Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 24
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
2.
Nat Genet ; 50(11): 1505-1513, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30297969

RESUMO

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

3.
Nat Genet ; 50(4): 559-571, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29632382

RESUMO

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.

4.
Diabetes ; 67(7): 1414-1427, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29703844

RESUMO

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética
6.
Sci Data ; 4: 170179, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29257133

RESUMO

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.


Assuntos
Diabetes Mellitus Tipo 2/genética , Variação Genética , Grupo com Ancestrais do Continente Europeu , Humanos
7.
Wellcome Open Res ; 2: 68, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28989980

RESUMO

Background: Observational studies have demonstrated that increased bone mineral density is associated with a higher risk of type 2 diabetes (T2D), but the relationship with risk of coronary heart disease (CHD) is less clear. Moreover, substantial uncertainty remains about the causal relevance of increased bone mineral density for T2D and CHD, which can be assessed by Mendelian randomisation studies.  Methods: We identified 235 independent single nucleotide polymorphisms (SNPs) associated at p<5×10 -8 with estimated heel bone mineral density (eBMD) in 116,501 individuals from the UK Biobank study, accounting for 13.9% of eBMD variance. For each eBMD-associated SNP, we extracted effect estimates from the largest available GWAS studies for T2D (DIAGRAM: n=26,676 T2D cases and 132,532 controls) and CHD (CARDIoGRAMplusC4D: n=60,801 CHD cases and 123,504 controls). A two-sample design using several Mendelian randomization approaches was used to investigate the causal relevance of eBMD for risk of T2D and CHD. In addition, we explored the relationship of eBMD, instrumented by the 235 SNPs, on 12 cardiovascular and metabolic risk factors. Finally, we conducted Mendelian randomization analysis in the reverse direction to investigate reverse causality. Results: Each one standard deviation increase in genetically instrumented eBMD (equivalent to 0.14 g/cm 2) was associated with an 8% higher risk of T2D (odds ratio [OR] 1.08; 95% confidence interval [CI]: 1.02 to 1.14; p=0.012) and 5% higher risk of CHD (OR 1.05; 95%CI: 1.00 to 1.10; p=0.034). Consistent results were obtained in sensitivity analyses using several different Mendelian randomization approaches. Equivalent increases in eBMD were also associated with lower plasma levels of HDL-cholesterol and increased insulin resistance. Mendelian randomization in the reverse direction using 94 T2D SNPs or 52 CHD SNPs showed no evidence of reverse causality with eBMD. Conclusions: These findings suggest a causal relationship between elevated bone mineral density with risks of both T2D and CHD.

8.
Diabetes ; 66(7): 2019-2032, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28341696

RESUMO

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.


Assuntos
Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu/genética , Jejum/metabolismo , Resistência à Insulina/genética , Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Afro-Americanos/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Finlândia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Hispano-Americanos/genética , Humanos , Razão de Chances
9.
Ann Rheum Dis ; 76(7): 1199-1206, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27974301

RESUMO

OBJECTIVE: Osteoarthritis (OA) has a strong genetic component but the success of previous genome-wide association studies (GWAS) has been restricted due to insufficient sample sizes and phenotype heterogeneity. Our aim was to examine the effect of clinically relevant endophenotyping according to site of maximal joint space narrowing (maxJSN) and bone remodelling response on GWAS signal detection in hip OA. METHODS: A stratified GWAS meta-analysis was conducted in 2118 radiographically defined hip OA cases and 6500 population-based controls. Signals were followed up by analysing differential expression of proximal genes for bone remodelling endophenotypes in 33 pairs of macroscopically intact and OA-affected cartilage. RESULTS: We report suggestive evidence (p<5×10-6) of association at 6 variants with OA endophenotypes that would have been missed by using presence of hip OA as the disease end point. For example, in the analysis of hip OA cases with superior maxJSN versus cases with non-superior maxJSN we detected association with a variant in the LRCH1 gene (rs754106, p=1.49×10-7, OR (95% CIs) 0.70 (0.61 to 0.80)). In the comparison of hypertrophic with non-hypertrophic OA the most significant variant was located between STT3B and GADL1 (rs6766414, p=3.13×10-6, OR (95% CIs) 1.45 (1.24 to 1.69)). Both of these associations were fully attenuated in non-stratified analyses of all hip OA cases versus population controls (p>0.05). STT3B was significantly upregulated in OA-affected versus intact cartilage, particularly in the analysis of hypertrophic and normotrophic compared with atrophic bone remodelling pattern (p=4.2×10-4). CONCLUSIONS: Our findings demonstrate that stratification of OA cases into more homogeneous endophenotypes can identify genes of potential functional importance otherwise obscured by disease heterogeneity.


Assuntos
Cartilagem Articular/diagnóstico por imagem , Hexosiltransferases/genética , Articulação do Quadril/diagnóstico por imagem , Proteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Osteoartrite do Quadril/diagnóstico por imagem , Atrofia , Remodelação Óssea/genética , Cartilagem Articular/metabolismo , Endofenótipos , Grupo com Ancestrais do Continente Europeu , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Articulação do Quadril/patologia , Humanos , Hipertrofia , Masculino , Osteoartrite do Quadril/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Radiografia
10.
J Am Soc Nephrol ; 28(2): 557-574, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27647854

RESUMO

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/genética , Adolescente , Adulto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
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
12.
Nature ; 536(7614): 41-47, 2016 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-27398621

RESUMO

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Alelos , Análise Mutacional de DNA , Europa (Continente)/etnologia , Exoma , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Tamanho da Amostra
13.
Nat Genet ; 47(12): 1415-25, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26551672

RESUMO

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.


Assuntos
Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/genética , Loci Gênicos , Predisposição Genética para Doença , Fator 3-beta Nuclear de Hepatócito/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor MT2 de Melatonina/genética , Sítios de Ligação , Estudos de Casos e Controles , Imunoprecipitação da Cromatina , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genômica , Fator 3-beta Nuclear de Hepatócito/metabolismo , Humanos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Fígado/metabolismo , Fígado/patologia , Anotação de Sequência Molecular , Receptor MT2 de Melatonina/metabolismo
14.
PLoS Genet ; 11(1): e1004876, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25625282

RESUMO

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.


Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 2/genética , Glucose-6-Fosfatase/genética , Insulina/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Exoma/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Receptor do Peptídeo Semelhante ao Glucagon 1 , Índice Glicêmico/genética , Humanos , Insulina/genética , Polimorfismo de Nucleotídeo Único , Receptores de Glucagon/genética
15.
PLoS One ; 9(6): e98608, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24926958

RESUMO

INTRODUCTION: Most studies seeking common variant associations with type 2 diabetes (T2D) have focused on individuals of European ancestry. These discoveries need to be evaluated in other major ancestral groups, to understand ethnic differences in predisposition, and establish whether these contribute to variation in T2D prevalence and presentation. This study aims to establish whether common variants conferring T2D-risk in Europeans contribute to T2D-susceptibility in the South Asian population of Sri Lanka. METHODOLOGY: Lead single nucleotide polymorphism (SNPs) at 37 T2D-risk loci attaining genome-wide significance in Europeans were genotyped in 878 T2D cases and 1523 normoglycaemic controls from Sri Lanka. Association testing was performed by logistic regression adjusting for age and sex and by the Cochran-Mantel-Haenszel test after stratifying according to self-identified ethnolinguistic subgroup. A weighted genetic risk score was generated to examine the combined effect of these SNPs on T2D-risk in the Sri Lankan population. RESULTS: Of the 36 SNPs passing quality control, sixteen showed nominal (p<0.05) association in Sri Lankan samples, fifteen of those directionally-consistent with the original signal. Overall, these association findings were robust to analyses that accounted for membership of ethnolinguistic subgroups. Overall, the odds ratios for 31 of the 36 SNPs were directionally-consistent with those observed in Europeans (p = 3.2×10(-6)). Allelic odds ratios and risk allele frequencies in Sri Lankan subjects were not systematically different to those reported in Europeans. Genetic risk score and risk of T2D were strongly related in Sri Lankans (per allele OR 1.10 [95%CI 1.08-1.13], p = 1.2×10(-17)). CONCLUSION: Our data indicate that most T2D-risk variants identified in Europeans have similar effects in South Asians from Sri Lanka, and that systematic difference in common variant associations are unlikely to explain inter-ethnic differences in prevalence or presentation of T2D.


Assuntos
Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu/etnologia , Polimorfismo de Nucleotídeo Único , Ásia Sudeste/etnologia , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Modelos Logísticos , Sri Lanka/etnologia
16.
PLoS Genet ; 8(8): e1002793, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22876189

RESUMO

Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the "Metabochip," a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits.


Assuntos
Antropometria/instrumentação , Metabolômica/instrumentação , Análise de Sequência com Séries de Oligonucleotídeos/instrumentação , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Alelos , Antropometria/métodos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Frequência do Gene , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Técnicas de Genotipagem , Humanos , Metabolômica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Fenótipo
17.
Nat Genet ; 44(9): 981-90, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22885922

RESUMO

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Genes/fisiologia , Predisposição Genética para Doença/genética , Humanos , Desequilíbrio de Ligação , Masculino , Paquistão/epidemiologia , Polimorfismo de Nucleotídeo Único/fisiologia , Fatores Sexuais
18.
PLoS Genet ; 7(9): e1002270, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21931564

RESUMO

We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)

Assuntos
Estudo de Associação Genômica Ampla , Redes e Vias Metabólicas/genética , Metaboloma/genética , Locos de Características Quantitativas/genética , Seleção Genética , Acetiltransferases/genética , Acetiltransferases/metabolismo , Dimetilaminas/sangue , Dimetilaminas/metabolismo , Feminino , Haplótipos , Humanos , Isobutiratos/metabolismo , Isobutiratos/urina , Espectroscopia de Ressonância Magnética , Metilaminas/metabolismo , Metilaminas/urina , Polimorfismo de Nucleotídeo Único
19.
Eur J Hum Genet ; 19(5): 610-4, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21267008

RESUMO

Imputation is an extremely valuable tool in conducting and synthesising genome-wide association studies (GWASs). Directly typed SNP quality control (QC) is thought to affect imputation quality. It is, therefore, common practise to use quality-controlled (QCed) data as an input for imputing genotypes. This study aims to determine the effect of commonly applied QC steps on imputation outcomes. We performed several iterations of imputing SNPs across chromosome 22 in a dataset consisting of 3177 samples with Illumina 610 k (Illumina, San Diego, CA, USA) GWAS data, applying different QC steps each time. The imputed genotypes were compared with the directly typed genotypes. In addition, we investigated the correlation between alternatively QCed data. We also applied a series of post-imputation QC steps balancing elimination of poorly imputed SNPs and information loss. We found that the difference between the unQCed data and the fully QCed data on imputation outcome was minimal. Our study shows that imputation of common variants is generally very accurate and robust to GWAS QC, which is not a major factor affecting imputation outcome. A minority of common-frequency SNPs with particular properties cannot be accurately imputed regardless of QC stringency. These findings may not generalise to the imputation of low frequency and rare variants.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Cromossomos Humanos Par 22 , Frequência do Gene , Humanos , Osteoartrite/genética , Polimorfismo de Nucleotídeo Único , Controle de Qualidade
20.
Ann Hum Genet ; 75(1): 10-9, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21133856

RESUMO

In the presence of epistasis multilocus association tests of human complex traits can provide powerful methods to detect susceptibility variants. We undertook multilocus analyses in 1924 type 2 diabetes cases and 2938 controls from the Wellcome Trust Case Control Consortium (WTCCC). We performed a two-dimensional genome-wide association (GWA) scan using joint two-locus tests of association including main and epistatic effects in 70,236 markers tagging common variants. We found two-locus association at 79 SNP-pairs at a Bonferroni-corrected P-value = 0.05 (uncorrected P-value = 2.14 × 10⁻¹¹). The 79 pair-wise results always contained rs11196205 in TCF7L2 paired with 79 variants including confirmed variants in FTO, TSPAN8, and CDKAL1, which are associated in the absence of epistasis. However, the majority (82%) of the 79 variants did not have compelling single-locus association signals (P-value = 5 × 10⁻4). Analyses conditional on the single-locus effects at TCF7L2 established that the joint two-locus results could be attributed to single-locus association at TCF7L2 alone. Interaction analyses among the peak 80 regions and among 23 previously established diabetes candidate genes identified five SNP-pairs with case-control and case-only epistatic signals. Our results demonstrate the feasibility of systematic scans in GWA data, but confirm that single-locus association can underlie and obscure multilocus findings.


Assuntos
Diabetes Mellitus Tipo 2/genética , Epistasia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA