RESUMEN
Current catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of gene regulatory elements in diverse cell types and tissues in the human body, we applied single-cell chromatin accessibility assays to 30 adult human tissue types from multiple donors. We integrated these datasets with previous single-cell chromatin accessibility data from 15 fetal tissue types to reveal the status of open chromatin for â¼1.2 million candidate cis-regulatory elements (cCREs) in 222 distinct cell types comprised of >1.3 million nuclei. We used these chromatin accessibility maps to delineate cell-type-specificity of fetal and adult human cCREs and to systematically interpret the noncoding variants associated with complex human traits and diseases. This rich resource provides a foundation for the analysis of gene regulatory programs in human cell types across tissues, life stages, and organ systems.
Asunto(s)
Cromatina/metabolismo , Genoma Humano , Análisis de la Célula Individual , Adulto , Análisis por Conglomerados , Feto/metabolismo , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Especificidad de Órganos , Filogenia , Secuencias Reguladoras de Ácidos Nucleicos/genética , Factores de RiesgoRESUMEN
Cell type-specific gene expression patterns and dynamics during development or in disease are controlled by cis-regulatory elements (CREs), such as promoters and enhancers. Distinct classes of CREs can be characterized by their epigenomic features, including DNA methylation, chromatin accessibility, combinations of histone modifications and conformation of local chromatin. Tremendous progress has been made in cataloguing CREs in the human genome using bulk transcriptomic and epigenomic methods. However, single-cell epigenomic and multi-omic technologies have the potential to provide deeper insight into cell type-specific gene regulatory programmes as well as into how they change during development, in response to environmental cues and through disease pathogenesis. Here, we highlight recent advances in single-cell epigenomic methods and analytical tools and discuss their readiness for human tissue profiling.
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Epigenómica , Secuencias Reguladoras de Ácidos Nucleicos , Humanos , Cromatina/genética , Regiones Promotoras Genéticas , Metilación de ADNRESUMEN
Genome-wide association studies (GWAS) have linked hundreds of thousands of sequence variants in the human genome to common traits and diseases. However, translating this knowledge into a mechanistic understanding of disease-relevant biology remains challenging, largely because such variants are predominantly in non-protein-coding sequences that still lack functional annotation at cell-type resolution. Recent advances in single-cell epigenomics assays have enabled the generation of cell type-, subtype- and state-resolved maps of the epigenome in heterogeneous human tissues. These maps have facilitated cell type-specific annotation of candidate cis-regulatory elements and their gene targets in the human genome, enhancing our ability to interpret the genetic basis of common traits and diseases.
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Epigenómica , Estudio de Asociación del Genoma Completo , Humanos , Secuencias Reguladoras de Ácidos Nucleicos , Genoma Humano , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding1. Translating these risk variants into mechanistic insights requires detailed maps of gene regulation in disease-relevant cell types2. Here we combined two approaches: a genome-wide association study of type 1 diabetes (T1D) using 520,580 samples, and the identification of candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cells using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) of 131,554 nuclei. Risk variants for T1D were enriched in cCREs that were active in T cells and other cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped with exocrine-specific cCREs that were linked to genes with exocrine-specific expression. At the CFTR locus, the T1D risk variant rs7795896 mapped to a ductal-specific cCRE that regulated CFTR; the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in the pathogenesis of T1D and highlight the power of large-scale genome-wide association studies and single-cell epigenomics for understanding the cellular origins of complex disease.
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Diabetes Mellitus Tipo 1/genética , Epigenómica , Predisposición Genética a la Enfermedad , Análisis de la Célula Individual , Cromatina/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Femenino , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Inmunidad/genética , Masculino , Conductos Pancreáticos/metabolismo , Conductos Pancreáticos/patologíaRESUMEN
Many sequence variants have been linked to complex human traits and diseases1, but deciphering their biological functions remains challenging, as most of them reside in noncoding DNA. Here we have systematically assessed the binding of 270 human transcription factors to 95,886 noncoding variants in the human genome using an ultra-high-throughput multiplex protein-DNA binding assay, termed single-nucleotide polymorphism evaluation by systematic evolution of ligands by exponential enrichment (SNP-SELEX). The resulting 828 million measurements of transcription factor-DNA interactions enable estimation of the relative affinity of these transcription factors to each variant in vitro and evaluation of the current methods to predict the effects of noncoding variants on transcription factor binding. We show that the position weight matrices of most transcription factors lack sufficient predictive power, whereas the support vector machine combined with the gapped k-mer representation show much improved performance, when assessed on results from independent SNP-SELEX experiments involving a new set of 61,020 sequence variants. We report highly predictive models for 94 human transcription factors and demonstrate their utility in genome-wide association studies and understanding of the molecular pathways involved in diverse human traits and diseases.
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Polimorfismo de Nucleótido Simple/genética , Técnica SELEX de Producción de Aptámeros , Máquina de Vectores de Soporte , Factores de Transcripción/metabolismo , Sitios de Unión/genética , Enfermedad/genética , Genoma Humano/genética , Humanos , Ligandos , Unión ProteicaRESUMEN
The mammalian cerebrum performs high-level sensory perception, motor control and cognitive functions through highly specialized cortical and subcortical structures1. Recent surveys of mouse and human brains with single-cell transcriptomics2-6 and high-throughput imaging technologies7,8 have uncovered hundreds of neural cell types distributed in different brain regions, but the transcriptional regulatory programs that are responsible for the unique identity and function of each cell type remain unknown. Here we probe the accessible chromatin in more than 800,000 individual nuclei from 45 regions that span the adult mouse isocortex, olfactory bulb, hippocampus and cerebral nuclei, and use the resulting data to map the state of 491,818 candidate cis-regulatory DNA elements in 160 distinct cell types. We find high specificity of spatial distribution for not only excitatory neurons, but also most classes of inhibitory neurons and a subset of glial cell types. We characterize the gene regulatory sequences associated with the regional specificity within these cell types. We further link a considerable fraction of the cis-regulatory elements to putative target genes expressed in diverse cerebral cell types and predict transcriptional regulators that are involved in a broad spectrum of molecular and cellular pathways in different neuronal and glial cell populations. Our results provide a foundation for comprehensive analysis of gene regulatory programs of the mammalian brain and assist in the interpretation of noncoding risk variants associated with various neurological diseases and traits in humans.
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Cerebro/citología , Cerebro/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos/genética , Animales , Atlas como Asunto , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades del Sistema Nervioso/genética , Neuroglía/clasificación , Neuroglía/metabolismo , Neuronas/clasificación , Neuronas/metabolismo , Análisis de Secuencia de ADN , Análisis de la Célula IndividualRESUMEN
To address the challenge of translating genetic discoveries for type 1 diabetes (T1D) into mechanistic insight, we have developed the T1D Knowledge Portal (T1DKP), an open-access resource for hypothesis development and target discovery in T1D.
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Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/genética , Genómica , Genética HumanaRESUMEN
Gene regulation is highly cell type-specific and understanding the function of non-coding genetic variants associated with complex traits requires molecular phenotyping at cell type resolution. In this study we performed single nucleus ATAC-seq (snATAC-seq) and genotyping in peripheral blood mononuclear cells from 13 individuals. Clustering chromatin accessibility profiles of 96,002 total nuclei identified 17 immune cell types and sub-types. We mapped chromatin accessibility QTLs (caQTLs) in each immune cell type and sub-type using individuals of European ancestry which identified 6,901 caQTLs at FDR < .10 and 4,220 caQTLs at FDR < .05, including those obscured from assays of bulk tissue such as with divergent effects on different cell types. For 3,941 caQTLs we further annotated putative target genes of variant activity using single cell co-accessibility, and caQTL variants were significantly correlated with the accessibility level of linked gene promoters. We fine-mapped loci associated with 16 complex immune traits and identified immune cell caQTLs at 622 candidate causal variants, including those with cell type-specific effects. At the 6q15 locus associated with type 1 diabetes, in line with previous reports, variant rs72928038 was a naïve CD4+ T cell caQTL linked to BACH2 and we validated the allelic effects of this variant on regulatory activity in Jurkat T cells. These results highlight the utility of snATAC-seq for mapping genetic effects on accessible chromatin in specific cell types.
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Secuenciación de Inmunoprecipitación de Cromatina , Cromatina , Humanos , Cromatina/genética , Herencia Multifactorial , Leucocitos Mononucleares , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families and communities. One of the seminal challenges in treating and studying addiction in human populations is the high prevalence of co-morbid conditions, including an increased risk of contracting a human immunodeficiency virus (HIV) infection. Of the ~15 million people who inject drugs globally, 17% are persons with HIV. Conversely, HIV is a risk factor for SUD because chronic pain syndromes, often encountered in persons with HIV, can lead to an increased use of opioid pain medications that in turn can increase the risk for opioid addiction. We hypothesize that SUD and HIV exert shared effects on brain cell types, including adaptations related to neuroplasticity, neurodegeneration, and neuroinflammation. Basic research is needed to refine our understanding of these affected cell types and adaptations. Studying the effects of SUD in the context of HIV at the single-cell level represents a compelling strategy to understand the reciprocal interactions among both conditions, made feasible by the availability of large, extensively-phenotyped human brain tissue collections that have been amassed by the Neuro-HIV research community. In addition, sophisticated animal models that have been developed for both conditions provide a means to precisely evaluate specific exposures and stages of disease. We propose that single-cell genomics is a uniquely powerful technology to characterize the effects of SUD and HIV in the brain, integrating data from human cohorts and animal models. We have formed the Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium to carry out this strategy.
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Glucocorticoids are key regulators of glucose homeostasis and pancreatic islet function, but the gene regulatory programs driving responses to glucocorticoid signaling in islets and the contribution of these programs to diabetes risk are unknown. In this study we used ATAC-seq and RNA-seq to map chromatin accessibility and gene expression from eleven primary human islet samples cultured in vitro with the glucocorticoid dexamethasone at multiple doses and durations. We identified thousands of accessible chromatin sites and genes with significant changes in activity in response to glucocorticoids. Chromatin sites up-regulated in glucocorticoid signaling were prominently enriched for glucocorticoid receptor binding sites and up-regulated genes were enriched for ion transport and lipid metabolism, whereas down-regulated chromatin sites and genes were enriched for inflammatory, stress response and proliferative processes. Genetic variants associated with glucose levels and T2D risk were enriched in glucocorticoid-responsive chromatin sites, including fine-mapped variants at 51 known signals. Among fine-mapped variants in glucocorticoid-responsive chromatin, a likely casual variant at the 2p21 locus had glucocorticoid-dependent allelic effects on beta cell enhancer activity and affected SIX2 and SIX3 expression. Our results provide a comprehensive map of islet regulatory programs in response to glucocorticoids through which we uncover a role for islet glucocorticoid signaling in mediating genetic risk of T2D.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Glucocorticoides/metabolismo , Islotes Pancreáticos/metabolismo , Transducción de Señal , Animales , Glucemia/metabolismo , Línea Celular , Cromatina/genética , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/sangre , Humanos , RatonesRESUMEN
Long noncoding RNAs (lncRNAs) can regulate target gene expression by acting in cis (locally) or in trans (non-locally). Here, we performed genome-wide expression analysis of Toll-like receptor (TLR)-stimulated human macrophages to identify pairs of cis-acting lncRNAs and protein-coding genes involved in innate immunity. A total of 229 gene pairs were identified, many of which were commonly regulated by signaling through multiple TLRs and were involved in the cytokine responses to infection by group B Streptococcus We focused on elucidating the function of one lncRNA, named lnc-MARCKS or ROCKI (Regulator of Cytokines and Inflammation), which was induced by multiple TLR stimuli and acted as a master regulator of inflammatory responses. ROCKI interacted with APEX1 (apurinic/apyrimidinic endodeoxyribonuclease 1) to form a ribonucleoprotein complex at the MARCKS promoter. In turn, ROCKI-APEX1 recruited the histone deacetylase HDAC1, which removed the H3K27ac modification from the promoter, thus reducing MARCKS transcription and subsequent Ca2+ signaling and inflammatory gene expression. Finally, genetic variants affecting ROCKI expression were linked to a reduced risk of certain inflammatory and infectious disease in humans, including inflammatory bowel disease and tuberculosis. Collectively, these data highlight the importance of cis-acting lncRNAs in TLR signaling, innate immunity, and pathophysiological inflammation.
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Regulación de la Expresión Génica , Inmunidad Innata/inmunología , Inflamación/inmunología , Macrófagos/inmunología , ARN Largo no Codificante/metabolismo , Infecciones Estreptocócicas/microbiología , Receptores Toll-Like/metabolismo , Células Cultivadas , Citocinas/metabolismo , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Genoma Humano , Histona Desacetilasa 1/genética , Histona Desacetilasa 1/metabolismo , Humanos , Inflamación/genética , Inflamación/microbiología , Macrófagos/metabolismo , Macrófagos/microbiología , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada/genética , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada/metabolismo , Regiones Promotoras Genéticas , ARN Largo no Codificante/genética , Infecciones Estreptocócicas/inmunología , Streptococcus agalactiae/aislamiento & purificación , Receptores Toll-Like/genéticaRESUMEN
The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Alelos , Análisis Mutacional de ADN , Europa (Continente)/etnología , Exoma , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Tamaño de la MuestraRESUMEN
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
Asunto(s)
Envejecimiento/genética , Peso al Nacer/genética , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/genética , Feto/metabolismo , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Adulto , Antropometría , Presión Sanguínea/genética , Ensamble y Desensamble de Cromatina , Estudios de Cohortes , Conjuntos de Datos como Asunto , Femenino , Sitios Genéticos/genética , Variación Genética/genética , Impresión Genómica/genética , Genotipo , Glucosa/metabolismo , Glucógeno/biosíntesis , Humanos , Insulina/metabolismo , Masculino , Fenotipo , Transducción de SeñalRESUMEN
[This corrects the article DOI: 10.1371/journal.pgen.1006728.].
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A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética , Americanos Mexicanos/genética , Diabetes Mellitus Tipo 2/etnología , Diabetes Mellitus Tipo 2/patología , Salud de la Familia , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Linaje , Fenotipo , Sitios de Carácter Cuantitativo/genética , Secuenciación Completa del Genoma/métodosRESUMEN
The extent to which shared genetic risk contributes to T1D and T2D etiology is unknown. In this study, we generated T1D association data of 15k samples imputed into the HRC panel which we compared to published T2D association data imputed into 1000 Genomes. The effects of genetic variants on T1D and T2D risk at known loci and genome-wide were positively correlated. Increased risk of T1D and T2D was correlated with higher fasting insulin and glucose level and decreased birth weight, among other correlations. Variants with T1D and T2D association were further enriched in pancreatic, adipose, B cell, and endoderm regulatory elements. We fine-mapped causal variants at known loci and found evidence for co-localization at five signals, four of which had same direction of effect. Shared risk variants were associated with quantitative measures of islet function and early growth, and were expression QTLs in relevant tissues. We further identified a shared variant at GLIS3 in islet accessible chromatin with allelic effects on enhancer activity. Our findings identify a shared genetic risk involving effects on islet function as well as insulin resistance, growth and development in the etiology of T1D and T2D, supporting a role for T2D-relevant processes in addition to autoimmunity in T1D risk.
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Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in ß cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, ß-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+ dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult ß cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in ß cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the ß cell.
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Diabetes Mellitus Tipo 2/genética , Insulina/metabolismo , Fosfoproteínas/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Alelos , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Clonación Molecular , Diabetes Mellitus Tipo 2/sangre , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Regulación de la Expresión Génica , Variación Genética , Homeostasis , Humanos , Insulina/sangre , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Hígado/metabolismo , Ratones , Proinsulina/sangre , Proinsulina/metabolismo , Sitios de Carácter Cuantitativo , TranscriptomaRESUMEN
Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
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Presión Sanguínea/genética , Sitios Genéticos , Hipertensión/genética , Herencia Multifactorial , Negro o Afroamericano/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Cadherinas/genética , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Hipertensión/etnología , Masculino , Proteínas de la Membrana/genética , Ratones , Polimorfismo de Nucleótido SimpleRESUMEN
We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
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Etnicidad/genética , Estudio de Asociación del Genoma Completo , Riñón/fisiopatología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/fisiopatología , Cloruro de Sodio/farmacología , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/genética , Alelos , Animales , Desoxirribonucleasa I/metabolismo , Diabetes Mellitus/genética , Modelos Animales de Enfermedad , Drosophila melanogaster/genética , Femenino , Tasa de Filtración Glomerular/genética , Humanos , Riñón/patología , Desequilibrio de Ligamiento , Masculino , Factores de Transcripción NFATC/genética , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo , Proteínas RGS/genética , Grupos Raciales/genética , Tolerancia a la Sal/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genéticaRESUMEN
Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.