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2.
Hum Mol Genet ; 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-31127295

RESUMO

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

3.
Genet Epidemiol ; 43(5): 559-576, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31016765

RESUMO

While current genome-wide association analyses often rely on meta-analysis of study-specific summary statistics, individual participant data (IPD) from multiple studies increase options for modeling. When multistudy IPD is available, however, it is unclear whether this data is to be imputed and modeled across all participants (mega-imputation and mega-analysis) or study-specifically (meta-imputation and meta-analysis). Here, we investigated different approaches toward imputation and analysis using 52,189 subjects from 25 studies of the International Age-related Macular Degeneration (AMD) Genomics Consortium including, 16,144 AMD cases and 17,832 controls for association analysis. From 27,448,454 genetic variants after 1,000-Genomes-based imputation, mega-imputation yielded ~400,000 more variants with high imputation quality (mostly rare variants) compared to meta-imputation. For AMD signal detection (P < 5 × 10-8 ) in mega-imputed data, most loci were detected with mega-analysis without adjusting for study membership (40 loci, including 34 known); we considered these loci genuine, since genetic effects and P-values were comparable across analyses. In meta-imputed data, we found 31 additional signals, mostly near chromosome tails or reference panel gaps, which disappeared after accounting for interaction of whole-genome amplification (WGA) with study membership or after excluding studies with WGA-participants. For signal detection with multistudy IPD, we recommend mega-imputation and mega-analysis, with meta-imputation followed by meta-analysis being a computationally appealing alternative.

4.
Nat Genet ; 51(4): 636-648, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926973

RESUMO

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.


Assuntos
Lipídeos/sangue , Lipídeos/genética , Fumar/sangue , Fumar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Estilo de Vida , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
Nat Genet ; 51(3): 452-469, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778226

RESUMO

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.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Homeostase/genética , Lipídeos/genética , Proteínas/genética , Animais , Distribuição da Gordura Corporal/métodos , Índice de Massa Corporal , Estudos de Casos e Controles , Drosophila/genética , Exoma/genética , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Fatores de Risco , Relação Cintura-Quadril/métodos
6.
Nat Commun ; 10(1): 376, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670697

RESUMO

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.


Assuntos
Exercício , Loci Gênicos/genética , Lipídeos/sangue , Lipídeos/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Brasil , Proteínas de Ligação ao Cálcio/genética , Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos/genética , Humanos , Proteínas com Homeodomínio LIM/genética , Metabolismo dos Lipídeos/genética , Masculino , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Triglicerídeos/sangue , Triglicerídeos/genética , Adulto Jovem
7.
Am J Epidemiol ; 188(6): 1033-1054, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698716

RESUMO

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

8.
Nat Commun ; 9(1): 5141, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510157

RESUMO

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

9.
Hum Mol Genet ; 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30239722

RESUMO

One in four adults worldwide are either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, is most informative for predicting risk of obesity sequellae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio adjusted for BMI (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

11.
PLoS One ; 13(6): e0198166, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29912962

RESUMO

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

12.
Nat Commun ; 9(1): 1946, 2018 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29769528

RESUMO

The problem of the genetics of related phenotypes is often addressed by analyzing adjusted-model traits, but such traits warrant cautious interpretation. Here, we adopt a joint view of adiposity traits in ~322,154 subjects (GIANT consortium). We classify 159 signals associated with body mass index (BMI), waist-to-hip ratio (WHR), or WHR adjusted for BMI (WHRadjBMI) at P < 5 × 10-8, into four classes based on the direction of their effects on BMI and WHR. Our classes help differentiate adiposity genetics with respect to anthropometry, fat depots, and metabolic health. Class-specific Mendelian randomization reveals that variants associated with both WHR-decrease and BMI increase are linked to metabolically rather favorable adiposity through beneficial hip fat. Class-specific enrichment analyses implicate digestive systems as a pathway in adiposity genetics. Our results demonstrate that WHRadjBMI variants capture relevant effects of "unexpected fat distribution given the BMI" and that a joint view of the genetics underlying related phenotypes can inform on important biology.

13.
Bioinformatics ; 34(19): 3412-3414, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29726908

RESUMO

Summary: Many genome-wide association studies and genome-wide screening for gene-environment (GxE) interactions have been performed to elucidate the underlying mechanisms of human traits and diseases. When the analyzed outcome is quantitative, the overall contribution of identified genetic variants to the outcome is often expressed as the percentage of phenotypic variance explained. This is commonly done using individual-level genotype data but it is challenging when results are derived through meta-analyses. Here, we present R package, 'VarExp', that allows for the estimation of the percentage of phenotypic variance explained using summary statistics only. It allows for a range of models to be evaluated, including marginal genetic effects, GxE interaction effects and both effects jointly. Its implementation integrates all recent methodological developments and does not need external data to be uploaded by users. Availability and implementation: The R package is available at https://gitlab.pasteur.fr/statistical-genetics/VarExp.git. Supplementary information: Supplementary data are available at Bioinformatics online.

14.
Mol Metab ; 12: 1-11, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29673576

RESUMO

OBJECTIVE: The aim was to assess whether loci associated with metabolic traits also have a significant role in BMI and mental traits/disorders METHODS: We first assessed the number of single nucleotide polymorphisms (SNPs) with genome-wide significance for human metabolism (NHGRI-EBI Catalog). These 516 SNPs (216 independent loci) were looked-up in genome-wide association studies for association with body mass index (BMI) and the mental traits/disorders educational attainment, neuroticism, schizophrenia, well-being, anxiety, depressive symptoms, major depressive disorder, autism-spectrum disorder, attention-deficit/hyperactivity disorder, Alzheimer's disease, bipolar disorder, aggressive behavior, and internalizing problems. A strict significance threshold of p < 6.92 × 10-6 was based on the correction for 516 SNPs and all 14 phenotypes, a second less conservative threshold (p < 9.69 × 10-5) on the correction for the 516 SNPs only. RESULTS: 19 SNPs located in nine independent loci revealed p-values < 6.92 × 10-6; the less strict criterion was met by 41 SNPs in 24 independent loci. BMI and schizophrenia showed the most pronounced genetic overlap with human metabolism with three loci each meeting the strict significance threshold. Overall, genetic variation associated with estimated glomerular filtration rate showed up frequently; single metabolite SNPs were associated with more than one phenotype. Replications in independent samples were obtained for BMI and educational attainment. CONCLUSIONS: Approximately 5-10% of the regions involved in the regulation of blood/urine metabolite levels seem to also play a role in BMI and mental traits/disorders and related phenotypes. If validated in metabolomic studies of the respective phenotypes, the associated blood/urine metabolites may enable novel preventive and therapeutic strategies.

15.
PLoS One ; 13(3): e0194321, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29529059

RESUMO

Late-stage age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly with a complex etiology. The most important non-modifiable risk factors for onset and progression of late AMD are age and genetic risk factors, however, little is known about the interplay between genetics and age or sex. Here, we conducted a large-scale age- and sex-stratified genome-wide association study (GWAS) using 1000 Genomes imputed genome-wide and ExomeChip data (>12 million variants). The data were established by the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) from 16,144 late AMD cases and 17,832 controls. Our systematic search for interaction effects yielded significantly stronger effects among younger individuals at two known AMD loci (near CFH and ARMS2/HTRA1). Accounting for age and gene-age interaction using a joint test identified two additional AMD loci compared to the previous main effect scan. One of these two is a novel AMD GWAS locus, near the retinal clusterin-like protein (CLUL1) gene, and the other, near the retinaldehyde binding protein 1 (RLBP1), was recently identified in a joint analysis of nuclear and mitochondrial variants. Despite considerable power in our data, neither sex-dependent effects nor effects with opposite directions between younger and older individuals were observed. This is the first genome-wide interaction study to incorporate age, sex and their interaction with genetic effects for late AMD. Results diminish the potential for a role of sex in the etiology of late AMD yet highlight the importance and existence of age-dependent genetic effects.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Degeneração Macular/genética , Fatores Etários , Fator H do Complemento/genética , Feminino , Loci Gênicos , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Fatores Sexuais
17.
Nat Genet ; 50(5): 766-767, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29549330

RESUMO

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

18.
Am J Hum Genet ; 102(3): 375-400, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29455858

RESUMO

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

19.
Nat Genet ; 50(1): 26-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29273807

RESUMO

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.

20.
Nat Commun ; 8(1): 744, 2017 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-28963451

RESUMO

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10-10, 6.0 × 10-5, and 2.9 × 10-3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.


Assuntos
Estatura/genética , Peso Corporal/genética , Grupo com Ancestrais do Continente Europeu/genética , Antropometria , Índice de Massa Corporal , Tamanho Corporal/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Relação Cintura-Quadril
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