RESUMEN
Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
Asunto(s)
Mapeo Cromosómico , Predisposición Genética a la Enfermedad , Índice Glucémico/genética , Obesidad/genética , Sitios de Carácter Cuantitativo/genética , Índice de Masa Corporal , Frecuencia de los Genes/genética , Estudio de Asociación del Genoma Completo , Quinasas del Centro Germinal , Glucosa-6-Fosfatasa/genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Proteínas Serina-Treonina Quinasas/genética , Trombospondinas/genéticaRESUMEN
Food preferences are the first factor driving food choice and thus nutrition. They involve numerous different senses such as taste and olfaction as well as various other factors such as personal experiences and hedonistic aspects. Although it is clear that several of these have a genetic basis, up to now studies have focused mostly on the effects of polymorphisms of taste receptor genes. Therefore, we have carried out one of the first large scale (4611 individuals) GWAS on food likings assessed for 20 specific food likings belonging to 4 different categories (vegetables, fatty, dairy and bitter). A two-step meta-analysis using three different isolated populations from Italy for the discovery step and two populations from The Netherlands and Central Asia for replication, revealed 15 independent genome-wide significant loci (p < 5 × 10(-8)) for 12 different foods. None of the identified genes coded for either taste or olfactory receptors suggesting that genetics impacts in determining food likings in a much broader way than simple differences in taste perception. These results represent a further step in uncovering the genes that underlie liking of common foods that in the end will greatly help understanding the genetics of human nutrition in general.
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Preferencias Alimentarias/fisiología , Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
Importance: Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. Objective: To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. Design, Setting, and Participants: The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50â¯775 individuals with type 2 diabetes and 270â¯269 controls and 60â¯801 individuals with coronary artery disease and 123â¯504 controls. Data collection took place in Europe and the United States between 1991 and 2016. Exposures: Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. Main Outcomes and Measures: Odds ratios (ORs) for type 2 diabetes and coronary artery disease. Results: Low-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. Conclusions and Relevance: In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.
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LDL-Colesterol/genética , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/genética , Variación Genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Proteínas de la Membrana/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Adulto , Anciano , LDL-Colesterol/sangre , Estudios de Cohortes , Diabetes Mellitus Tipo 2/sangre , Quimioterapia Combinada/efectos adversos , Ezetimiba/administración & dosificación , Ezetimiba/efectos adversos , Estudios de Asociación Genética , Humanos , Hidroximetilglutaril-CoA Reductasas/genética , Lipoproteínas/genética , Proteínas de Transporte de Membrana , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo Genético , Proproteína Convertasa 9/genética , Receptores de LDL/genética , Riesgo , Simvastatina/administración & dosificación , Simvastatina/efectos adversosRESUMEN
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (Pâ=â4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (Nâ=â4,232 African Americans, Nâ=â1,776 Asians, and Nâ=â29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (pâ=â4.3×10(-3), nâ=â22,044), increased triglycerides (pâ=â2.6×10(-14), nâ=â93,440), increased waist-to-hip ratio (pâ=â1.8×10(-5), nâ=â77,167), increased glucose two hours post oral glucose tolerance testing (pâ=â4.4×10(-3), nâ=â15,234), increased fasting insulin (pâ=â0.015, nâ=â48,238), but with lower in HDL-cholesterol concentrations (pâ=â4.5×10(-13), nâ=â96,748) and decreased BMI (pâ=â1.4×10(-4), nâ=â121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
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Adiponectina/sangre , Diabetes Mellitus Tipo 2/genética , Estudio de Asociación del Genoma Completo , Adiponectina/genética , Negro o Afroamericano , Pueblo Asiatico , HDL-Colesterol/genética , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina/genética , Masculino , Redes y Vías Metabólicas , Polimorfismo de Nucleótido Simple , Relación Cintura-Cadera , Población BlancaRESUMEN
OBJECTIVE: Circulating levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides are recognized risk factors for cardiovascular disease. We tested the hypothesis that the cumulative effects of common genetic variants for lipids are collectively associated with subclinical atherosclerosis and incident coronary heart disease. APPROACH AND RESULTS: Participants were drawn from the Erasmus Rucphen Family Study (n=2269) and the Rotterdam Study (n=8130). Linear regression and Cox proportional hazards models were applied to assess the influence of 4 risk scores derived from common genetic variants for lipids (total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triglycerides) on carotid plaque, intima-media thickness, incident myocardial infarction, and coronary heart disease. Adjusted for age and sex, all 4 risk scores were associated with carotid plaque. This relationship was the strongest for the LDL-C score, which increased plaque score by 0.102 per SD increase in genetic risk score (P=3.2 × 10(-8)). The LDL-C score was also nominally associated with intima-media thickness, which increased 0.006 mm per SD increase in score (P=0.05). Both the total cholesterol and LDL-C scores were associated with incident myocardial infarction and coronary heart disease with hazard ratios between 1.10 and 1.13 per SD increase in score. Inclusion of additional risk factors as covariates minimally affected these results. CONCLUSIONS: Common genetic variants with small effects on lipid levels are, in combination, significantly associated with subclinical and clinical cardiovascular outcomes. As knowledge of genetic variation increases, preclinical genetic screening tools might enhance the prediction and prevention of clinical events.
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Enfermedades de las Arterias Carótidas/genética , Enfermedad Coronaria/genética , Lípidos/sangre , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Enfermedades Asintomáticas , Biomarcadores/sangre , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/diagnóstico , Enfermedades de las Arterias Carótidas/epidemiología , Grosor Intima-Media Carotídeo , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Enfermedad Coronaria/sangre , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/epidemiología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Modelos Lineales , Masculino , Persona de Mediana Edad , Infarto del Miocardio/genética , Países Bajos/epidemiología , Fenotipo , Pronóstico , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Triglicéridos/sangreRESUMEN
Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
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Diabetes Mellitus Tipo 2 , Glucosa , Humanos , Estudio de Asociación del Genoma Completo , Glucemia/genética , Diabetes Mellitus Tipo 2/genética , ColonRESUMEN
Fueled by the successes of genome-wide association studies, numerous studies have investigated the predictive ability of genetic risk models in type 2 diabetes. In this paper, we review these studies from a methodological perspective, focusing on the variables included in the risk models as well as the study designs and populations investigated. We argue and show that differences in study design and characteristics of the study population have an impact on the observed predictive ability of risk models. This observation emphasizes that genetic risk prediction studies should be conducted in those populations in which the prediction models will ultimately be applied, if proven useful. Of all genetic risk prediction studies to date, only a few were conducted in populations that might be relevant for targeting preventive interventions.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Salud Pública , Factores de RiesgoRESUMEN
Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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Glucemia/genética , Carácter Cuantitativo Heredable , Población Blanca/genética , Alelos , Epigénesis Genética , Perfilación de la Expresión Génica , Genoma Humano , Estudio de Asociación del Genoma Completo , Hemoglobina Glucada/metabolismo , Humanos , Herencia Multifactorial/genética , Mapeo Físico de Cromosoma , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
Asunto(s)
Anorexia Nerviosa/genética , Glucemia/metabolismo , Intolerancia a la Glucosa/genética , Proteínas Sustrato del Receptor de Insulina/genética , Resistencia a la Insulina/genética , Insulina/sangre , Factores de Transcripción de Tipo Kruppel/genética , Adulto , Anorexia Nerviosa/sangre , Anorexia Nerviosa/etnología , Anorexia Nerviosa/fisiopatología , Ayuno/sangre , Femenino , Expresión Génica , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/etnología , Intolerancia a la Glucosa/fisiopatología , Humanos , Proteínas Sustrato del Receptor de Insulina/sangre , Factores de Transcripción de Tipo Kruppel/sangre , Masculino , Persona de Mediana Edad , Fenotipo , Caracteres Sexuales , Factores Sexuales , Relación Cintura-Cadera , Población BlancaRESUMEN
BACKGROUND: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). METHODS: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). RESULTS: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. CONCLUSIONS: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
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Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Estudios de Casos y Controles , Estudio de Asociación del Genoma Completo , Humanos , Metaanálisis como Asunto , Polimorfismo Genético , Factores de RiesgoRESUMEN
Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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Adiposidad/genética , Leptina/metabolismo , Grupos Raciales/genética , Regulación del Desarrollo de la Expresión Génica , Variación Genética , Genotipo , Humanos , Leptina/sangre , Leptina/química , Leptina/genética , Modelos Moleculares , Conformación ProteicaRESUMEN
Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Homeostasis/genética , Lípidos/genética , Proteínas/genética , Animales , Distribución de la Grasa Corporal/métodos , Índice de Masa Corporal , Estudios de Casos y Controles , Drosophila/genética , Exoma/genética , Femenino , Frecuencia de los Genes/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Factores de Riesgo , Relación Cintura-Cadera/métodosRESUMEN
In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
Asunto(s)
Presión Sanguínea/genética , Etnicidad/genética , Adolescente , Animales , Femenino , Expresión Génica/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Túbulos Renales/fisiología , Masculino , Ratones , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Transcriptoma/genética , Regulación hacia Arriba/genéticaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.
Asunto(s)
Glucemia/genética , Estudio de Asociación del Genoma Completo , Población Blanca/genética , Glucemia/análisis , Diabetes Mellitus Tipo 2/genética , Femenino , Variación Genética , Genotipo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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Diabetes Mellitus Tipo 2/genética , Alelos , Mapeo Cromosómico/estadística & datos numéricos , Diabetes Mellitus Tipo 2/clasificación , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Humanos , Masculino , Población Blanca/genética , Secuenciación del Exoma/estadística & datos numéricosRESUMEN
High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
Asunto(s)
Presión Sanguínea/genética , Sitios de Carácter Cuantitativo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Células Cultivadas , Femenino , Sitios Genéticos , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Genética de Población/métodos , Estudio de Asociación del Genoma Completo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hipertensión/genética , Estilo de Vida , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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Índice de Masa Corporal , Ingestión de Energía/genética , Metabolismo Energético/genética , Variación Genética , Obesidad/genética , Adulto , Animales , Drosophila/genética , Femenino , Frecuencia de los Genes , Humanos , Masculino , Proteínas/genética , SíndromeRESUMEN
In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
RESUMEN
In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article.