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1.
Cell ; 167(5): 1398-1414.e24, 2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-27863251

RESUMO

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.


Assuntos
Epigenômica , Doenças do Sistema Imunitário/genética , Monócitos/metabolismo , Neutrófilos/metabolismo , Linfócitos T/metabolismo , Transcrição Gênica , Adulto , Idoso , Processamento Alternativo , Feminino , Predisposição Genética para Doença , Células-Tronco Hematopoéticas/metabolismo , Código das Histonas , Humanos , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas , Adulto Jovem
2.
Cell ; 167(5): 1415-1429.e19, 2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-27863252

RESUMO

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla , Células-Tronco Hematopoéticas/metabolismo , Doenças do Sistema Imunitário/genética , Alelos , Diferenciação Celular , Predisposição Genética para Doença , Células-Tronco Hematopoéticas/patologia , Humanos , Doenças do Sistema Imunitário/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , População Branca/genética
3.
Nature ; 526(7571): 82-90, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26367797

RESUMO

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.


Assuntos
Doença/genética , Variação Genética/genética , Genoma Humano/genética , Saúde , Adiponectina/sangue , Alelos , Estudos de Coortes , Exoma/genética , Feminino , Predisposição Genética para Doença/genética , Genética Médica , Genética Populacional , Estudo de Associação Genômica Ampla , Genômica , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Anotação de Sequência Molecular , Receptores de LDL/genética , Padrões de Referência , Análise de Sequência de DNA , Triglicerídeos/sangue , Reino Unido
4.
Am J Hum Genet ; 100(6): 865-884, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28552196

RESUMO

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.


Assuntos
Antropometria , Genoma Humano , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Análise de Sequência de DNA/métodos , Estatura/genética , Estudos de Coortes , Metilação de DNA/genética , Bases de Dados Genéticas , Feminino , Variação Genética , Humanos , Lipodistrofia/genética , Masculino , Metanálise como Assunto , Obesidade/genética , Mapeamento Físico do Cromossomo , Caracteres Sexuais , Síndrome , Reino Unido
5.
BMJ Open Respir Res ; 9(1)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35715193

RESUMO

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease. Patients present at different stages and disease course is varied. Blood monocytes have been linked to all-cause mortality, and neutrophils to progression to IPF in patients with the indeterminate for usual interstitial pneumonia CT pattern. OBJECTIVE: To determine association between blood monocytes, neutrophils and lymphocytes levels (and their derived indexes), with lung function decline and mortality in IPF. METHODS: We performed a retrospective analysis of an IPF cohort (n=128) who had their first clinical visit at the Oxford Interstitial Lung Disease Service between 2013 and 2017. Association between blood monocytes, neutrophils, lymphocytes and derived indexes (within 4 months of visit) and decline in forced vital capacity (FVC) and all-cause mortality were assessed using Cox proportional hazard regression analysis. Kaplan-Meier analysis was used to assess time-to-event for 10% FVC decline and mortality for patients dichotomised to high and low leucocyte counts. RESULTS: Median length of follow-up was 31.0 months (IQR 16.2-42.4); 41.4% demonstrated FVC decline >10% per year and 43.8% died. In multivariate models (incorporating age, gender and initial FVC%), raised neutrophils, lymphopaenia and neutrophil:lymphocyte ratio were associated with FVC decline (p≤0.01); while both monocytes and neutrophil levels (and their derived indexes) were associated with all-cause mortality (p≤0.01). Kaplan-Meier analysis also showed association between neutrophils and its derived indexes but not monocyte, with FVC decline. CONCLUSION: Blood neutrophil and lymphopaenia are more sensitive than monocytes as prognostic indicators of disease progression in those with established IPF.


Assuntos
Fibrose Pulmonar Idiopática , Progressão da Doença , Humanos , Linfócitos , Neutrófilos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
6.
BMJ Open Respir Res ; 8(1)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34799353

RESUMO

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Identifying patients early may allow intervention which could limit progression. The 'indeterminate for usual interstitial pneumonia' (iUIP) CT pattern, defined in the 2018 IPF guidelines, could be a precursor to IPF but there is limited data on how patients with iUIP progress over time. OBJECTIVE: To evaluate the radiological progression of iUIP and explore factors linked to progression to IPF. METHODS: We performed a retrospective analysis of a lung fibrosis clinic cohort (n=230) seen between 2013 and 2017. Cases with iUIP were identified; first ever CTs for each patient found and categorised as 'non-progressor' or 'progressors' (the latter defined as increase in extent of disease or to 'definite' or 'probable' UIP CT pattern) during their follow-up. Lung function trends, haematological data and patient demographics were examined to explore disease evolution and potential contribution to progression. RESULTS: 48 cases with iUIP CT pattern were identified. Of these, 32 had follow-up CT scans, of which 23 demonstrated progression. 17 patients in this cohort were diagnosed with IPF over a mean (SD) period of 3.9 (±1.9) years. Monocyte (HR: 23, 95% CI: 1.6 to 340, p=0.03) and neutrophil levels (HR: 1.8, 95% CI: 1.3 to 2.3, p<0.001), obtained around the time of initial CT, were associated with progression to IPF using Cox proportional hazard modelling. CONCLUSION: 53% of our evaluable patients with iUIP progressed to IPF over a mean of 4 years. Monocyte and neutrophil levels at initial CT were significantly associated with progression in disease. These data provide a single-centre analysis of the evolution of patients with iUIP CT pattern, and first signal for potential factors associated with progression to IPF.


Assuntos
Fibrose Pulmonar Idiopática , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Monócitos , Neutrófilos , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
7.
Front Immunol ; 12: 623430, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746960

RESUMO

Idiopathic pulmonary fibrosis (IPF) is the most severe form of chronic lung fibrosis. Circulating monocytes have been implicated in immune pathology in IPF but their phenotype is unknown. In this work, we determined the immune phenotype of monocytes in IPF using multi-colour flow cytometry, RNA sequencing and corresponding serum factors, and mapped the main findings to amount of lung fibrosis and single cell transcriptomic landscape of myeloid cells in IPF lungs. We show that monocytes from IPF patients displayed increased expression of CD64 (FcγR1) which correlated with amount of lung fibrosis, and an amplified type I IFN response ex vivo. These were accompanied by markedly raised CSF-1 levels, IL-6, and CCL-2 in serum of IPF patients. Interrogation of single cell transcriptomic data from human IPF lungs revealed increased proportion of CD64hi monocytes and "transitional macrophages" with higher expression of CCL-2 and type I IFN genes. Our study shows that monocytes in IPF patients are phenotypically distinct from age-matched controls, with a primed type I IFN pathway that may contribute to driving chronic inflammation and fibrosis. These findings strengthen the potential role of monocytes in the pathogenesis of IPF.


Assuntos
Fibrose Pulmonar Idiopática/imunologia , Interferon Tipo I/metabolismo , Pulmão/imunologia , Monócitos/imunologia , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CCL2/sangue , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Imunofenotipagem , Interferon Tipo I/genética , Interleucina-6/sangue , Pulmão/metabolismo , Pulmão/patologia , Fator Estimulador de Colônias de Macrófagos/sangue , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/metabolismo , Fenótipo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Análise de Célula Única
8.
Nat Commun ; 12(1): 2298, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863903

RESUMO

Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility.


Assuntos
Doenças Autoimunes/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica/imunologia , Neutrófilos/imunologia , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Adulto , Idoso , Doenças Autoimunes/imunologia , Cromatina/metabolismo , Sequenciamento de Cromatina por Imunoprecipitação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas/genética , Locos de Características Quantitativas/imunologia , Adulto Jovem
9.
Nat Genet ; 53(9): 1311-1321, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34493871

RESUMO

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.


Assuntos
Metilação de DNA/genética , DNA/metabolismo , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Mapeamento Cromossômico , Epigênese Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Transcriptoma/genética
10.
Blood Adv ; 4(24): 6230-6239, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33351117

RESUMO

Although COVID-19 has been reported to be associated with high rates of venous thromboembolism (VTE), the risk of VTE and bleeding after hospitalization for COVID-19 remains unclear, and the optimal hospital VTE prevention strategy is not known. We collected retrospective observational data on thrombosis and bleeding in 303 consecutive adult patients admitted to the hospital for at least 24 hours for COVID-19. Patients presenting with VTE on admission were excluded. Data were collected until 90 days after admission or known death by using medical records and an established national VTE network. Maximal level of care was ward based in 78% of patients, with 22% requiring higher dependency care (12% noninvasive ventilation, 10% invasive ventilation). Almost all patients (97.0%) received standard thromboprophylaxis or were already receiving therapeutic anticoagulation (17.5%). Symptomatic image-confirmed VTE occurred in 5.9% of patients during index hospitalization, and in 7.2% at 90 days after admission (23.9% in patients requiring higher dependency care); half the events were isolated segmental or subsegmental defects on lung imaging. Bleeding occurred in 13 patients (4.3%) during index hospitalization (1.3% had major bleeding). The majority of bleeds occurred in patients on the general ward, and 6 patients were receiving treatment-dose anticoagulation, highlighting the need for caution in intensifying standard thromboprophylaxis strategies. Of 152 patients discharged from the hospital without an indication for anticoagulation, 97% did not receive thromboprophylaxis after discharge, and 3% received 7 days of treatment with low molecular weight heparin after discharge. The rate of symptomatic VTE in this group at 42 days after discharge was 2.6%, highlighting the need for large prospective randomized controlled trials of extended thromboprophylaxis after discharge in COVID-19.


Assuntos
COVID-19/complicações , COVID-19/epidemiologia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Testes de Coagulação Sanguínea , COVID-19/virologia , Diagnóstico por Imagem/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças , Inglaterra/epidemiologia , Feminino , Seguimentos , Hospitalização , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2 , Avaliação de Sintomas , Fatores de Tempo , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/prevenção & controle
11.
Nat Genet ; 51(2): 343-353, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30692680

RESUMO

Loci discovered by genome-wide association studies predominantly map outside protein-coding genes. The interpretation of the functional consequences of non-coding variants can be greatly enhanced by catalogs of regulatory genomic regions in cell lines and primary tissues. However, robust and readily applicable methods are still lacking by which to systematically evaluate the contribution of these regions to genetic variation implicated in diseases or quantitative traits. Here we propose a novel approach that leverages genome-wide association studies' findings with regulatory or functional annotations to classify features relevant to a phenotype of interest. Within our framework, we account for major sources of confounding not offered by current methods. We further assess enrichment of genome-wide association studies for 19 traits within Encyclopedia of DNA Elements- and Roadmap-derived regulatory regions. We characterize unique enrichment patterns for traits and annotations driving novel biological insights. The method is implemented in standalone software and an R package, to facilitate its application by the research community.


Assuntos
Doença/genética , Genoma/genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Humanos , Anotação de Sequência Molecular/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Software
12.
Cancer Cell ; 36(2): 123-138.e10, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31303423

RESUMO

Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.


Assuntos
Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Cromossomos Humanos Par 21 , Subunidade beta Comum dos Receptores de Citocinas/genética , Síndrome de Down/genética , Fator de Transcrição GATA1/genética , Leucemia Mieloide/genética , Reação Leucemoide/genética , Mutação , Animais , Modelos Animais de Doenças , Progressão da Doença , Síndrome de Down/diagnóstico , Fator de Transcrição GATA1/metabolismo , Regulação Leucêmica da Expressão Gênica , Predisposição Genética para Doença , Células HEK293 , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/patologia , Reação Leucemoide/diagnóstico , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Fenótipo , Transcrição Gênica
13.
Nat Commun ; 10(1): 357, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664637

RESUMO

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.


Assuntos
Alelos , Loci Gênicos , Variação Genética , RNA Mensageiro/genética , Crânio/metabolismo , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cefalometria , Criança , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Frequência do Gene , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Crânio/anatomia & histologia , População Branca
15.
Sci Rep ; 6: 22223, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26927695

RESUMO

The impact of microRNA (miRNA) on the genetics of human complex traits, especially in the context of miRNA-target gene networks, has not been fully assessed. Here, we developed a novel analytical method, MIGWAS, to comprehensively evaluate enrichment of genome-wide association study (GWAS) signals in miRNA-target gene networks. We applied the method to the GWAS results of the 18 human complex traits from >1.75 million subjects, and identified significant enrichment in rheumatoid arthritis (RA), kidney function, and adult height (P < 0.05/18 = 0.0028, most significant enrichment in RA with P = 1.7 × 10(-4)). Interestingly, these results were consistent with current literature-based knowledge of the traits on miRNA obtained through the NCBI PubMed database search (adjusted P = 0.024). Our method provided a list of miRNA and target gene pairs with excess genetic association signals, part of which included drug target genes. We identified a miRNA (miR-4728-5p) that downregulates PADI2, a novel RA risk gene considered as a promising therapeutic target (rs761426, adjusted P = 2.3 × 10(-9)). Our study indicated the significant impact of miRNA-target gene networks on the genetics of human complex traits, and provided resources which should contribute to drug discovery and nucleic acid medicine.


Assuntos
Artrite Reumatoide/genética , Hidrolases/genética , MicroRNAs/genética , Adulto , Estatura/genética , Regulação para Baixo , Redes Reguladoras de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Rim/fisiologia , Terapia de Alvo Molecular , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Proteína-Arginina Desiminase do Tipo 2 , Desiminases de Arginina em Proteínas , Risco
16.
Nat Genet ; 48(4): 466-72, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26901065

RESUMO

Genetic association studies have yielded a wealth of biological discoveries. However, these studies have mostly analyzed one trait and one SNP at a time, thus failing to capture the underlying complexity of the data sets. Joint genotype-phenotype analyses of complex, high-dimensional data sets represent an important way to move beyond simple genome-wide association studies (GWAS) with great potential. The move to high-dimensional phenotypes will raise many new statistical problems. Here we address the central issue of missing phenotypes in studies with any level of relatedness between samples. We propose a multiple-phenotype mixed model and use a computationally efficient variational Bayesian algorithm to fit the model. On a variety of simulated and real data sets from a range of organisms and trait types, we show that our method outperforms existing state-of-the-art methods from the statistics and machine learning literature and can boost signals of association.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Algoritmos , Animais , Animais não Endogâmicos , Teorema de Bayes , Plaquetas/fisiologia , Galinhas , Feminino , Humanos , Masculino , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Ratos , Linfócitos T/fisiologia , Triticum/genética
17.
Cell Rep ; 17(8): 2137-2150, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27851974

RESUMO

Epigenome-wide association studies (EWAS) provide an alternative approach for studying human disease through consideration of non-genetic variants such as altered DNA methylation. To advance the complex interpretation of EWAS, we developed eFORGE (http://eforge.cs.ucl.ac.uk/), a new standalone and web-based tool for the analysis and interpretation of EWAS data. eFORGE determines the cell type-specific regulatory component of a set of EWAS-identified differentially methylated positions. This is achieved by detecting enrichment of overlap with DNase I hypersensitive sites across 454 samples (tissues, primary cell types, and cell lines) from the ENCODE, Roadmap Epigenomics, and BLUEPRINT projects. Application of eFORGE to 20 publicly available EWAS datasets identified disease-relevant cell types for several common diseases, a stem cell-like signature in cancer, and demonstrated the ability to detect cell-composition effects for EWAS performed on heterogeneous tissues. Our approach bridges the gap between large-scale epigenomics data and EWAS-derived target selection to yield insight into disease etiology.


Assuntos
Epigenômica , Transdução de Sinais , Software , Estatística como Assunto , Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Humanos , Cariotipagem , Esclerose Múltipla/genética , Especificidade de Órgãos/genética , Transdução de Sinais/genética , Células-Tronco/metabolismo
18.
Nat Genet ; 48(11): 1303-1312, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27668658

RESUMO

Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.


Assuntos
Loci Gênicos , Genoma Humano , Estudo de Associação Genômica Ampla , Cardiopatias/genética , Doenças Hematológicas/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Locos de Características Quantitativas , Análise de Sequência de DNA
20.
Nat Commun ; 5: 4871, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25225788

RESUMO

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.


Assuntos
Alelos , Apolipoproteína C-III/genética , Lipoproteínas VLDL/sangue , Triglicerídeos/sangue , Processamento Alternativo , Criança , Feminino , Frequência do Gene , Humanos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Gêmeos/genética , População Branca
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