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2.
Nat Commun ; 12(1): 5242, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475398

RESUMO

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 ß cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving ß cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in ß cell transcriptional stress response and T2D genetics.


Assuntos
Diabetes Mellitus Tipo 2/genética , Estresse do Retículo Endoplasmático/genética , Células Secretoras de Insulina/patologia , Polimorfismo de Nucleotídeo Único , Ativação Transcricional/genética , Alelos , Animais , Linhagem Celular , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/patologia , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Locos de Características Quantitativas , Elementos Nucleotídeos Curtos e Dispersos/genética
3.
Cell ; 184(20): 5247-5260.e19, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34534445

RESUMO

3' untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3'UTR function, suggesting that simple sequences predominately explain 3'UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3'UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.

4.
Nat Genet ; 53(8): 1166-1176, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34326544

RESUMO

Effective interpretation of genome function and genetic variation requires a shift from epigenetic mapping of cis-regulatory elements (CREs) to characterization of endogenous function. We developed hybridization chain reaction fluorescence in situ hybridization coupled with flow cytometry (HCR-FlowFISH), a broadly applicable approach to characterize CRISPR-perturbed CREs via accurate quantification of native transcripts, alongside CRISPR activity screen analysis (CASA), a hierarchical Bayesian model to quantify CRE activity. Across >325,000 perturbations, we provide evidence that CREs can regulate multiple genes, skip over the nearest gene and display activating and/or silencing effects. At the cholesterol-level-associated FADS locus, we combine endogenous screens with reporter assays to exhaustively characterize multiple genome-wide association signals, functionally nominate causal variants and, importantly, identify their target genes.


Assuntos
Hibridização in Situ Fluorescente/métodos , Sequências Reguladoras de Ácido Nucleico , Proteínas Adaptadoras de Transdução de Sinal/genética , Teorema de Bayes , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Desoxirribonuclease I/genética , Desoxirribonuclease I/metabolismo , Ácidos Graxos Dessaturases/genética , Citometria de Fluxo , Fator de Transcrição GATA1/genética , Humanos , Células K562 , Proteínas com Domínio LIM/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Locos de Características Quantitativas , RNA Guia
5.
Nature ; 593(7858): 238-243, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33828297

RESUMO

Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease1. Many of the underlying causal variants may affect enhancers2,3, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types4. Here we apply this ABC model to create enhancer-gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.


Assuntos
Elementos Facilitadores Genéticos/genética , Predisposição Genética para Doença , Variação Genética/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Doenças Inflamatórias Intestinais/genética , Linhagem Celular , Cromossomos Humanos Par 10/genética , Ciclofilinas/genética , Células Dendríticas , Feminino , Humanos , Macrófagos/metabolismo , Masculino , Mitocôndrias/metabolismo , Especificidade de Órgãos/genética , Fenótipo
6.
Nat Genet ; 53(2): 195-204, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462486

RESUMO

Admixed populations are routinely excluded from genomic studies due to concerns over population structure. Here, we present a statistical framework and software package, Tractor, to facilitate the inclusion of admixed individuals in association studies by leveraging local ancestry. We test Tractor with simulated and empirical two-way admixed African-European cohorts. Tractor generates accurate ancestry-specific effect-size estimates and P values, can boost genome-wide association study (GWAS) power and improves the resolution of association signals. Using a local ancestry-aware regression model, we replicate known hits for blood lipids, discover novel hits missed by standard GWAS and localize signals closer to putative causal variants.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Modelos Genéticos , Software , Colesterol/sangue , Colesterol/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Haplótipos/genética , Proteínas de Homeodomínio/genética , Humanos , Lipídeos/sangue , Linhagem , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética
7.
Nat Commun ; 11(1): 1237, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144282

RESUMO

Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants.


Assuntos
Doenças Autoimunes/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Linhagem Celular Tumoral , Predisposição Genética para Doença , Variação Genética/imunologia , Haplótipos/genética , Haplótipos/imunologia , Humanos , Desequilíbrio de Ligação , Herança Multifatorial/imunologia , Estudo de Prova de Conceito
8.
Nat Genet ; 52(2): 138-145, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31959994

RESUMO

Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and ß-thalassemia1. BCL11A represses the genes encoding HbF and regulates human hemoglobin switching through variation in its expression during development2-7. However, the mechanisms underlying the developmental expression of BCL11A remain mysterious. Here we show that BCL11A is regulated at the level of messenger RNA (mRNA) translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a pattern reciprocal to that of BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, we show that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independently of its role in regulating let-7 microRNAs, and that BCL11A is the major target of LIN28B-mediated HbF induction. Our results reveal a previously unappreciated mechanism underlying human hemoglobin switching that illuminates new therapeutic opportunities.


Assuntos
Hemoglobinas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/genética , Adulto , Animais , Sítios de Ligação , Células Cultivadas , Células Eritroides/metabolismo , Eritropoese/genética , Regulação da Expressão Gênica , Hemoglobinas/genética , Humanos , Recém-Nascido , MicroRNAs/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , RNA Ribossômico 18S/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/metabolismo , Ribossomos/genética , Ribossomos/metabolismo
10.
Nature ; 575(7784): 652-657, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31748747

RESUMO

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Y/genética , Predisposição Genética para Doença/genética , Instabilidade Genômica/genética , Leucócitos/patologia , Mosaicismo , Adulto , Idoso , Biologia Computacional , Bases de Dados Genéticas , Feminino , Marcadores Genéticos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Reino Unido
11.
Cell Rep ; 27(11): 3228-3240.e7, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31189107

RESUMO

Human erythropoiesis serves as a paradigm of physiologic cellular differentiation. This process is also of considerable interest for better understanding anemias and identifying new therapies. Here, we apply deep transcriptomic and accessible chromatin profiling to characterize a faithful ex vivo human erythroid differentiation system from hematopoietic stem and progenitor cells. We reveal stage-specific transcriptional states and chromatin accessibility during various stages of erythropoiesis, including 14,260 differentially expressed genes and 63,659 variably accessible chromatin peaks. Our analysis suggests differentiation stage-predominant roles for specific master regulators, including GATA1 and KLF1. We integrate chromatin profiles with common and rare genetic variants associated with erythroid cell traits and diseases, finding that variants regulating different erythroid phenotypes likely act at variable points during differentiation. In addition, we identify a regulator of terminal erythropoiesis, TMCC2, more broadly illustrating the value of this comprehensive analysis to improve our understanding of erythropoiesis in health and disease.


Assuntos
Montagem e Desmontagem da Cromatina , Eritropoese , Transcriptoma , Idoso , Células Cultivadas , Cromatina/química , Cromatina/metabolismo , Células Precursoras Eritroides/citologia , Células Precursoras Eritroides/metabolismo , Feminino , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Células HEK293 , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
Elife ; 82019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31070582

RESUMO

Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding regions of the genome and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in specific and relevant biological pathways, allowing regulators of human erythropoiesis and modifiers of blood diseases to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.


Assuntos
Doenças Genéticas Inatas , Predisposição Genética para Doença , Hematopoese/genética , Locos de Características Quantitativas/genética , Eritrócitos/metabolismo , Eritrócitos/patologia , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética
13.
Elife ; 82019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31033440

RESUMO

Iron and heme play central roles in the production of red blood cells, but the underlying mechanisms remain incompletely understood. Heme-regulated eIF2α kinase (HRI) controls translation by phosphorylating eIF2α. Here, we investigate the global impact of iron, heme, and HRI on protein translation in vivo in murine primary erythroblasts using ribosome profiling. We validate the known role of HRI-mediated translational stimulation of integratedstressresponse mRNAs during iron deficiency in vivo. Moreover, we find that the translation of mRNAs encoding cytosolic and mitochondrial ribosomal proteins is substantially repressed by HRI during iron deficiency, causing a decrease in cytosolic and mitochondrial protein synthesis. The absence of HRI during iron deficiency elicits a prominent cytoplasmic unfolded protein response and impairs mitochondrial respiration. Importantly, ATF4 target genes are activated during iron deficiency to maintain mitochondrial function and to enable erythroid differentiation. We further identify GRB10 as a previously unappreciated regulator of terminal erythropoiesis.


Assuntos
Eritropoese/fisiologia , Heme/metabolismo , Ferro/metabolismo , Mitocôndrias/metabolismo , Proteostase/fisiologia , eIF-2 Quinase/metabolismo , Fator 4 Ativador da Transcrição/genética , Anemia Ferropriva , Animais , Diferenciação Celular , Eritroblastos , Fator de Iniciação 2 em Eucariotos/metabolismo , Proteína Adaptadora GRB10/genética , Proteína Adaptadora GRB10/metabolismo , Camundongos , Camundongos Knockout , Oxigênio/metabolismo , Fosforilação , Biossíntese de Proteínas , Proteínas Ribossômicas , Resposta a Proteínas não Dobradas , eIF-2 Quinase/genética
14.
Cell ; 176(6): 1325-1339.e22, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827679

RESUMO

Lineage tracing provides key insights into the fate of individual cells in complex organisms. Although effective genetic labeling approaches are available in model systems, in humans, most approaches require detection of nuclear somatic mutations, which have high error rates, limited scale, and do not capture cell state information. Here, we show that somatic mutations in mtDNA can be tracked by single-cell RNA or assay for transposase accessible chromatin (ATAC) sequencing. We leverage somatic mtDNA mutations as natural genetic barcodes and demonstrate their utility as highly accurate clonal markers to infer cellular relationships. We track native human cells both in vitro and in vivo and relate clonal dynamics to gene expression and chromatin accessibility. Our approach should allow clonal tracking at a 1,000-fold greater scale than with nuclear genome sequencing, with simultaneous information on cell state, opening the way to chart cellular dynamics in human health and disease.


Assuntos
DNA Mitocondrial/genética , Mitocôndrias/genética , Sequência de Bases , Linhagem da Célula , Cromatina , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Genômica/métodos , Células HEK293 , Células-Tronco Hematopoéticas/fisiologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Análise de Célula Única , Transposases
15.
Nat Genet ; 51(4): 683-693, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30858613

RESUMO

Widespread linkage disequilibrium and incomplete annotation of cell-to-cell state variation represent substantial challenges to elucidating mechanisms of trait-associated genetic variation. Here we perform genetic fine-mapping for blood cell traits in the UK Biobank to identify putative causal variants. These variants are enriched in genes encoding proteins in trait-relevant biological pathways and in accessible chromatin of hematopoietic progenitors. For regulatory variants, we explore patterns of developmental enhancer activity, predict molecular mechanisms, and identify likely target genes. In several instances, we localize multiple independent variants to the same regulatory element or gene. We further observe that variants with pleiotropic effects preferentially act in common progenitor populations to direct the production of distinct lineages. Finally, we leverage fine-mapped variants in conjunction with continuous epigenomic annotations to identify trait-cell type enrichments within closely related populations and in single cells. Our study provides a comprehensive framework for single-variant and single-cell analyses of genetic associations.


Assuntos
Hematopoese/genética , Polimorfismo de Nucleotídeo Único/genética , Linhagem da Célula/genética , Cromatina/genética , Mapeamento Cromossômico/métodos , Epigenômica/métodos , Estudo de Associação Genômica Ampla/métodos , Humanos , Desequilíbrio de Ligação/genética , Fenótipo , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico/genética
16.
J Exp Med ; 216(5): 1050-1060, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-30914438

RESUMO

Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing the pathogenicity of noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrate that this single-nucleotide alteration leads to reduced canonical splicing and increased use of an alternative splice acceptor site that causes a partial intron retention event. The resultant altered GATA1 contains a five-amino acid insertion at the C-terminus of the C-terminal zinc finger and has no observable activity. Collectively, our results demonstrate how altered splicing of GATA1, which reduces levels of the normal form of this master transcription factor, can result in distinct changes in human hematopoiesis.


Assuntos
Processamento Alternativo/genética , Anemia Diseritropoética Congênita/genética , Fator de Transcrição GATA1/genética , Hematopoese/genética , Íntrons/genética , Mutação de Sentido Incorreto , Síndromes Mielodisplásicas/genética , Adulto , Criança , Éxons , Células HEK293 , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Síndromes Mielodisplásicas/patologia , Sítios de Splice de RNA/genética , Transcrição Genética/genética , Transfecção
18.
Am J Hum Genet ; 103(6): 930-947, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30503522

RESUMO

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.


Assuntos
Anemia de Diamond-Blackfan/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Exoma/genética , Éxons/genética , Feminino , Deleção de Genes , Estudos de Associação Genética/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Mutação/genética , Fenótipo , Proteínas Ribossômicas/genética , Ribossomos/genética , Análise de Sequência de RNA/métodos , Sequenciamento Completo do Exoma/métodos
20.
Nat Genet ; 50(10): 1483-1493, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30177862

RESUMO

Biological interpretation of genome-wide association study data frequently involves assessing whether SNPs linked to a biological process, for example, binding of a transcription factor, show unsigned enrichment for disease signal. However, signed annotations quantifying whether each SNP allele promotes or hinders the biological process can enable stronger statements about disease mechanism. We introduce a method, signed linkage disequilibrium profile regression, for detecting genome-wide directional effects of signed functional annotations on disease risk. We validate the method via simulations and application to molecular quantitative trait loci in blood, recovering known transcriptional regulators. We apply the method to expression quantitative trait loci in 48 Genotype-Tissue Expression tissues, identifying 651 transcription factor-tissue associations including 30 with robust evidence of tissue specificity. We apply the method to 46 diseases and complex traits (average n = 290 K), identifying 77 annotation-trait associations representing 12 independent transcription factor-trait associations, and characterize the underlying transcriptional programs using gene-set enrichment analyses. Our results implicate new causal disease genes and new disease mechanisms.


Assuntos
Doença/genética , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Locos de Características Quantitativas , Fatores de Transcrição/metabolismo , Sítios de Ligação/genética , Células Sanguíneas/metabolismo , Células Sanguíneas/patologia , Análise Química do Sangue , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Fenótipo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Fatores de Risco
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