Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-31006013

RESUMO

BACKGROUND: There is little information in haemodialysis (HD) patients on whether temporal changes in serum calcium, phosphate or intact parathyroid hormone (iPTH) are associated with mortality. METHODS: We analysed associations of phosphate, total calcium and iPTH with all-cause and cardiovascular mortality in 8817 incident HD patients from the European second Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) cohort enrolled in 2007-09, which were prospectively followed for a median of 3 years, using time-dependent Cox proportional hazards models. We evaluated changes in risk over time depending on changes in phosphate, calcium or iPTH. RESULTS: The association of phosphate and iPTH with all-cause mortality was U-shaped, with the lowest risk ranges between 1.20 and 1.89 mmol/L for phosphate and between 239 and 710 ng/L for iPTH. For total calcium, the associations were J-shaped, with an increased risk for all-cause mortality at levels >2.36 mmol/L. Lowest risk ranges for cardiovascular mortality did not change markedly for all three parameters. If iPTH was below the lowest risk range at baseline (iPTH <239 ng/L), a subsequent increase in levels was associated with improved survival. For phosphate, an increase or decrease out of the lowest risk range was associated with increased mortality risk. For calcium, this was only the case when the values increased above the lowest risk range. CONCLUSION: In the AROii cohort, the ranges of bone mineral biomarkers associated with the lowest mortality ranges were largely consistent with the current Kidney Disease: Improving Global Outcomes chronic kidney disease-mineral and bone disorder guideline recommendations. Allowing a suppressed iPTH to increase was associated with a lower mortality, whereas shifts of phosphate or calcium outside the lowest risk range increased mortality.

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.
J Lipid Res ; 58(9): 1834-1844, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28512139

RESUMO

High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10-30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (P = 3.47 × 10-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10-4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.


Assuntos
Apolipoproteínas A/metabolismo , Estudo de Associação Genômica Ampla/métodos , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo , Animais , Apolipoproteínas A/genética , Humanos , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/metabolismo , Caracteres Sexuais
4.
Eur Heart J ; 38(23): 1823-1831, 2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-28444229

RESUMO

Aims: Lp(a) concentrations represent a major cardiovascular risk factor and are almost entirely controlled by one single locus (LPA). However, many genetic factors in LPA governing the enormous variance of Lp(a) levels are still unknown. Since up to 70% of the LPA coding sequence are located in a difficult to access hypervariable copy number variation named KIV-2, we hypothesized that it may contain novel functional variants with pronounced effects on Lp(a) concentrations. We performed a large scale mutation analysis in the KIV-2 using an extreme phenotype approach. Methods and Results: We compiled an discovery set of 123 samples showing discordance between LPA isoform phenotype and Lp(a) concentrations and controls. Using ultra-deep sequencing, we identified a splice site variant (G4925A) in preferential association with the smaller LPA isoforms. Follow-up in a European general population (n = 2892) revealed an exceptionally high carrier frequency of 22.1% in the general population. The variant explains 20.6% of the Lp(a) variance in carriers of low molecular weight (LMW) apo(a) isoforms (P = 5.75e-38) and reduces Lp(a) concentrations by 31.3 mg/dL. Accordingly the odds ratio for cardiovascular disease was reduced from 1.39 [95% confidence interval (CI): 1.17-1.66, P = 1.89e-04] for wildtype LMW individuals to 1.19 [95%CI: 0.92; 1.56, P = 0.19] in LMW individuals who were additionally positive for G4925A. Functional studies point towards a reduction of splicing efficiency by this novel variant. Conclusion: A highly frequent but until now undetected variant in the LPA KIV-2 region is strongly associated with reduced Lp(a) concentrations and reduced cardiovascular risk in LMW individuals.


Assuntos
Doenças Cardiovasculares/genética , Kringles/genética , Lipoproteína(a)/genética , Adulto , Idoso , Variações do Número de Cópias de DNA/genética , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Lipoproteína(a)/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Fatores de Risco
5.
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
6.
Nat Genet ; 48(10): 1284-1287, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27571263

RESUMO

Genotype imputation is a key component of genetic association studies, where it increases power, facilitates meta-analysis, and aids interpretation of signals. Genotype imputation is computationally demanding and, with current tools, typically requires access to a high-performance computing cluster and to a reference panel of sequenced genomes. Here we describe improvements to imputation machinery that reduce computational requirements by more than an order of magnitude with no loss of accuracy in comparison to standard imputation tools. We also describe a new web-based service for imputation that facilitates access to new reference panels and greatly improves user experience and productivity.


Assuntos
Algoritmos , Genótipo , Simulação por Computador , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Internet
7.
Hum Mol Genet ; 25(16): 3635-3646, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27412012

RESUMO

Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 - 44), rs5104 in APOA4 (P = 1.79 × 10-24) and rs4241819 in KLKB1 (P = 5.6 × 10-14). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 - 07). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10-05). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1 The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations.


Assuntos
Apolipoproteínas A/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Alelos , Apolipoproteínas A/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , Feminino , Humanos , Rim/metabolismo , Lipídeos/sangue , Lipídeos/genética , Masculino , Triglicerídeos/sangue , Triglicerídeos/genética
8.
Nucleic Acids Res ; 44(W1): W64-9, 2016 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-27084948

RESUMO

Next generation sequencing (NGS) allows investigating mitochondrial DNA (mtDNA) characteristics such as heteroplasmy (i.e. intra-individual sequence variation) to a higher level of detail. While several pipelines for analyzing heteroplasmies exist, issues in usability, accuracy of results and interpreting final data limit their usage. Here we present mtDNA-Server, a scalable web server for the analysis of mtDNA studies of any size with a special focus on usability as well as reliable identification and quantification of heteroplasmic variants. The mtDNA-Server workflow includes parallel read alignment, heteroplasmy detection, artefact or contamination identification, variant annotation as well as several quality control metrics, often neglected in current mtDNA NGS studies. All computational steps are parallelized with Hadoop MapReduce and executed graphically with Cloudgene. We validated the underlying heteroplasmy and contamination detection model by generating four artificial sample mix-ups on two different NGS devices. Our evaluation data shows that mtDNA-Server detects heteroplasmies and artificial recombinations down to the 1% level with perfect specificity and outperforms existing approaches regarding sensitivity. mtDNA-Server is currently able to analyze the 1000G Phase 3 data (n = 2,504) in less than 5 h and is freely accessible at https://mtdna-server.uibk.ac.at.


Assuntos
DNA Mitocondrial/genética , Variação Genética , Mitocôndrias/genética , Análise de Sequência de DNA/estatística & dados numéricos , Interface Usuário-Computador , Gráficos por Computador , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Internet , Anotação de Sequência Molecular , Sensibilidade e Especificidade , Alinhamento de Sequência
9.
Nucleic Acids Res ; 44(W1): W58-63, 2016 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-27084951

RESUMO

Mitochondrial DNA (mtDNA) profiles can be classified into phylogenetic clusters (haplogroups), which is of great relevance for evolutionary, forensic and medical genetics. With the extensive growth of the underlying phylogenetic tree summarizing the published mtDNA sequences, the manual process of haplogroup classification would be too time-consuming. The previously published classification tool HaploGrep provided an automatic way to address this issue. Here, we present the completely updated version HaploGrep 2 offering several advanced features, including a generic rule-based system for immediate quality control (QC). This allows detecting artificial recombinants and missing variants as well as annotating rare and phantom mutations. Furthermore, the handling of high-throughput data in form of VCF files is now directly supported. For data output, several graphical reports are generated in real time, such as a multiple sequence alignment format, a VCF format and extended haplogroup QC reports, all viewable directly within the application. In addition, HaploGrep 2 generates a publication-ready phylogenetic tree of all input samples encoded relative to the revised Cambridge Reference Sequence. Finally, new distance measures and optimizations of the algorithm increase accuracy and speed-up the application. HaploGrep 2 can be accessed freely and without any registration at http://haplogrep.uibk.ac.at.


Assuntos
DNA Mitocondrial/genética , Haplótipos , Filogenia , Interface Usuário-Computador , Algoritmos , Evolução Biológica , DNA Mitocondrial/classificação , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Internet , Mitocôndrias/genética , Controle de Qualidade , Alinhamento de Sequência , Análise de Sequência de DNA
10.
Exp Gerontol ; 72: 162-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26423240

RESUMO

Telomere length is considered as a biological marker for aging. It is expected that telomeres shorten with age and with conditions associated with oxidative stress and inflammation. Both are present in patients with chronic kidney disease (CKD) who have a very high cardiovascular risk. We investigated whether CKD duration is associated with relative telomere length (RTL) in 4802 patients from the German Chronic Kidney Disease (GCKD) study. We measured RTL in each sample in quadruplicates using a quantitative polymerase chain reaction (qPCR). We observed a U-shaped association of RTL with CKD duration: the longest RTL was found in those 339 patients who reported the shortest disease duration (<6 months) and shorter RTL in 2108 patients with duration between 6 months and less than 5 years. Most importantly, those 2331 patients who reported a CKD duration of 5 years and more had significantly longer RTL compared to those with intermediate CKD duration (6 months to less than 5 years): mean 0.954, 95%CI 0.946-0.961 versus 0.937, 95%CI 0.929-0.944, p=0.002). Due to the cross-sectional nature of the study these surprising results have to be considered with caution and as hypothesis-generating. Whether the longer RTL in patients with long-lasting disease is caused by an activation of telomerase to counteract the shortening of RTL due to oxidative stress and inflammation or whether they are caused by a survival bias needs to be investigated in longitudinal studies. Our data are in support of a higher plasticity of shortening and elongations of RTL as until recently anticipated.


Assuntos
Envelhecimento/genética , Insuficiência Renal Crônica/genética , Telômero/ultraestrutura , Idoso , Biomarcadores , Estudos Transversais , Feminino , Alemanha , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco
11.
Atherosclerosis ; 242(2): 529-34, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26302167

RESUMO

BACKGROUND: Chronic kidney disease (CKD) affects 10-15% of the general population and affected individuals are at an increased risk for cardiovascular disease (CVD). Since telomere length is considered to be involved in biological aging, we tested whether relative telomere length (RTL) might be a marker for these two diseases. METHODS: The German Chronic Kidney Disease (GCKD) study is an ongoing prospective cohort study including patients with CKD of moderate severity. RTL was measured by qPCR in 4955 out of 5217 GCKD patients at baseline. RESULTS: RTL was distributed in the cohort with a mean ± SD of 0.95 ± 0.19. CVD was present in 1266 patients. Each decrease of RTL by 0.1 unit was associated with a higher probability for prevalent CVD: OR = 1.06, 95% CI 1.02-1.11, p = 0.007 (adjusted for age, sex, eGFR, BMI, ln-CRP, smoking, hypertension, diabetes, and lipids). Similar findings were observed for history of specific CVD entities, such as coronary artery disease (OR = 1.05, p = 0.025), myocardial infarction (OR = 1.08, p = 0.013) and percutaneous transluminal coronary angioplasty (OR = 1.06, p = 0.032). The strongest associations were found for interventions at the carotid arteries (OR = 1.25, p = 0.001) as well as aortic aneurysms (OR = 1.22, p = 0.001). CONCLUSIONS: In the presence of CKD there is a significant association between shorter RTL and CVD manifestations. RTL appears to be a marker reflecting changes in homeostasis associated with CKD that may contribute to the excess CVD risk.


Assuntos
Doenças Cardiovasculares/genética , Falência Renal Crônica/genética , Telômero/ultraestrutura , Idoso , Aneurisma Aórtico/complicações , Aneurisma Aórtico/genética , Doenças Cardiovasculares/complicações , Feminino , Alemanha , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reação em Cadeia da Polimerase , Estudos Prospectivos , Fatores de Risco
12.
Biol Direct ; 10: 43, 2015 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-26282399

RESUMO

High-throughput technologies, such as next-generation sequencing, have turned molecular biology into a data-intensive discipline, requiring bioinformaticians to use high-performance computing resources and carry out data management and analysis tasks on large scale. Workflow systems can be useful to simplify construction of analysis pipelines that automate tasks, support reproducibility and provide measures for fault-tolerance. However, workflow systems can incur significant development and administration overhead so bioinformatics pipelines are often still built without them. We present the experiences with workflows and workflow systems within the bioinformatics community participating in a series of hackathons and workshops of the EU COST action SeqAhead. The organizations are working on similar problems, but we have addressed them with different strategies and solutions. This fragmentation of efforts is inefficient and leads to redundant and incompatible solutions. Based on our experiences we define a set of recommendations for future systems to enable efficient yet simple bioinformatics workflow construction and execution.


Assuntos
Biologia Computacional/métodos , Processamento Eletrônico de Dados/métodos , Fluxo de Trabalho , Sequenciamento de Nucleotídeos em Larga Escala , Reprodutibilidade dos Testes
13.
PLoS One ; 10(8): e0135643, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26262956

RESUMO

BACKGROUND: Oral squamous cell carcinoma (OSCC) is mainly caused by smoking and alcohol abuse and shows a five-year survival rate of ~50%. We aimed to explore the variation of somatic mitochondrial DNA (mtDNA) mutations in primary oral tumors, recurrences and metastases. METHODS: We performed an in-depth validation of mtDNA next-generation sequencing (NGS) on an Illumina HiSeq 2500 platform for its application to cancer tissues, with the goal to detect low-level heteroplasmies and to avoid artifacts. Therefore we genotyped the mitochondrial genome (16.6 kb) from 85 tissue samples (tumors, recurrences, resection edges, metastases and blood) collected from 28 prospectively recruited OSCC patients applying both Sanger sequencing and high-coverage NGS (~35,000 reads per base). RESULTS: We observed a strong correlation between Sanger sequencing and NGS in estimating the mixture ratio of heteroplasmies (r = 0.99; p<0.001). Non-synonymous heteroplasmic variants were enriched among cancerous tissues. The proportions of somatic and inherited variants in a given gene region were strongly correlated (r = 0.85; p<0.001). Half of the patients shared mutations between benign and cancerous tissue samples. Low level heteroplasmies (<10%) were more frequent in benign samples compared to tumor samples, where heteroplasmies >10% were predominant. Four out of six patients who developed a local tumor recurrence showed mutations in the recurrence that had also been observed in the primary tumor. Three out of five patients, who had tumor metastases in the lymph nodes of their necks, shared mtDNA mutations between primary tumors and lymph node metastases. The percentage of mutation heteroplasmy increased from the primary tumor to lymph node metastases. CONCLUSIONS: We conclude that Sanger sequencing is valid for heteroplasmy quantification for heteroplasmies ≥10% and that NGS is capable of reliably detecting and quantifying heteroplasmies down to the 1%-level. The finding of shared mutations between primary tumors, recurrences and metastasis indicates a clonal origin of malignant cells in oral cancer.


Assuntos
Carcinoma de Células Escamosas/genética , Genoma Mitocondrial , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Bucais/genética , Mutação , Carcinoma de Células Escamosas/patologia , DNA Mitocondrial/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Dados de Sequência Molecular , Neoplasias Bucais/patologia , Recidiva Local de Neoplasia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodos
14.
BMC Evol Biol ; 14: 17, 2014 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-24467713

RESUMO

BACKGROUND: Myanmar is the largest country in mainland Southeast Asia with a population of 55 million people subdivided into more than 100 ethnic groups. Ruled by changing kingdoms and dynasties and lying on the trade route between India and China, Myanmar was influenced by numerous cultures. Since its independence from British occupation, tensions between the ruling Bamar and ethnic minorities increased. RESULTS: Our aim was to search for genetic footprints of Myanmar's geographic, historic and sociocultural characteristics and to contribute to the picture of human colonization by describing and dating of new mitochondrial DNA (mtDNA) haplogroups. Therefore, we sequenced the mtDNA control region of 327 unrelated donors and the complete mitochondrial genome of 44 selected individuals according to highest quality standards. CONCLUSION: Phylogenetic analyses of the entire mtDNA genomes uncovered eight new haplogroups and three unclassified basal M-lineages. The multi-ethnic population and the complex history of Myanmar were reflected in its mtDNA heterogeneity. Population genetic analyses of Burmese control region sequences combined with population data from neighboring countries revealed that the Myanmar haplogroup distribution showed a typical Southeast Asian pattern, but also Northeast Asian and Indian influences. The population structure of the extraordinarily diverse Bamar differed from that of the Karen people who displayed signs of genetic isolation. Migration analyses indicated a considerable genetic exchange with an overall positive migration balance from Myanmar to neighboring countries. Age estimates of the newly described haplogroups point to the existence of evolutionary windows where climatic and cultural changes gave rise to mitochondrial haplogroup diversification in Asia.


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , DNA Mitocondrial/genética , Evolução Molecular , Ásia Sudeste/etnologia , Grupo com Ancestrais do Continente Asiático/classificação , Sequência de Bases , Cultura , Grupo com Ancestrais do Continente Europeu/genética , Genética Populacional , Genoma Mitocondrial , Haplótipos , Humanos , Mianmar/etnologia , Filogenia
15.
PLoS One ; 8(3): e59508, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23527209

RESUMO

Single nucleotide polymorphisms (SNPs) play a prominent role in modern genetics. Current genotyping technologies such as Sequenom iPLEX, ABI TaqMan and KBioscience KASPar made the genotyping of huge SNP sets in large populations straightforward and allow the generation of hundreds of thousands of genotypes even in medium sized labs. While data generation is straightforward, the subsequent data conversion, storage and quality control steps are time-consuming, error-prone and require extensive bioinformatic support. In order to ease this tedious process, we developed SNPflow. SNPflow is a lightweight, intuitive and easily deployable application, which processes genotype data from Sequenom MassARRAY (iPLEX) and ABI 7900HT (TaqMan, KASPar) systems and is extendible to other genotyping methods as well. SNPflow automatically converts the raw output files to ready-to-use genotype lists, calculates all standard quality control values such as call rate, expected and real amount of replicates, minor allele frequency, absolute number of discordant replicates, discordance rate and the p-value of the HWE test, checks the plausibility of the observed genotype frequencies by comparing them to HapMap/1000-Genomes, provides a module for the processing of SNPs, which allow sex determination for DNA quality control purposes and, finally, stores all data in a relational database. SNPflow runs on all common operating systems and comes as both stand-alone version and multi-user version for laboratory-wide use. The software, a user manual, screenshots and a screencast illustrating the main features are available at http://genepi-snpflow.i-med.ac.at.


Assuntos
Biologia Computacional/métodos , Bases de Dados Genéticas , Polimorfismo de Nucleotídeo Único/genética , Software , Genótipo
16.
Atherosclerosis ; 225(2): 363-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23058813

RESUMO

OBJECTIVE: Effect modification by obesity or obesity-related phenotypes (e.g. physical activity and diet) was observed in some candidate gene studies on lipids. We aimed to evaluate gene-obesity interaction effects on HDL (HDL-C), LDL (LDL-C) and total cholesterol (TC) levels using genetic predisposition scores. METHODS: We derived imputed genotypes for 104 SNPs in 84 lipid-associated loci in the population-based studies KORA F3 (n = 1406) and KORA F4 (n = 1515). We inferred specific unbiased weights for each SNP from linear regression estimates in KORA F4. Weighted genotypic predisposition SNP-scores were then calculated for each lipid trait in KORA F3. Interaction terms of SNP-scores with each of the obesity parameters (BMI, waist-hip-ratio, waist circumference) were included in age- and sex-adjusted linear regression models on HDL-C, LDL-C and TC. RESULTS: All three SNP-scores were shown to be highly associated with their respective lipid levels (p = 1.11 × 10(-47) for HDL-C, p = 3.25 × 10(-19) for LDL-C and 1.53 × 10(-13) for TC). BMI, WHR and waist circumference modified the effect of the weighted HDL-C SNP-score on HDL-C significantly (all interaction p-values < 0.0062). No interaction term was significant for LDL-C or TC. Accounting for gene-obesity interaction substantially increased the proportion of HDL-C variance explained by 3-3.5%. CONCLUSION: Our investigation revealed a significant interaction effect between obesity parameters and a SNP-score on HDL-C: the combined effect of HDL-C-increasing alleles on HDL-C is attenuated with increasing levels of obesity-relevant parameters. Future studies aiming to detect new genetic variants or to model genetic predictions of HDL-C levels should take obesity or obesity associated parameters into account.


Assuntos
HDL-Colesterol/sangue , Interação Gene-Ambiente , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , LDL-Colesterol/sangue , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Alemanha/epidemiologia , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Obesidade/sangue , Obesidade/diagnóstico , Obesidade/epidemiologia , Fenótipo , Medição de Risco , Fatores de Risco , Fatores Sexuais , Circunferência da Cintura/genética , Relação Cintura-Quadril
17.
BMC Bioinformatics ; 13: 200, 2012 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-22888776

RESUMO

BACKGROUND: The MapReduce framework enables a scalable processing and analyzing of large datasets by distributing the computational load on connected computer nodes, referred to as a cluster. In Bioinformatics, MapReduce has already been adopted to various case scenarios such as mapping next generation sequencing data to a reference genome, finding SNPs from short read data or matching strings in genotype files. Nevertheless, tasks like installing and maintaining MapReduce on a cluster system, importing data into its distributed file system or executing MapReduce programs require advanced knowledge in computer science and could thus prevent scientists from usage of currently available and useful software solutions. RESULTS: Here we present Cloudgene, a freely available platform to improve the usability of MapReduce programs in Bioinformatics by providing a graphical user interface for the execution, the import and export of data and the reproducibility of workflows on in-house (private clouds) and rented clusters (public clouds). The aim of Cloudgene is to build a standardized graphical execution environment for currently available and future MapReduce programs, which can all be integrated by using its plug-in interface. Since Cloudgene can be executed on private clusters, sensitive datasets can be kept in house at all time and data transfer times are therefore minimized. CONCLUSIONS: Our results show that MapReduce programs can be integrated into Cloudgene with little effort and without adding any computational overhead to existing programs. This platform gives developers the opportunity to focus on the actual implementation task and provides scientists a platform with the aim to hide the complexity of MapReduce. In addition to MapReduce programs, Cloudgene can also be used to launch predefined systems (e.g. Cloud BioLinux, RStudio) in public clouds. Currently, five different bioinformatic programs using MapReduce and two systems are integrated and have been successfully deployed. Cloudgene is freely available at http://cloudgene.uibk.ac.at.


Assuntos
Biologia Computacional/métodos , Redes de Comunicação de Computadores , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Software , Genoma , Reprodutibilidade dos Testes
18.
Hum Mutat ; 32(1): 25-32, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20960467

RESUMO

An ongoing source of controversy in mitochondrial DNA (mtDNA) research is based on the detection of numerous errors in mtDNA profiles that led to erroneous conclusions and false disease associations. Most of these controversies could be avoided if the samples' haplogroup status would be taken into consideration. Knowing the mtDNA haplogroup affiliation is a critical prerequisite for studying mechanisms of human evolution and discovering genes involved in complex diseases, and validating phylogenetic consistency using haplogroup classification is an important step in quality control. However, despite the availability of Phylotree, a regularly updated classification tree of global mtDNA variation, the process of haplogroup classification is still time-consuming and error-prone, as researchers have to manually compare the polymorphisms found in a population sample to those summarized in Phylotree, polymorphism by polymorphism, sample by sample. We present HaploGrep, a fast, reliable and straight-forward algorithm implemented in a Web application to determine the haplogroup affiliation of thousands of mtDNA profiles genotyped for the entire mtDNA or any part of it. HaploGrep uses the latest version of Phylotree and offers an all-in-one solution for quality assessment of mtDNA profiles in clinical genetics, population genetics and forensics. HaploGrep can be accessed freely at http://haplogrep.uibk.ac.at.


Assuntos
Algoritmos , DNA Mitocondrial/classificação , DNA Mitocondrial/genética , Haplótipos/genética , Bases de Dados Genéticas , Humanos , Software/tendências
19.
BMC Bioinformatics ; 11: 318, 2010 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-20546565

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) based on single nucleotide polymorphisms (SNPs) revolutionized our perception of the genetic regulation of complex traits and diseases. Copy number variations (CNVs) promise to shed additional light on the genetic basis of monogenic as well as complex diseases and phenotypes. Indeed, the number of detected associations between CNVs and certain phenotypes are constantly increasing. However, while several software packages support the determination of CNVs from SNP chip data, the downstream statistical inference of CNV-phenotype associations is still subject to complicated and inefficient in-house solutions, thus strongly limiting the performance of GWAS based on CNVs. RESULTS: CONAN is a freely available client-server software solution which provides an intuitive graphical user interface for categorizing, analyzing and associating CNVs with phenotypes. Moreover, CONAN assists the evaluation process by visualizing detected associations via Manhattan plots in order to enable a rapid identification of genome-wide significant CNV regions. Various file formats including the information on CNVs in population samples are supported as input data. CONCLUSIONS: CONAN facilitates the performance of GWAS based on CNVs and the visual analysis of calculated results. CONAN provides a rapid, valid and straightforward software solution to identify genetic variation underlying the 'missing' heritability for complex traits that remains unexplained by recent GWAS. The freely available software can be downloaded at http://genepi-conan.i-med.ac.at.


Assuntos
Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla/métodos , Genoma , Software , Genômica , Fenótipo , Polimorfismo de Nucleotídeo Único
20.
BMC Bioinformatics ; 11: 122, 2010 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-20214782

RESUMO

BACKGROUND: Mitochondrial DNA (mtDNA) is widely being used for population genetics, forensic DNA fingerprinting and clinical disease association studies. The recent past has uncovered severe problems with mtDNA genotyping, not only due to the genotyping method itself, but mainly to the post-lab transcription, storage and report of mtDNA genotypes. DESCRIPTION: eCOMPAGT, a system to store, administer and connect phenotype data to all kinds of genotype data is now enhanced by the possibility of storing mtDNA profiles and allowing their validation, linking to phenotypes and export as numerous formats. mtDNA profiles can be imported from different sequence evaluation programs, compared between evaluations and their haplogroup affiliations stored. Furthermore, eCOMPAGT has been improved in its sophisticated transparency (support of MySQL and Oracle), security aspects (by using database technology) and the option to import, manage and store genotypes derived from various genotyping methods (SNPlex, TaqMan, and STRs). It is a software solution designed for project management, laboratory work and the evaluation process all-in-one. CONCLUSIONS: The extended mtDNA version of eCOMPAGT was designed to enable error-free post-laboratory data handling of human mtDNA profiles. This software is suited for small to medium-sized human genetic, forensic and clinical genetic laboratories. The direct support of MySQL and the improved database security options render eCOMPAGT a powerful tool to build an automated workflow architecture for several genotyping methods. eCOMPAGT is freely available at http://dbis-informatik.uibk.ac.at/ecompagt.


Assuntos
DNA Mitocondrial/química , Estudos de Associação Genética/métodos , Genética Populacional , Genótipo , Fenótipo , Software , Biologia Computacional/métodos , Bases de Dados Genéticas , Humanos , Neoplasias/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA