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1.
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).

2.
Bioinformatics ; 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-30204848

RESUMO

Summary: Estimating linkage disequilibrium (LD) is essential for a wide range of summary statistics-based association methods for genome-wide association studies. Large genetic datasets, e.g. the TOPMed WGS project and UK Biobank, enable more accurate and comprehensive LD estimates, but increase the computational burden of LD estimation. Here, we describe emeraLD (Efficient Methods for Estimation and Random Access of LD), a computational tool that leverages sparsity and haplotype structure to estimate LD up to 2 orders of magnitude faster than current tools. Availability and implementation: emeraLD is implemented in C++, and is open source under GPLv3. Source code and documentation are freely available at http://github.com/statgen/emeraLD. Supplementary information: Supplementary data are available at Bioinformatics online.

3.
G3 (Bethesda) ; 8(10): 3255-3267, 2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30131328

RESUMO

The emergence of very large cohorts in genomic research has facilitated a focus on genotype-imputation strategies to power rare variant association. These strategies have benefited from improvements in imputation methods and association tests, however little attention has been paid to ways in which array design can increase rare variant association power. Therefore, we developed a novel framework to select tag SNPs using the reference panel of 26 populations from Phase 3 of the 1000 Genomes Project. We evaluate tag SNP performance via mean imputed r2 at untyped sites using leave-one-out internal validation and standard imputation methods, rather than pairwise linkage disequilibrium. Moving beyond pairwise metrics allows us to account for haplotype diversity across the genome for improve imputation accuracy and demonstrates population-specific biases from pairwise estimates. We also examine array design strategies that contrast multi-ethnic cohorts vs. single populations, and show a boost in performance for the former can be obtained by prioritizing tag SNPs that contribute information across multiple populations simultaneously. Using our framework, we demonstrate increased imputation accuracy for rare variants (frequency < 1%) by 0.5-3.1% for an array of one million sites and 0.7-7.1% for an array of 500,000 sites, depending on the population. Finally, we show how recent explosive growth in non-African populations means tag SNPs capture on average 30% fewer other variants than in African populations. The unified framework presented here will enable investigators to make informed decisions for the design of new arrays, and help empower the next phase of rare variant association for global health.

4.
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.

6.
Sci Rep ; 7: 45040, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28452372

RESUMO

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.


Assuntos
Biologia Computacional/métodos , Loci Gênicos , Rim/fisiologia , Frequência do Gene , Genoma Humano , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Polimorfismo de Nucleotídeo Único
7.
Bioinformatics ; 33(13): 2056-2058, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28200055

RESUMO

Summary: To enable direct comparison of ancestry background in different studies, we developed LASER to estimate individual ancestry by placing either sezquenced or genotyped samples in a common ancestry space, regardless of the sequencing strategy or genotyping array used to characterize each sample. Here we describe the LASER server to facilitate application of the method to a wide range of genetic studies. The server provides genetic ancestry estimation for different geographic regions and user-friendly interactive visualization of the results. Availability and Implementation: The LASER server is freely accessible at http://laser.sph.umich.edu/. Contact: dtaliun@umich.edu or wangcl@gis.a-star.edu.sg. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Variação Genética , Filogeografia/métodos , Grupos Populacionais/genética , Análise de Sequência de DNA/métodos , Software , Humanos
8.
IEEE/ACM Trans Comput Biol Bioinform ; 13(2): 315-25, 2016 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27045830

RESUMO

Scaling linkage disequilibrium (LD) based haplotype block recognition to the entire human genome has always been a challenge. The best-known algorithm has quadratic runtime complexity and, even when sophisticated search space pruning is applied, still requires several days of computations. Here, we propose a novel sampling-based algorithm, called S-MIG (++), where the main idea is to estimate the area that most likely contains all haplotype blocks by sampling a very small number of SNP pairs. A subsequent refinement step computes the exact blocks by considering only the SNP pairs within the estimated area. This approach significantly reduces the number of computed LD statistics, making the recognition of haplotype blocks very fast. We theoretically and empirically prove that the area containing all haplotype blocks can be estimated with a very high degree of certainty. Through experiments on the 243,080 SNPs on chromosome 20 from the 1,000 Genomes Project, we compared our previous algorithm MIG (++) with the new S-MIG (++) and observed a runtime reduction from 2.8 weeks to 34.8 hours. In a parallelized version of the S-MIG (++) algorithm using 32 parallel processes, the runtime was further reduced to 5.1 hours.


Assuntos
Genômica/métodos , Haplótipos/genética , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Algoritmos , Genoma Humano , Humanos , Modelos Genéticos , Reconhecimento Automatizado de Padrão
9.
Nat Commun ; 7: 10023, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26831199

RESUMO

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.


Assuntos
Predisposição Genética para Doença , Insuficiência Renal Crônica/genética , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos
10.
Bioinformatics ; 32(10): 1583-5, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26803158

RESUMO

UNLABELLED: Familial aggregation analysis is the first fundamental step to perform when assessing the extent of genetic background of a disease. However, there is a lack of software to analyze the familial clustering of complex phenotypes in very large pedigrees. Such pedigrees can be utilized to calculate measures that express trait aggregation on both the family and individual level, providing valuable directions in choosing families for detailed follow-up studies. We developed FamAgg, an open source R package that contains both established and novel methods to investigate familial aggregation of traits in large pedigrees. We demonstrate its use and interpretation by analyzing a publicly available cancer dataset with more than 20 000 participants distributed across approximately 400 families. AVAILABILITY AND IMPLEMENTATION: The FamAgg package is freely available at the Bioconductor repository, http://www.bioconductor.org/packages/FamAgg CONTACT: Christian.Weichenberger@eurac.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Software , Linhagem
11.
Diabetes ; 65(3): 803-17, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26631737

RESUMO

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.


Assuntos
Albuminúria/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Túbulos Renais/metabolismo , Adulto , Idoso , Albuminúria/etiologia , Animais , Catepsina C/genética , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Feminino , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Ratos , Receptores de Superfície Celular/genética , Sulfotransferases/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
12.
Hum Mol Genet ; 23(24): 6684-93, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25080503

RESUMO

Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.


Assuntos
Cromossomos Humanos Par 14/química , Cromossomos Humanos Par 17/química , Loci Gênicos , Osteoprotegerina/genética , Polimorfismo Genético , Característica Quantitativa Herdável , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Osteoprotegerina/sangue
13.
BMC Bioinformatics ; 15: 10, 2014 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-24423111

RESUMO

BACKGROUND: The new sequencing technologies enable to scan very long and dense genetic sequences, obtaining datasets of genetic markers that are an order of magnitude larger than previously available. Such genetic sequences are characterized by common alleles interspersed with multiple rarer alleles. This situation has renewed the interest for the identification of haplotypes carrying the rare risk alleles. However, large scale explorations of the linkage-disequilibrium (LD) pattern to identify haplotype blocks are not easy to perform, because traditional algorithms have at least Θ(n2) time and memory complexity. RESULTS: We derived three incremental optimizations of the widely used haplotype block recognition algorithm proposed by Gabriel et al. in 2002. Our most efficient solution, called MIG ++, has only Θ(n) memory complexity and, on a genome-wide scale, it omits >80% of the calculations, which makes it an order of magnitude faster than the original algorithm. Differently from the existing software, the MIG ++ analyzes the LD between SNPs at any distance, avoiding restrictions on the maximal block length. The haplotype block partition of the entire HapMap II CEPH dataset was obtained in 457 hours. By replacing the standard likelihood-based D' variance estimator with an approximated estimator, the runtime was further improved. While producing a coarser partition, the approximate method allowed to obtain the full-genome haplotype block partition of the entire 1000 Genomes Project CEPH dataset in 44 hours, with no restrictions on allele frequency or long-range correlations. These experiments showed that LD-based haplotype blocks can span more than one million base-pairs in both HapMap II and 1000 Genomes datasets. An application to the North American Rheumatoid Arthritis Consortium (NARAC) dataset shows how the MIG ++ can support genome-wide haplotype association studies. CONCLUSIONS: The MIG ++ enables to perform LD-based haplotype block recognition on genetic sequences of any length and density. In the new generation sequencing era, this can help identify haplotypes that carry rare variants of interest. The low computational requirements open the possibility to include the haplotype block structure into genome-wide association scans, downstream analyses, and visual interfaces for online genome browsers.


Assuntos
Biologia Computacional/métodos , Haplótipos/genética , Análise de Sequência de DNA/métodos , Software , Algoritmos , Artrite Reumatoide/genética , Frequência do Gene , Genoma/genética , Humanos , Desequilíbrio de Ligação/genética , Modelos Genéticos
14.
J Am Soc Nephrol ; 24(12): 2105-17, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24029420

RESUMO

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Variação Genética , Rim/fisiologia , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/genética , Bases de Dados Genéticas , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Fenótipo
15.
Genet Epidemiol ; 37(2): 205-13, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23307621

RESUMO

Biological plausibility and other prior information could help select genome-wide association (GWA) findings for further follow-up, but there is no consensus on which types of knowledge should be considered or how to weight them. We used experts' opinions and empirical evidence to estimate the relative importance of 15 types of information at the single-nucleotide polymorphism (SNP) and gene levels. Opinions were elicited from 10 experts using a two-round Delphi survey. Empirical evidence was obtained by comparing the frequency of each type of characteristic in SNPs established as being associated with seven disease traits through GWA meta-analysis and independent replication, with the corresponding frequency in a randomly selected set of SNPs. SNP and gene characteristics were retrieved using a specially developed bioinformatics tool. Both the expert and the empirical evidence rated previous association in a meta-analysis or more than one study as conferring the highest relative probability of true association, whereas previous association in a single study ranked much lower. High relative probabilities were also observed for location in a functional protein domain, although location in a region evolutionarily conserved in vertebrates was ranked high by the data but not by the experts. Our empirical evidence did not support the importance attributed by the experts to whether the gene encodes a protein in a pathway or shows interactions relevant to the trait. Our findings provide insight into the selection and weighting of different types of knowledge in SNP or gene prioritization, and point to areas requiring further research.


Assuntos
Seguimentos , Pesquisa em Genética , Polimorfismo de Nucleotídeo Único , Biologia Computacional/métodos , Estudo de Associação Genômica Ampla , Humanos , Metanálise como Assunto , Probabilidade
16.
Genet Epidemiol ; 37(2): 214-21, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23280596

RESUMO

Prioritization is the process whereby a set of possible candidate genes or SNPs is ranked so that the most promising can be taken forward into further studies. In a genome-wide association study, prioritization is usually based on the P-values alone, but researchers sometimes take account of external annotation information about the SNPs such as whether the SNP lies close to a good candidate gene. Using external information in this way is inherently subjective and is often not formalized, making the analysis difficult to reproduce. Building on previous work that has identified 14 important types of external information, we present an approximate Bayesian analysis that produces an estimate of the probability of association. The calculation combines four sources of information: the genome-wide data, SNP information derived from bioinformatics databases, empirical SNP weights, and the researchers' subjective prior opinions. The calculation is fast enough that it can be applied to millions of SNPS and although it does rely on subjective judgments, those judgments are made explicit so that the final SNP selection can be reproduced. We show that the resulting probability of association is intuitively more appealing than the P-value because it is easier to interpret and it makes allowance for the power of the study. We illustrate the use of the probability of association for SNP prioritization by applying it to a meta-analysis of kidney function genome-wide association studies and demonstrate that SNP selection performs better using the probability of association compared with P-values alone.


Assuntos
Teorema de Bayes , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Bases de Dados Genéticas , Humanos , Rim/fisiologia , Metanálise como Assunto , Modelos Genéticos , Probabilidade
17.
Hum Mol Genet ; 21(24): 5329-43, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22962313

RESUMO

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Sistemas de Transporte de Aminoácidos Básicos/genética , Cadeia Pesada da Proteína-1 Reguladora de Fusão/genética , Predisposição Genética para Doença/genética , Taxa de Filtração Glomerular/genética , Taxa de Filtração Glomerular/fisiologia , Humanos , Subunidades beta de Inibinas/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteínas de Membrana/genética
18.
PLoS Genet ; 8(3): e1002584, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22479191

RESUMO

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.


Assuntos
Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Falência Renal Crônica/genética , Rim/fisiopatologia , Peixe-Zebra/genética , Afro-Americanos/genética , Idoso , Animais , Caspase 9/genética , Quinases Ciclina-Dependentes/genética , RNA Helicases DEAD-box/genética , DNA Helicases/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Seguimentos , Técnicas de Silenciamento de Genes , Humanos , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Diester Fosfórico Hidrolases/genética
19.
Bioinformatics ; 28(3): 444-5, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22155946

RESUMO

SUMMARY: The GWAtoolbox is an R package that standardizes and accelerates the handling of data from genome-wide association studies (GWAS), particularly in the context of large-scale GWAS meta-analyses. A key feature of GWAtoolbox is its ability to perform quality control (QC) of any number of files in a matter of minutes. The implemented workflow has been structured to check three particular data quality aspects: (i) data formatting, (ii) quality of the GWAS results and (iii) data consistency across studies. Output consists of an extensive list of quality statistics and plots which allow inspection of individual files and between-study comparison to identify systematic bias. AVAILABILITY: http://www.eurac.edu/GWAtoolbox CONTACT: cfuchsb@umich.edu; daniel.taliun@eurac.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Estudo de Associação Genômica Ampla , Software , Projeto HapMap , Humanos , Metanálise como Assunto , Controle de Qualidade
20.
J Med Genet ; 48(8): 549-56, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21690246

RESUMO

BACKGROUND: Thyroid hormones have important roles in growth, development and control of metabolism, and their dysregulation can lead to disease. OBJECTIVES: To identify genes contributing to hyperthyrotropinaemia. DESIGN, SETTING, PARTICIPANTS: Linkage and association analyses using 1258 individuals from three Alpine villages. OUTCOME MEASURES: The study applied two different upper limits of the reference range (URR) for serum thyroid stimulating hormone (TSH) values (TSH ≥4.6 mU/l and TSH >3.0 mU/l), along with normal or low fT4 (free thyroxine) values or thyroid medical treatment to define two groups of individuals for analysis: one hyperthyrotropinaemic or high-TSH (H-TSH) (TSH ≥4.6 mU/l) group; and a larger group (TSH >3.0 mU/l) called hyperthyrotropinaemic and upper reference range TSH (H+URR-TSH). RESULTS: Non-parametric genome-wide linkage analysis was performed on pedigrees generated from the two groups. Linkage analysis in the H+URR-TSH group revealed a significant peak on chromosome 3q28-q29 (LOD 3.34) and a suggestive linkage peak on chromosome 6q26-27 (LOD 2.66). Analysis in the smaller hyperthyrotropinaemic (H-TSH) group supported linkage to chromosome 6q26-27. Single SNP and gene based SNP association analyses under the linkage peaks identified the PDE10A and DACT2 genes as candidates at the chromosome 6 locus. CONCLUSIONS: PDE10A or DACT2 were identified as candidate genes contributing to hyperthyrotropinaemia (and possibly hypothyroidism) in this sample. Studies in additional populations support association of variants at this locus with TSH values, especially in the PDE10A gene. Genetic linkage in families with hyperthyrotropinaemia suggests the presence of functional variants that contribute to pathological disruption of the hypothalamus-pituitary-thyroid axis.


Assuntos
Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 6/genética , Ligação Genética , Loci Gênicos/genética , Predisposição Genética para Doença , Genética Populacional , Doenças da Glândula Tireoide/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Itália , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética
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