 patients with aSAH and related to the HP CNV. RESULTS: The HP2 allele associated with a favourable long-term outcome after high-volume but not low-volume aSAH (multivariable logistic regression). However rs2000999 did not predict outcome. The HP2 allele associated with lower CSF haemoglobin-haptoglobin complex levels. The CSF Hb concentration after high-volume and low-volume aSAH was, respectively, higher and lower than the Hb-binding capacity of CSF haptoglobin. CONCLUSION: The HP2 allele carries a favourable long-term prognosis after high-volume aSAH. Haptoglobin and the Hb clearance pathway are therapeutic targets after aSAH.


Assuntos
Haptoglobinas/genética , Aneurisma Intracraniano/genética , Hemorragia Subaracnóidea/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Feminino , Genótipo , Humanos , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/mortalidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Recuperação de Função Fisiológica , Hemorragia Subaracnóidea/mortalidade , Taxa de Sobrevida , Adulto Jovem
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