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3.
Bioinformatics ; 35(15): 2555-2561, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576415

RESUMO

MOTIVATION: Very low-depth sequencing has been proposed as a cost-effective approach to capture low-frequency and rare variation in complex trait association studies. However, a full characterization of the genotype quality and association power for very low-depth sequencing designs is still lacking. RESULTS: We perform cohort-wide whole-genome sequencing (WGS) at low depth in 1239 individuals (990 at 1× depth and 249 at 4× depth) from an isolated population, and establish a robust pipeline for calling and imputing very low-depth WGS genotypes from standard bioinformatics tools. Using genotyping chip, whole-exome sequencing (75× depth) and high-depth (22×) WGS data in the same samples, we examine in detail the sensitivity of this approach, and show that imputed 1× WGS recapitulates 95.2% of variants found by imputed GWAS with an average minor allele concordance of 97% for common and low-frequency variants. In our study, 1× further allowed the discovery of 140 844 true low-frequency variants with 73% genotype concordance when compared to high-depth WGS data. Finally, using association results for 57 quantitative traits, we show that very low-depth WGS is an efficient alternative to imputed GWAS chip designs, allowing the discovery of up to twice as many true association signals than the classical imputed GWAS design. AVAILABILITY AND IMPLEMENTATION: The HELIC genotype and WGS datasets have been deposited to the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/home): EGAD00010000518; EGAD00010000522; EGAD00010000610; EGAD00001001636, EGAD00001001637. The peakplotter software is available at https://github.com/wtsi-team144/peakplotter, the transformPhenotype app can be downloaded at https://github.com/wtsi-team144/transformPhenotype. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

4.
Nat Commun ; 9(1): 5460, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30568165

RESUMO

The original version of this Article contained an error in Fig. 2. In panel a, the two legend items "rare" and "common" were inadvertently swapped. This has been corrected in both the PDF and HTML versions of the Article.

5.
Nat Commun ; 9(1): 4674, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405126

RESUMO

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10-8; APOC3 and triglyceride levels, P = 1.5 × 10-26), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10-8), indicating a role for this gene in lipid metabolism.

7.
Eur Respir J ; 52(5)2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30093573

RESUMO

Lymphangioleiomyomatosis (LAM) is a rare disease of women. Decline in lung function is variable, making appropriate targeting of therapy difficult. We used unbiased serum proteomics to identify markers associated with outcome in LAM.101 women with LAM and 22 healthy controls were recruited from the National Centre for LAM in the UK. 152 DNA and serum samples with linked lung function and outcome data were obtained from patients in the National Heart, Lung and Blood Institute LAM Registry in the USA. Proteomic analysis was performed on a discovery cohort of 50 LAM and 20 control serum samples using a SCIEX SWATH mass spectrometric workflow. Protein levels were quantitated by ELISA and single nucleotide polymorphisms in GC (group-specific component) encoding vitamin D binding protein (VTDB) were genotyped.Proteomic analysis showed VTDB was 2.6-fold lower in LAM than controls. Serum VTDB was lower in progressive compared with stable LAM (p=0.001) and correlated with diffusing capacity of the lung for carbon monoxide (p=0.01). Median time to death or lung transplant was reduced by 46 months in those with CC genotypes at rs4588 and 38 months in those with non-A-containing haplotypes at rs7041/4588 (p=0.014 and 0.008, respectively).The VTDB axis is associated with disease severity and outcome, and GC genotype could help predict transplant-free survival in LAM.

8.
Nat Genet ; 49(12): 1758-1766, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29083408

RESUMO

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.


Assuntos
Exoma/genética , Estudos de Associação Genética/métodos , Variação Genética , Lipídeos/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Degeneração Macular/sangue , Degeneração Macular/genética , Fenótipo , Fatores de Risco
9.
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
10.
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
11.
Nat Commun ; 8: 15606, 2017 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-28548082

RESUMO

Next-generation association studies can be empowered by sequence-based imputation and by studying founder populations. Here we report ∼9.5 million variants from whole-genome sequencing (WGS) of a Cretan-isolated population, and show enrichment of rare and low-frequency variants with predicted functional consequences. We use a WGS-based imputation approach utilizing 10,422 reference haplotypes to perform genome-wide association analyses and observe 17 genome-wide significant, independent signals, including replicating evidence for association at eight novel low-frequency variant signals. Two novel cardiometabolic associations are at lead variants unique to the founder population sequences: chr16:70790626 (high-density lipoprotein levels beta -1.71 (SE 0.25), P=1.57 × 10-11, effect allele frequency (EAF) 0.006); and rs145556679 (triglycerides levels beta -1.13 (SE 0.17), P=2.53 × 10-11, EAF 0.013). Our findings add empirical support to the contribution of low-frequency variants in complex traits, demonstrate the advantage of including population-specific sequences in imputation panels and exemplify the power gains afforded by population isolates.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Adulto , Idoso , Feminino , Variação Genética , Grécia , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/métodos
12.
Public Health Nutr ; 20(6): 1063-1074, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27989266

RESUMO

OBJECTIVE: We carried out de novo recruitment of a population-based cohort (MANOLIS study) and describe the specific population, which displays interesting characteristics in terms of diet and health in old age, through deep phenotyping. DESIGN: Cross-sectional study where anthropometric, biochemical and clinical measurements were taken in addition to interview-based completion of an extensive questionnaire on health and lifestyle parameters. Dietary patterns were derived through principal component analysis based on a validated FFQ. SETTING: Geographically isolated Mylopotamos villages on Mount Idi, Crete, Greece. SUBJECTS: Adults (n 1553). RESULTS: Mean age of the participants was 61·6 years and 55·8 % were women. Of the population, 82·7 % were overweight or obese with a significantly different prevalence between overweight men and women (43·4 v. 34·7 %, P=0·002). The majority (70·6 %) of participants were married, while a larger proportion of women were widowed than men (27·8 v. 3·5 %, P<0·001). Smoking was more prevalent in men (38·7 v. 8·2 %, P<0·001), as 88·8% of women had never smoked. Four dietary patterns emerged as characteristic of the population; these were termed 'local', 'high fat and sugar, 'Greek café/tavern' and 'olive oil, fruits and vegetables'. Individuals more adherent to the local dietary pattern presented higher blood glucose (ß=4·026, P<0·001). Similarly, individuals with higher compliance with the Greek café/tavern pattern had higher waist-to-hip ratio (ß=0·012, P<0·001), blood pressure (ß=1·015, P=0·005) and cholesterol (ß=5·398, P<0·001). CONCLUSIONS: Profiling of the MANOLIS elderly population identifies unique unhealthy dietary patterns that are associated with cardiometabolic indices.


Assuntos
Doenças Cardiovasculares/epidemiologia , Dieta , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antropometria , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/complicações , Estudos de Coortes , Estudos Transversais , Exercício , Feminino , Grécia/epidemiologia , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Avaliação Nutricional , Obesidade/complicações , Sobrepeso/complicações , Fatores de Risco , Inquéritos e Questionários , Relação Cintura-Quadril
13.
Nat Genet ; 48(11): 1303-1312, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27668658

RESUMO

Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.


Assuntos
Loci Gênicos , Genoma Humano , Estudo de Associação Genômica Ampla , Cardiopatias/genética , Doenças Hematológicas/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Locos de Características Quantitativas , Análise de Sequência de DNA
14.
Nat Genet ; 48(10): 1279-83, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27548312

RESUMO

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.


Assuntos
Genótipo , Haplótipos , Polimorfismo de Nucleotídeo Único , Alelos , Técnicas Genéticas , Estudo de Associação Genômica Ampla , Humanos , Internet , Valores de Referência
15.
Hum Mol Genet ; 25(18): 4094-4106, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27466198

RESUMO

It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.


Assuntos
HDL-Colesterol/genética , LDL-Colesterol/genética , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Adolescente , Adulto , Idoso , Criança , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Grupo com Ancestrais do Continente Europeu , Exoma/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Lipídeos/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , Triglicerídeos/genética
16.
Hum Mol Genet ; 25(11): 2360-2365, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27146844

RESUMO

Cohort-wide very low-depth whole-genome sequencing (WGS) can comprehensively capture low-frequency sequence variation for the cost of a dense genome-wide genotyping array. Here, we analyse 1x sequence data across the APOC3 gene in a founder population from the island of Crete in Greece (n = 1239) and find significant evidence for association with blood triglyceride levels with the previously reported R19X cardioprotective null mutation (ß = -1.09,σ = 0.163, P = 8.2 × 10-11) and a second loss of function mutation, rs138326449 (ß = -1.17,σ = 0.188, P = 1.14 × 10-9). The signal cannot be recapitulated by imputing genome-wide genotype data on a large reference panel of 5122 individuals including 249 with 4x WGS data from the same population. Gene-level meta-analysis with other studies reporting burden signals at APOC3 provides robust evidence for a replicable cardioprotective rare variant aggregation (P = 3.2 × 10-31, n = 13 480).


Assuntos
Apolipoproteína C-III/genética , Doenças Cardiovasculares/genética , Sequenciamento de Nucleotídeos em Larga Escala , Triglicerídeos/genética , Alelos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Efeito Fundador , Genética Populacional , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Grécia , Humanos , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue
17.
Nature ; 523(7561): 459-462, 2015 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-26131930

RESUMO

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.


Assuntos
Estatura/genética , Cognição , Homozigoto , Evolução Biológica , Pressão Sanguínea/genética , LDL-Colesterol/genética , Estudos de Coortes , Escolaridade , Feminino , Volume Expiratório Forçado/genética , Genoma Humano/genética , Humanos , Medidas de Volume Pulmonar , Masculino , Fenótipo
19.
Nat Commun ; 5: 5345, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25373335

RESUMO

Isolated populations are emerging as a powerful study design in the search for low-frequency and rare variant associations with complex phenotypes. Here we genotype 2,296 samples from two isolated Greek populations, the Pomak villages (HELIC-Pomak) in the North of Greece and the Mylopotamos villages (HELIC-MANOLIS) in Crete. We compare their genomic characteristics to the general Greek population and establish them as genetic isolates. In the MANOLIS cohort, we observe an enrichment of missense variants among the variants that have drifted up in frequency by more than fivefold. In the Pomak cohort, we find novel associations at variants on chr11p15.4 showing large allele frequency increases (from 0.2% in the general Greek population to 4.6% in the isolate) with haematological traits, for example, with mean corpuscular volume (rs7116019, P=2.3 × 10(-26)). We replicate this association in a second set of Pomak samples (combined P=2.0 × 10(-36)). We demonstrate significant power gains in detecting medical trait associations.


Assuntos
Deriva Genética , Variação Genética/genética , Genética Populacional , Genótipo , Mutação de Sentido Incorreto/genética , População/genética , Adolescente , Células Sanguíneas/citologia , Tamanho Celular , Estudos de Coortes , Frequência do Gene/genética , Estudo de Associação Genômica Ampla , Grécia , Haplótipos/genética , Humanos , Fenótipo , Isolamento Social
20.
Nat Commun ; 5: 4871, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25225788

RESUMO

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.


Assuntos
Alelos , Apolipoproteína C-III/genética , Lipoproteínas VLDL/sangue , Triglicerídeos/sangue , Processamento Alternativo , Criança , Grupo com Ancestrais do Continente Europeu , Feminino , Frequência do Gene , Humanos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Gêmeos/genética
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