RESUMEN
Understanding differences in adipose gene expression between individuals with different levels of clinical traits may reveal the genes and mechanisms leading to cardiometabolic diseases. However, adipose is a heterogeneous tissue. To account for cell-type heterogeneity, we estimated cell-type proportions in 859 subcutaneous adipose tissue samples with bulk RNA sequencing (RNA-seq) using a reference single-nuclear RNA-seq data set. Cell-type proportions were associated with cardiometabolic traits; for example, higher macrophage and adipocyte proportions were associated with higher and lower BMI, respectively. We evaluated cell-type proportions and BMI as covariates in tests of association between >25,000 gene expression levels and 22 cardiometabolic traits. For >95% of genes, the optimal, or best-fit, models included BMI as a covariate, and for 79% of associations, the optimal models also included cell type. After adjusting for the optimal covariates, we identified 2,664 significant associations (P ≤ 2e-6) for 1,252 genes and 14 traits. Among genes proposed to affect cardiometabolic traits based on colocalized genome-wide association study and adipose expression quantitative trait locus signals, 25 showed a corresponding association between trait and gene expression levels. Overall, these results suggest the importance of modeling cell-type proportion when identifying gene expression associations with cardiometabolic traits.
Asunto(s)
Enfermedades Cardiovasculares , Estudio de Asociación del Genoma Completo , Humanos , Índice de Masa Corporal , Obesidad/genética , Expresión Génica , Enfermedades Cardiovasculares/genéticaAsunto(s)
Adaptación Psicológica , Racismo Sistemático , Emociones , Humanos , Racismo Sistemático/psicologíaRESUMEN
Chromatin accessibility and gene expression in relevant cell contexts can guide identification of regulatory elements and mechanisms at genome-wide association study (GWAS) loci. To identify regulatory elements that display differential activity across adipocyte differentiation, we performed ATAC-seq and RNA-seq in a human cell model of preadipocytes and adipocytes at days 4 and 14 of differentiation. For comparison, we created a consensus map of ATAC-seq peaks in 11 human subcutaneous adipose tissue samples. We identified 58,387 context-dependent chromatin accessibility peaks and 3,090 context-dependent genes between all timepoint comparisons (log2 fold change>1, FDR<5%) with 15,919 adipocyte- and 18,244 preadipocyte-dependent peaks. Adipocyte-dependent peaks showed increased overlap (60.1%) with Roadmap Epigenomics adipocyte nuclei enhancers compared to preadipocyte-dependent peaks (11.5%). We linked context-dependent peaks to genes based on adipocyte promoter capture Hi-C data, overlap with adipose eQTL variants, and context-dependent gene expression. Of 16,167 context-dependent peaks linked to a gene, 5,145 were linked by two or more strategies to 1,670 genes. Among GWAS loci for cardiometabolic traits, adipocyte-dependent peaks, but not preadipocyte-dependent peaks, showed significant enrichment (LD score regression P<0.005) for waist-to-hip ratio and modest enrichment (P < 0.05) for HDL-cholesterol. We identified 659 peaks linked to 503 genes by two or more approaches and overlapping a GWAS signal, suggesting a regulatory mechanism at these loci. To identify variants that may alter chromatin accessibility between timepoints, we identified 582 variants in 454 context-dependent peaks that demonstrated allelic imbalance in accessibility (FDR<5%), of which 55 peaks also overlapped GWAS variants. At one GWAS locus for palmitoleic acid, rs603424 was located in an adipocyte-dependent peak linked to SCD and exhibited allelic differences in transcriptional activity in adipocytes (P = 0.003) but not preadipocytes (P = 0.09). These results demonstrate that context-dependent peaks and genes can guide discovery of regulatory variants at GWAS loci and aid identification of regulatory mechanisms.
Asunto(s)
Diferenciación Celular/genética , Cromatina/genética , Expresión Génica/genética , Sitios de Carácter Cuantitativo/genética , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Alelos , Desequilibrio Alélico/genética , Sitios de Unión/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Cromatina/metabolismo , Secuenciación de Inmunoprecipitación de Cromatina/métodos , Epigenómica/métodos , Técnicas Genéticas , Estudio de Asociación del Genoma Completo/métodos , Humanos , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/metabolismo , Regiones Promotoras Genéticas/genética , Secuencias Reguladoras de Ácidos Nucleicos/genéticaRESUMEN
Identifying the molecular mechanisms by which genome-wide association study (GWAS) loci influence traits remains challenging. Chromatin accessibility quantitative trait loci (caQTLs) help identify GWAS loci that may alter GWAS traits by modulating chromatin structure, but caQTLs have been identified in a limited set of human tissues. Here we mapped caQTLs in human liver tissue in 20 liver samples and identified 3,123 caQTLs. The caQTL variants are enriched in liver tissue promoter and enhancer states and frequently disrupt binding motifs of transcription factors expressed in liver. We predicted target genes for 861 caQTL peaks using proximity, chromatin interactions, correlation with promoter accessibility or gene expression, and colocalization with expression QTLs. Using GWAS signals for 19 liver function and/or cardiometabolic traits, we identified 110 colocalized caQTLs and GWAS signals, 56 of which contained a predicted caPeak target gene. At the LITAF LDL-cholesterol GWAS locus, we validated that a caQTL variant showed allelic differences in protein binding and transcriptional activity. These caQTLs contribute to the epigenomic characterization of human liver and help identify molecular mechanisms and genes at GWAS loci.
Asunto(s)
Cromatina/metabolismo , Hígado/metabolismo , Sitios de Carácter Cuantitativo , Secuencias de Aminoácidos , Sitios de Unión , Ensamble y Desensamble de Cromatina , Elementos de Facilitación Genéticos , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Regiones Promotoras Genéticas , Unión Proteica , Factores de Transcripción/química , Factores de Transcripción/metabolismo , TranscriptomaRESUMEN
Introduction: The American Academy of Pediatrics (AAP) recommends that pediatricians promote school readiness with children and families. To our knowledge, no published resident-focused curricula addressing school readiness are currently available. We sought to fill this gap by developing and evaluating a school readiness curriculum for pediatrics residents. Methods: We conducted a literature review and targeted needs assessment of pediatrics residents. We then developed a school readiness curriculum and piloted it over several months, adjusting it iteratively each month. The final curriculum was delivered to 34 primarily first-year pediatrics residents over 11 months and included three self-guided observations at local preschools using a templated observation guide, followed by a 1.5-hour in-person facilitated workshop with three components: a PowerPoint presentation, a discussion about preschool observations, and a case study with hands-on developmental questionnaire practice. The curriculum was evaluated with preintervention, immediate postintervention, and 2-months delayed postintervention surveys. Results: Our curriculum successfully increased pediatrics residents' knowledge regarding the correct definition of school readiness and appropriate management plan for school readiness concerns, confidence discussing school readiness and addressing families' school readiness concerns, and behavior raising the topic of school readiness with families during well child checks. Discussion: A school readiness curriculum had a beneficial effect of increasing pediatrics residents' knowledge, confidence, and behavior addressing school readiness in clinical encounters, meeting a priority of the AAP.
Asunto(s)
Internado y Residencia , Pediatría , Niño , Competencia Clínica , Curriculum , Humanos , Instituciones Académicas , Estados UnidosRESUMEN
Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2<0.01). Two loci exhibited allelic heterogeneity, ADIPOQ and CDH13. Of seven association signals at the ADIPOQ locus, two signals colocalized with adipose tissue expression quantitative trait loci (eQTLs) for three transcripts: trait-increasing alleles at one signal were associated with increased ADIPOQ and LINC02043, while trait-increasing alleles at the other signal were associated with decreased ADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the seven ADIPOQ signals include a missense variant (ADIPOQ G90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at the CDH13 locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant for CDH13, while a second signal included a distal intron 1 enhancer variant that showed ~2-fold allelic differences in transcriptional reporter activity. Fine-mapping and experimental validation demonstrated that multiple, distinct association signals at these loci can influence multiple transcripts through multiple molecular mechanisms.
Asunto(s)
Adiponectina/genética , Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Alelos , Cadherinas/genética , Cadherinas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Humanos , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Masculino , Síndrome Metabólico/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Secuencias Reguladoras de Ácidos Nucleicos , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.
Asunto(s)
Pueblo Asiatico/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Aldehído Deshidrogenasa Mitocondrial/genética , Alelos , Ancirinas/genética , Índice de Masa Corporal , Estudios de Casos y Controles , Europa (Continente)/etnología , Proteínas del Ojo/genética , Asia Oriental/etnología , Femenino , Estudio de Asociación del Genoma Completo , Proteínas de Homeodominio/genética , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , ARN Mensajero/análisis , Factores de Transcripción/genética , Transcripción Genética , Proteína Homeobox SIX3RESUMEN
OBJECTIVE: To compare school readiness in preschoolers with and without attention-deficit/hyperactivity disorder (ADHD) symptoms using a comprehensive framework. We hypothesized that preschoolers with ADHD symptoms have higher odds of school readiness impairment. METHODS: Children ages 4 to 5 years (n = 93) were divided into 2 groups on the basis of presence of ADHD symptoms (ADHD group, n = 45; comparison group, n = 48). School readiness was assessed through 10 component measures, including direct assessments and standardized questionnaires, regarding 5 school readiness domains: physical well-being and motor development, social and emotional development, approaches to learning, language, and cognition and general knowledge. Analysis of covariance compared group mean scores on component measures. Domain impairment was defined as score ≥1 SD from the test population mean in the unfavorable direction on ≥1 measure in the domain. School readiness impairment was defined as impairment in ≥2 of 5 domains. Logistic regression predicted impairment within domains and overall readiness. RESULTS: The ADHD group demonstrated significantly worse mean scores on 8 of 10 component measures and greater odds of impairment in all domains except for cognition and general knowledge. Overall, 79% of the ADHD group and 13% of the comparison group had school readiness impairment (odds ratio 21, 95% confidence interval 5.67-77.77, P < .001). CONCLUSIONS: Preschoolers with ADHD symptoms are likely to have impaired school readiness. We recommend early identification of school readiness impairment by using a comprehensive 5-domain framework in children with ADHD symptoms paired with targeted intervention to improve outcomes.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/psicología , Conducta Infantil/psicología , Pruebas de Estado Mental y Demencia , Conducta Infantil/fisiología , Preescolar , Femenino , Humanos , MasculinoRESUMEN
Identifying the regulatory mechanisms of genome-wide association study (GWAS) loci affecting adipose tissue has been restricted due to limited characterization of adipose transcriptional regulatory elements. We profiled chromatin accessibility in three frozen human subcutaneous adipose tissue needle biopsies and preadipocytes and adipocytes from the Simpson Golabi-Behmel Syndrome (SGBS) cell strain using an assay for transposase-accessible chromatin (ATAC-seq). We identified 68,571 representative accessible chromatin regions (peaks) across adipose tissue samples (FDR < 5%). GWAS loci for eight cardiometabolic traits were enriched in these peaks (P < 0.005), with the strongest enrichment for waist-hip ratio. Of 110 recently described cardiometabolic GWAS loci colocalized with adipose tissue eQTLs, 59 loci had one or more variants overlapping an adipose tissue peak. Annotated variants at the SNX10 waist-hip ratio locus and the ATP2A1-SH2B1 body mass index locus showed allelic differences in regulatory assays. These adipose tissue accessible chromatin regions elucidate genetic variants that may alter adipose tissue function to impact cardiometabolic traits.
Asunto(s)
Tejido Adiposo/metabolismo , Cromatina/genética , Perfilación de la Expresión Génica , Genoma Humano , Genómica , Sitios de Carácter Cuantitativo , Carácter Cuantitativo Heredable , Adipocitos/metabolismo , Anciano , Alelos , Desequilibrio Alélico , Animales , Sitios de Unión , Secuenciación de Inmunoprecipitación de Cromatina , Mapeo Cromosómico , Susceptibilidad a Enfermedades , Estudio de Asociación del Genoma Completo , Genómica/métodos , Humanos , Masculino , Ratones , Persona de Mediana Edad , Unión ProteicaRESUMEN
As veterinary educators, we have a responsibility to ensure that our graduates are prepared for working life. Veterinary practices, like any other businesses, rely on good employees, and the implications of a poor match between newly employed veterinarian and employing practice could be extremely costly in terms of personal well-being and enjoyment of work as well as the time, financial, and goodwill costs of high staff turnover for the practice. Contemporary veterinary curricula encompass a range of teaching to complement the clinical content; including communication, teamwork, problem solving, and business skills, to support good practice and increase the employability of new graduates. Previous studies have examined the qualities required of early career veterinarians as viewed by educators, recent graduates, pet owners, and practitioners; however, nobody has previously constructed a picture of the employment market for new veterinary graduates by exploring the nature of its recruitment advertising. Three months of UK veterinary job advertisements were examined. Content analysis yielded 10 distinct characteristics desired by employers of early career veterinarians. The most common by far was "enthusiasm," followed by an interest in a particular area of practice, being an "all-rounder" (i.e., having a broad range of skills), demonstrating good communication skills, teamwork, client care, and independence, as well as being caring, ambitious, and having high clinical standards. While several of these qualities are expected and are specifically taught in veterinary school, the dominance of "enthusiasm" as a specifically desired trait raises interesting questions about the characteristics of veterinary students who we are supporting, encouraging, or maybe even suppressing, during veterinary training.