Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Am J Hum Genet ; 105(4): 706-718, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564435

RESUMO

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

3.
Nature ; 570(7759): 71-76, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31118516

RESUMO

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.


Assuntos
Diabetes Mellitus Tipo 2/genética , Exoma/genética , Sequenciamento Completo do Exoma , Animais , Estudos de Casos e Controles , Técnicas de Apoio para a Decisão , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Knockout
4.
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.

5.
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
6.
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
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.
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.

10.
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.

11.
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).

12.
Diabetes Care ; 41(3): 554-561, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29326107

RESUMO

OBJECTIVE: The rs7903146 T allele in transcription factor 7 like 2 (TCF7L2) is strongly associated with type 2 diabetes (T2D), but the mechanisms for increased risk remain unclear. We evaluated the physiologic and hormonal effects of TCF7L2 genotype before and after interventions that influence glucose physiology. RESEARCH DESIGN AND METHODS: We genotyped rs7903146 in 608 individuals without diabetes and recorded biochemical data before and after 1) one dose of glipizide (5 mg) on visit 1 and 2) a 75-g oral glucose tolerance test (OGTT) performed after administration of metformin 500 mg twice daily over 2 days. Incretin levels were measured in 150 of the 608 participants. RESULTS: TT risk-allele homozygotes had 1.6 mg/dL higher baseline fasting glucose levels and 2.5 pg/mL lower glucagon levels per T allele than carriers of other genotypes at baseline. In a subset of participants, the T allele was associated with higher basal glucagon-like peptide 1 (GLP-1) levels at visit 1 (ß = 1.52, P = 0.02 and ß = 0.96, P = 0.002 for total and active GLP-1, respectively), and across all points of the OGTT after metformin administration. Regarding drug response, the T allele was associated with a shorter time (ß = -7.00, P = 0.03) and a steeper slope (ß = 0.23, P = 0.04) to trough glucose levels after glipizide administration, and lower visit 2 fasting glucose level adjusted for visit 1 fasting glucose level (ß = -1.02, P = 0.04) and a greater decline in glucose level between visits (ß = -1.61, P = 0.047) after metformin administration. CONCLUSIONS: Our findings demonstrate that common variation at TCF7L2 influences acute responses to both glipizide and metformin in people without diabetes and highlight altered incretin signaling as a potential mechanism by which TCF7L2 variation increases T2D risk.


Assuntos
Glipizida/uso terapêutico , Incretinas/uso terapêutico , Metformina/uso terapêutico , Polimorfismo de Nucleotídeo Único , Compostos de Sulfonilureia/uso terapêutico , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Adulto , Idoso , Alelos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Técnicas de Genotipagem , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco
13.
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.

14.
Diabetes ; 67(2): 334-342, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29141982

RESUMO

Rare fully penetrant mutations in AKT2 are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function AKT2 coding variant (p.Pro50Thr) was identified that is nearly specific to Finns (frequency 1.1%), with the low-frequency allele associated with an increase in fasting plasma insulin level and risk of type 2 diabetes. The effects of the p.Pro50Thr AKT2 variant (p.P50T/AKT2) on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated. We identified carriers (N = 20) and matched noncarriers (N = 25) for this allele in the population-based Metabolic Syndrome in Men (METSIM)study and invited these individuals back for positron emission tomography study with [18F]-fluorodeoxyglucose during euglycemic hyperinsulinemia. When we compared p.P50T/AKT2 carriers to noncarriers, we found a 39.4% reduction in whole-body GU (P = 0.006) and a 55.6% increase in the rate of endogenous glucose production (P = 0.038). We found significant reductions in GU in multiple tissues-skeletal muscle (36.4%), liver (16.1%), brown adipose (29.7%), and bone marrow (32.9%)-and increases of 16.8-19.1% in seven tested brain regions. These data demonstrate that the p.P50T substitution of AKT2 influences insulin-mediated GU in multiple insulin-sensitive tissues and may explain, at least in part, the increased risk of type 2 diabetes in p.P50T/AKT2 carriers.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Resistência à Insulina , Mutação com Perda de Função , Proteínas Proto-Oncogênicas c-akt/genética , Absorção Fisiológica/efeitos dos fármacos , Idoso , Alelos , Substituição de Aminoácidos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/metabolismo , Diagnóstico Precoce , Finlândia , Fluordesoxiglucose F18/metabolismo , Seguimentos , Estudos de Associação Genética , Variação Genética , Heterozigoto , Humanos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas c-akt/metabolismo
15.
Circ Cardiovasc Genet ; 10(5)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29030403

RESUMO

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.


Assuntos
Pressão Sanguínea/genética , Loci Gênicos , Antiporters/genética , Moléculas de Adesão Celular Neuronais/genética , Bases de Dados Factuais , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Proteínas dos Microfilamentos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores de Retorno de Linfócitos/genética
17.
Am J Hum Genet ; 100(6): 865-884, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28552196

RESUMO

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.


Assuntos
Antropometria , Genoma Humano , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Análise de Sequência de DNA/métodos , Estatura/genética , Estudos de Coortes , Metilação de DNA/genética , Bases de Dados Genéticas , Feminino , Variação Genética , Humanos , Lipodistrofia/genética , Masculino , Metanálise como Assunto , Obesidade/genética , Mapeamento Físico do Cromossomo , Caracteres Sexuais , Síndrome , Reino Unido
18.
J Clin Endocrinol Metab ; 102(8): 2678-2689, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28453780

RESUMO

Context: Variation in genes that cause maturity-onset diabetes of the young (MODY) has been associated with diabetes incidence and glycemic traits. Objectives: This study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions. Design and Setting: This was a secondary analysis of a multicenter, randomized clinical trial, the Diabetes Prevention Program (DPP), involving 27 US academic institutions. We genotyped 22 missense and 221 common variants in the MODY-causing genes in the participants in the DPP. Participants and Interventions: The study included 2806 genotyped DPP participants randomized to receive intensive lifestyle intervention (n = 935), metformin (n = 927), or placebo (n = 944). Main Outcome Measures: Association of MODY genetic variants with diabetes incidence at a median of 3 years and measures of 1-year ß-cell function, insulinogenic index, and oral disposition index. Analyses were stratified by treatment group for significant single-nucleotide polymorphism × treatment interaction (Pint < 0.05). Sequence kernel association tests examined the association between an aggregate of rare missense variants and insulinogenic traits. Results: After 1 year, the minor allele of rs3212185 (HNF4A) was associated with improved ß-cell function in the metformin and lifestyle groups but not the placebo group; the minor allele of rs6719578 (NEUROD1) was associated with an increase in insulin secretion in the metformin group but not in the placebo and lifestyle groups. Conclusions: These results provide evidence that genetic variation among MODY genes may influence response to insulin-sensitizing interventions.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diabetes Mellitus Tipo 2/genética , Terapia por Exercício , Fator 4 Nuclear de Hepatócito/genética , Programas de Redução de Peso , Diabetes Mellitus Tipo 2/prevenção & controle , Variação Genética , Glucoquinase/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-beta Nuclear de Hepatócito/genética , Proteínas de Homeodomínio/genética , Humanos , Metformina/uso terapêutico , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Comportamento de Redução do Risco , Transativadores/genética , Resultado do Tratamento
19.
BMC Proc ; 10(Suppl 7): 245-249, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27980644

RESUMO

The new generation of whole genome sequencing platforms offers great possibilities and challenges for dissecting the genetic basis of complex traits. With a very high number of sequence variants, a naïve multiple hypothesis threshold correction hinders the identification of reliable associations by the overreduction of statistical power. In this report, we examine 2 alternative approaches to improve the statistical power of a whole genome association study to detect reliable genetic associations. The approaches were tested using the Genetic Analysis Workshop 19 (GAW19) whole genome sequencing data. The first tested method estimates the real number of effective independent tests actually being performed in whole genome association project by the use of an extreme value distribution and a set of phenotype simulations. Given the familiar nature of the GAW19 data and the finite number of pedigree founders in the sample, the number of correlations between genotypes is greater than in a set of unrelated samples. Using our procedure, we estimate that the effective number represents only 15 % of the total number of independent tests performed. However, even using this corrected significance threshold, no genome-wide significant association could be detected for systolic and diastolic blood pressure traits. The second approach implements a biological relevance-driven hypothesis tested by exploiting prior computational predictions on the effect of nonsynonymous genetic variants detected in a whole genome sequencing association study. This guided testing approach was able to identify 2 promising single-nucleotide polymorphisms (SNPs), 1 for each trait, targeting biologically relevant genes that could help shed light on the genesis of the human hypertension. The first gene, PFH14, associated with systolic blood pressure, interacts directly with genes involved in calcium-channel formation and the second gene, MAP4, encodes a microtubule-associated protein and had already been detected by previous genome-wide association study experiments conducted in an Asian population. Our results highlight the necessity of the development of alternative approached to improve the efficiency on the detection of reasonable candidate associations in whole genome sequencing studies.

20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA