375 research outputs found
Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis
BACKGROUND: Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis. METHODS: We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy. FINDINGS: In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04–1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08–1·29), 1·10 (1·00–1·22), and 1·05 (0·92–1·20), respectively, per 1 SD increment in plasma urate. INTERPRETATION: Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions
The use of negative control outcomes in Mendelian randomization to detect potential population stratification
Mendelian randomization and the goal of inferring causation from observational studies in the vision sciences
Meta-analysis and Mendelian randomization:A review
Mendelian randomization (MR) uses genetic variants as instrumental variables to infer whether a risk factor causally affects a health outcome. Meta‐analysis has been used historically in MR to combine results from separate epidemiological studies, with each study using a small but select group of genetic variants. In recent years, it has been used to combine genome‐wide association study (GWAS) summary data for large numbers of genetic variants. Heterogeneity among the causal estimates obtained from multiple genetic variants points to a possible violation of the necessary instrumental variable assumptions. In this article, we provide a basic introduction to MR and the instrumental variable theory that it relies upon. We then describe how random effects models, meta‐regression, and robust regression are being used to test and adjust for heterogeneity in order to improve the rigor of the MR approach
A transcriptome-wide Mendelian randomization study to uncover tissue-dependent regulatory mechanisms across the human phenome
Clinical, hematological and cytogenetic profile in fibroblast growth factor receptor 1 rearranged hematoloymphoid malignancies
The background of this study is FGFR1 belongs to a family of four, high-affinity receptor tyrosine kinase and is a legitimate oncogene associated with uterine, cervical, prostate, bladder, colorectal and lung cancers. It is rarely concomitant in myeloid and lymphoid neoplasms but has an aggressive clinical course with a high mortality rate when present. Cytogenetic abnormalities involving the FGFR1 gene is most frequently observed in AML, MPN with eosinophilia, T-ALL and T-LBL with ZMYM2 gene being the most common fusion partner. Methods of this study was to authors report a series of 4 cases with FGFR1 rearrangements. Results is three patients presented as T-cell Lymphoblastic lymphoma (T-LBL) and one as mixed phenotype acute leukemia (MPAL). The T-LBL cases harboured the FGFR1/ ZMYM2 fusion and the MPAL case harbored the CNTRL/FGFR1 fusion as identified by conventional cytogenetics and confirmed by molecular studies. Conclusion is authors herewith describe the clinical, biochemical, molecular and cytogenetic features observed in these cases
Hybrid CPU/GPU Acceleration of Detection of 2-SNP Epistatic Interactions in GWAS
This is a post-peer-review, pre-copyedit version of an article published in Lecture Notes in Computer Science. The final authenticated version is available online at: https://doi.org/10.1007/978-3-319-09873-9_57[Abstract] High-throughput genotyping technologies allow the collection of up to a few million genetic markers (such as SNPs) of an individual within a few minutes of time. Detecting epistasis, such as 2-SNP interactions, in Genome-Wide Association Studies is an important but time consuming operation since statistical computations have to be performed for each pair of measured markers. In this work we present EpistSearch, a parallelized tool that, following the log-linear model approach, uses a novel filter to determine the interactions between all SNP-pairs. Our tool is parallelized using a hybrid combination of Pthreads and CUDA in order to take advantage of CPU/GPU architectures. Experimental results with simulated and real datasets show that EpistSearch outperforms previous approaches, either using GPUs or only CPU cores. For instance, an exhaustive analysis of a real-world dataset with 500,000 SNPs and 5,000 individuals requires less than 42 minutes on a machine with 6 CPU cores and a GTX Titan GPU
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