Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 40
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Am J Nephrol ; 49(3): 193-202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30808845

RESUMO

BACKGROUND: Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. METHODS: We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. RESULTS: We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. CONCLUSIONS: Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.

2.
PLoS One ; 12(12): e0186456, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29236708

RESUMO

BACKGROUND: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences. OBJECTIVE: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption. DESIGN: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts. RESULTS: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA. CONCLUSIONS: These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.


Assuntos
Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Estudo de Associação Genômica Ampla , Alimentos Marinhos , Adulto , Idoso , Estudos de Coortes , Europa (Continente) , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos
3.
PLoS Genet ; 13(6): e1006812, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28614350

RESUMO

Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (Pv), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (Pm). Correlations between Pv and Pm were stronger for SNPs with established marginal effects (Spearman's ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When Pv and Pm were compared for all pruned SNPs, only BMI was statistically significant (Spearman's ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the Pv distribution (Pbinomial <0.05). SNPs from the top 1% of the Pm distribution for BMI had more significant Pv values (PMann-Whitney = 1.46×10-5), and the odds ratio of SNPs with nominally significant (<0.05) Pm and Pv was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant G×E interaction P-values (Pint<0.05) were enriched with nominally significant Pv values (Pbinomial = 8.63×10-9 and 8.52×10-7 for SNP × smoking and SNP × physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for G×E, and variance-based prioritization can be used to identify them.


Assuntos
HDL-Colesterol/genética , LDL-Colesterol/genética , Interação Gene-Ambiente , Obesidade/genética , Índice de Massa Corporal , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Obesidade/sangue , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Fatores de Risco , Fumar/genética
4.
Sci Rep ; 7: 44846, 2017 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-28349935

RESUMO

The presence of autoantibodies usually precedes autoimmune disease, but is sometimes considered an incidental finding with no clinical relevance. The prevalence of immune-mediated diseases was studied in a group of individuals from the Estonian Genome Project (n = 51,862), and 6 clinically significant autoantibodies were detected in a subgroup of 994 (auto)immune-mediated disease-free individuals. The overall prevalence of individuals with immune-mediated diseases in the primary cohort was 30.1%. Similarly, 23.6% of the participants in the disease-free subgroup were seropositive for at least one autoantibody. Several phenotypic parameters were associated with autoantibodies. The results suggest that (i) immune-mediated diseases are diagnosed in nearly one-third of a random European population, (ii) 6 common autoantibodies are detectable in almost one-third of individuals without diagnosed autoimmune diseases, (iii) tissue non-specific autoantibodies, especially at high levels, may reflect preclinical disease in symptom-free individuals, and (iv) the incidental positivity of anti-TPO in men with positive familial anamnesis of maternal autoimmune disease deserves further medical attention. These results encourage physicians to evaluate autoantibodies in addition to treating a variety of patient health complaints to detect autoimmune-mediated disease early.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Adolescente , Adulto , Idoso , Doenças Assintomáticas , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Vigilância da População , Prevalência , Fatores de Risco , Adulto Jovem
5.
J Am Soc Nephrol ; 28(3): 981-994, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27920155

RESUMO

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.


Assuntos
Exoma/genética , Taxa de Filtração Glomerular/genética , Rim/embriologia , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Son Of Sevenless/genética , Animais , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Peixe-Zebra
7.
Sci Rep ; 6: 35278, 2016 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-27731410

RESUMO

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.


Assuntos
Cromossomos Humanos X , Doença da Artéria Coronariana/genética , Estudos de Coortes , Feminino , Humanos , Internacionalidade , Masculino
8.
Nat Genet ; 48(10): 1151-1161, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27618447

RESUMO

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.


Assuntos
Pressão Sanguínea/genética , Variação Genética , Hipertensão/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos
10.
Am J Hum Genet ; 99(1): 8-21, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27346685

RESUMO

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.


Assuntos
Eritrócitos/citologia , Eritropoese/genética , Exoma/genética , Pleiotropia Genética , Variação Genética/genética , Genótipo , Afro-Americanos/genética , Desequilíbrio Alélico , Índices de Eritrócitos , Eritrócitos/metabolismo , Frequência do Gene , Hematócrito , Hemoglobinas/genética , Humanos , Locos de Características Quantitativas/genética
11.
Am J Hum Genet ; 99(1): 22-39, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27346689

RESUMO

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of âˆ¼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.


Assuntos
Exoma/genética , Loci Gênicos/genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Doenças do Sistema Imunitário/genética , Leucócitos/citologia , Contagem de Células Sanguíneas , Humanos , Controle de Qualidade
13.
Eur J Hum Genet ; 24(10): 1488-95, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27142678

RESUMO

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 × 10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.


Assuntos
Antígenos Nucleares/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Sono/genética , Encéfalo/metabolismo , Humanos , Transmissão Sináptica/genética
14.
Nature ; 533(7604): 539-42, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27225129

RESUMO

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.


Assuntos
Encéfalo/metabolismo , Escolaridade , Feto/metabolismo , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Doença de Alzheimer/genética , Transtorno Bipolar/genética , Cognição , Biologia Computacional , Interação Gene-Ambiente , Humanos , Anotação de Sequência Molecular , Esquizofrenia/genética , Reino Unido
15.
Nat Genet ; 48(6): 624-33, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27089181

RESUMO

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.


Assuntos
Transtornos de Ansiedade/genética , Depressão/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Teorema de Bayes , Humanos , Neuroticismo , Fenótipo
16.
Nat Commun ; 7: 11122, 2016 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-27005778

RESUMO

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.


Assuntos
Doenças Cardiovasculares/genética , Lipoproteína(a)/genética , Metabolômica/métodos , Adulto , Idoso , Doenças Cardiovasculares/metabolismo , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Lipoproteínas VLDL/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Triglicerídeos/metabolismo , Adulto Jovem
18.
Lancet Respir Med ; 3(10): 769-81, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26423011

RESUMO

BACKGROUND: Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. METHODS: We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 × 10(-8). FINDINGS: UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50,008 unique samples: 10,002 individuals with low FEV1, 10,000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2.29 × 10(-16)) and between individuals with and without doctor-diagnosed asthma (p=6.06 × 10(-11)). We discovered six novel genome-wide significant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5' end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue. INTERPRETATION: By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. FUNDING: Medical Research Council.


Assuntos
Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bancos de Espécimes Biológicos , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado/genética , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Reino Unido , Adulto Jovem
19.
PLoS Genet ; 11(10): e1005378, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26426971

RESUMO

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.


Assuntos
Índice de Massa Corporal , Tamanho Corporal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Fatores Etários , Idoso , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Caracteres Sexuais , Relação Cintura-Quadril
20.
Nat Genet ; 47(10): 1121-1130, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26343387

RESUMO

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.


Assuntos
Doença da Artéria Coronariana/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA