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1.
Nat Commun ; 12(1): 764, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536417

RESUMO

Genome-wide association studies (GWAS) have identified thousands of genomic regions affecting complex diseases. The next challenge is to elucidate the causal genes and mechanisms involved. One approach is to use statistical colocalization to assess shared genetic aetiology across multiple related traits (e.g. molecular traits, metabolic pathways and complex diseases) to identify causal pathways, prioritize causal variants and evaluate pleiotropy. We propose HyPrColoc (Hypothesis Prioritisation for multi-trait Colocalization), an efficient deterministic Bayesian algorithm using GWAS summary statistics that can detect colocalization across vast numbers of traits simultaneously (e.g. 100 traits can be jointly analysed in around 1 s). We perform a genome-wide multi-trait colocalization analysis of coronary heart disease (CHD) and fourteen related traits, identifying 43 regions in which CHD colocalized with ≥1 trait, including 5 previously unknown CHD loci. Across the 43 loci, we further integrate gene and protein expression quantitative trait loci to identify candidate causal genes.


Assuntos
Algoritmos , Biologia Computacional/métodos , Doença das Coronárias/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Locos de Características Quantitativas/genética , Doença das Coronárias/diagnóstico , Genômica/métodos , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Fatores de Risco
2.
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
4.
Nat Genet ; 51(3): 481-493, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804560

RESUMO

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.


Assuntos
Predisposição Genética para Doença/genética , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fumar/genética
5.
Circ Genom Precis Med ; 12(2): e002413, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30657332

RESUMO

BACKGROUND: The Asp358Ala variant (rs2228145; A>C) in the IL (interleukin)-6 receptor ( IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth and to assess the effect of blocking the IL-6 signaling pathway in mouse models of aortic aneurysm rupture or dissection. METHODS: Using data from 2863 participants with AAA from 9 prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/y). In a series of complementary randomized trials in mice, the effect of blocking the IL-6 signaling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter, and time to aortic rupture and death. RESULTS: After adjusting for age and sex, baseline aneurysm size was 0.55 mm (95% CI, 0.13-0.98 mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. Change in AAA growth was -0.06 mm per year (-0.18 to 0.06) per copy of the minor allele; a result that was not statistically significant. Although all available worldwide data were used, the genetic analyses were not powered for an effect size as small as that observed. In 2 mouse models of AAA, selective blockage of the IL-6 trans-signaling pathway, but not combined blockage of both, the classical and trans-signaling pathways, was associated with improved survival ( P<0.05). CONCLUSIONS: Our proof-of-principle data are compatible with the concept that IL-6 trans-signaling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.


Assuntos
Aneurisma da Aorta Abdominal/patologia , Receptores de Interleucina-6/metabolismo , Alelos , Angiotensina II/toxicidade , Animais , Anticorpos/imunologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/mortalidade , Biomarcadores/metabolismo , Modelos Animais de Doenças , Humanos , Interleucina-6/sangue , Modelos Lineares , Camundongos , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , Transdução de Sinais , Taxa de Sobrevida , Fator de Crescimento Transformador beta/imunologia
6.
Nucleic Acids Res ; 47(1): e3, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30239796

RESUMO

Quantitative trait locus (QTL) mapping of molecular phenotypes such as metabolites, lipids and proteins through genome-wide association studies represents a powerful means of highlighting molecular mechanisms relevant to human diseases. However, a major challenge of this approach is to identify the causal gene(s) at the observed QTLs. Here, we present a framework for the 'Prioritization of candidate causal Genes at Molecular QTLs' (ProGeM), which incorporates biological domain-specific annotation data alongside genome annotation data from multiple repositories. We assessed the performance of ProGeM using a reference set of 227 previously reported and extensively curated metabolite QTLs. For 98% of these loci, the expert-curated gene was one of the candidate causal genes prioritized by ProGeM. Benchmarking analyses revealed that 69% of the causal candidates were nearest to the sentinel variant at the investigated molecular QTLs, indicating that genomic proximity is the most reliable indicator of 'true positive' causal genes. In contrast, cis-gene expression QTL data led to three false positive candidate causal gene assignments for every one true positive assignment. We provide evidence that these conclusions also apply to other molecular phenotypes, suggesting that ProGeM is a powerful and versatile tool for annotating molecular QTLs. ProGeM is freely available via GitHub.


Assuntos
Estudos de Associação Genética , Estudo de Associação Genômica Ampla/métodos , Anotação de Sequência Molecular/métodos , Locos de Características Quantitativas/genética , Mapeamento Cromossômico/métodos , Humanos , Lipídeos/genética , Fenótipo , Proteínas/genética
7.
Nat Commun ; 9(1): 3853, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30228274

RESUMO

In the originally published version of this Article, financial support was not fully acknowledged. The sentence "KS was supported by the 'Biomedical Research Program' funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation" has been added to the acknowledgement section in both the PDF and HTML versions of the Article.

8.
Nat Commun ; 9(1): 3268, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111768

RESUMO

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.


Assuntos
Proteínas Sanguíneas/genética , Doenças Cardiovasculares/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Adulto , Doenças Cardiovasculares/metabolismo , Mapeamento Cromossômico , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Transdução de Sinais/genética
9.
Nature ; 558(7708): 73-79, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29875488

RESUMO

Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.


Assuntos
Proteínas Sanguíneas/genética , Genômica , Proteoma/genética , Feminino , Fator de Crescimento de Hepatócito/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Masculino , Mutação de Sentido Incorreto/genética , Mieloblastina/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Proteínas Proto-Oncogênicas/genética , Locos de Características Quantitativas/genética , Vasculite/genética , alfa 1-Antitripsina/genética
10.
Genet Epidemiol ; 41(8): 714-725, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28944551

RESUMO

Mendelian randomization uses genetic variants to make causal inferences about the effect of a risk factor on an outcome. With fine-mapped genetic data, there may be hundreds of genetic variants in a single gene region any of which could be used to assess this causal relationship. However, using too many genetic variants in the analysis can lead to spurious estimates and inflated Type 1 error rates. But if only a few genetic variants are used, then the majority of the data is ignored and estimates are highly sensitive to the particular choice of variants. We propose an approach based on summarized data only (genetic association and correlation estimates) that uses principal components analysis to form instruments. This approach has desirable theoretical properties: it takes the totality of data into account and does not suffer from numerical instabilities. It also has good properties in simulation studies: it is not particularly sensitive to varying the genetic variants included in the analysis or the genetic correlation matrix, and it does not have greatly inflated Type 1 error rates. Overall, the method gives estimates that are less precise than those from variable selection approaches (such as using a conditional analysis or pruning approach to select variants), but are more robust to seemingly arbitrary choices in the variable selection step. Methods are illustrated by an example using genetic associations with testosterone for 320 genetic variants to assess the effect of sex hormone related pathways on coronary artery disease risk, in which variable selection approaches give inconsistent inferences.


Assuntos
Análise da Randomização Mendeliana , Modelos Genéticos , Doença das Coronárias/sangue , Doença das Coronárias/patologia , Predisposição Genética para Doença , Humanos , Análise de Componente Principal , Fatores de Risco , Testosterona/sangue
11.
Nat Genet ; 49(7): 1113-1119, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530674

RESUMO

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.


Assuntos
Artérias/patologia , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Aterosclerose/genética , Adesão Celular/genética , Quimiotaxia de Leucócito/genética , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Metabolismo Energético/genética , Feminino , Predisposição Genética para Doença , Genótipo , Código das Histonas , Humanos , Masculino , Músculo Liso Vascular/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco
12.
Bioinformatics ; 32(20): 3207-3209, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27318201

RESUMO

PhenoScanner is a curated database of publicly available results from large-scale genetic association studies. This tool aims to facilitate 'phenome scans', the cross-referencing of genetic variants with many phenotypes, to help aid understanding of disease pathways and biology. The database currently contains over 350 million association results and over 10 million unique genetic variants, mostly single nucleotide polymorphisms. It is accompanied by a web-based tool that queries the database for associations with user-specified variants, providing results according to the same effect and non-effect alleles for each input variant. The tool provides the option of searching for trait associations with proxies of the input variants, calculated using the European samples from 1000 Genomes and Hapmap. AVAILABILITY AND IMPLEMENTATION: PhenoScanner is available at www.phenoscanner.medschl.cam.ac.uk CONTACT: jrs95@medschl.cam.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Bases de Dados Factuais , Estudos de Associação Genética , Variação Genética , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Software
13.
Cell Calcium ; 58(6): 577-88, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26434503

RESUMO

Rises in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) are central in platelet activation, yet many aspects of the underlying mechanisms are poorly understood. Most studies examine how experimental manipulations affect agonist-evoked rises in [Ca(2+)]cyt, but these only monitor the net effect of manipulations on the processes controlling [Ca(2+)]cyt (Ca(2+) buffering, sequestration, release, entry and removal), and cannot resolve the source of the Ca(2+) or the transporters or channels affected. To investigate the effects of protein kinase C (PKC) on platelet Ca(2+) signalling, we here monitor Ca(2+) flux around the platelet by measuring net Ca(2+) fluxes to or from the extracellular space and the intracellular Ca(2+) stores, which act as the major sources and sinks for Ca(2+) influx into and efflux from the cytosol, as well as monitoring the cytosolic Na(+) concentration ([Na(+)]cyt), which influences platelet Ca(2+) fluxes via Na(+)/Ca(2+) exchange. The intracellular store Ca(2+) concentration ([Ca(2+)]st) was monitored using Fluo-5N, the extracellular Ca(2+) concentration ([Ca(2+)]ext) was monitored using Fluo-4 whilst [Ca(2+)]cyt and [Na(+)]cyt were monitored using Fura-2 and SFBI, respectively. PKC inhibition using Ro-31-8220 or bisindolylmaleimide I potentiated ADP- and thrombin-evoked rises in [Ca(2+)]cyt in the absence of extracellular Ca(2+). PKC inhibition potentiated ADP-evoked but reduced thrombin-evoked intracellular Ca(2+) release and Ca(2+) removal into the extracellular medium. SERCA inhibition using thapsigargin and 2,5-di(tert-butyl) l,4-benzohydroquinone abolished the effect of PKC inhibitors on ADP-evoked changes in [Ca(2+)]cyt but only reduced the effect on thrombin-evoked responses. Thrombin evokes substantial rises in [Na(+)]cyt which would be expected to reduce Ca(2+) removal via the Na(+)/Ca(2+) exchanger (NCX). Thrombin-evoked rises in [Na(+)]cyt were potentiated by PKC inhibition, an effect which was not due to altered changes in non-selective cation permeability of the plasma membrane as assessed by Mn(2+) quench of Fura-2 fluorescence. PKC inhibition was without effect on thrombin-evoked rises in [Ca(2+)]cyt following SERCA inhibition and either removal of extracellular Na(+) or inhibition of Na(+)/K(+)-ATPase activity by removal of extracellular K(+) or treatment with digoxin. These data suggest that PKC limits ADP-evoked rises in [Ca(2+)]cyt by acceleration of SERCA activity, whilst rises in [Ca(2+)]cyt evoked by the stronger platelet activator thrombin are limited by PKC through acceleration of both SERCA and Na(+)/K(+)-ATPase activity, with the latter limiting the effect of thrombin on rises in [Na(+)]cyt and so forward mode NCX activity. The use of selective PKC inhibitors indicated that conventional and not novel PKC isoforms are responsible for the inhibition of agonist-evoked Ca(2+) signalling.


Assuntos
Plaquetas/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Proteína Quinase C/metabolismo , Difosfato de Adenosina/metabolismo , Plaquetas/efeitos dos fármacos , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Membrana Celular/metabolismo , Citosol/metabolismo , Humanos , Indóis/farmacologia , Isoenzimas/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Isoformas de Proteínas/metabolismo , Proteína Quinase C/genética , Trombina/metabolismo
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