161 research outputs found

    Sparse regression models for unraveling group and individual associations in eQTL mapping

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    BackgroundAs a promising tool for dissecting the genetic basis of common diseases, expression quantitative trait loci (eQTL) study has attracted increasing research interest. Traditional eQTL methods focus on testing the associations between individual single-nucleotide polymorphisms (SNPs) and gene expression traits. A major drawback of this approach is that it cannot model the joint effect of a set of SNPs on a set of genes, which may correspond to biological pathways.ResultsTo alleviate this limitation, in this paper, we propose geQTL, a sparse regression method that can detect both group-wise and individual associations between SNPs and expression traits. geQTL can also correct the effects of potential confounders. Our method employs computationally efficient technique, thus it is able to fulfill large scale studies. Moreover, our method can automatically infer the proper number of group-wise associations. We perform extensive experiments on both simulated datasets and yeast datasets to demonstrate the effectiveness and efficiency of the proposed method. The results show that geQTL can effectively detect both individual and group-wise signals and outperforms the state-of-the-arts by a large margin.ConclusionsThis paper well illustrates that decoupling individual and group-wise associations for association mapping is able to improve eQTL mapping accuracy, and inferring individual and group-wise associations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-0986-9) contains supplementary material, which is available to authorized users

    Detection of regulator genes and eQTLs in gene networks

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    Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

    The GTEx Consortium atlas of genetic regulatory effects across human tissues

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    The GTEx Consortium atlas of genetic regulatory effects across human tissues

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    Statistical Estimation of Correlated Genome Associations to a Quantitative Trait Network

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    Many complex disease syndromes, such as asthma, consist of a large number of highly related, rather than independent, clinical or molecular phenotypes. This raises a new technical challenge in identifying genetic variations associated simultaneously with correlated traits. In this study, we propose a new statistical framework called graph-guided fused lasso (GFlasso) to directly and effectively incorporate the correlation structure of multiple quantitative traits such as clinical metrics and gene expressions in association analysis. Our approach represents correlation information explicitly among the quantitative traits as a quantitative trait network (QTN) and then leverages this network to encode structured regularization functions in a multivariate regression model over the genotypes and traits. The result is that the genetic markers that jointly influence subgroups of highly correlated traits can be detected jointly with high sensitivity and specificity. While most of the traditional methods examined each phenotype independently and combined the results afterwards, our approach analyzes all of the traits jointly in a single statistical framework. This allows our method to borrow information across correlated phenotypes to discover the genetic markers that perturb a subset of the correlated traits synergistically. Using simulated datasets based on the HapMap consortium and an asthma dataset, we compared the performance of our method with other methods based on single-marker analysis and regression-based methods that do not use any of the relational information in the traits. We found that our method showed an increased power in detecting causal variants affecting correlated traits. Our results showed that, when correlation patterns among traits in a QTN are considered explicitly and directly during a structured multivariate genome association analysis using our proposed methods, the power of detecting true causal SNPs with possibly pleiotropic effects increased significantly without compromising performance on non-pleiotropic SNPs

    A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease

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    Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology

    Cell type-specific genetic regulation of gene expression across human tissues

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    The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type-interaction QTLs for seven cell types and show that cell type-interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type-interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue
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