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New insights into the genetic control of gene expression using a Bayesian multi-tissue approach.

ABSTRACT: The majority of expression quantitative trait locus (eQTL) studies have been carried out in single tissues or cell types, using methods that ignore information shared across tissues. Although global analysis of RNA expression in multiple tissues is now feasible, few integrated statistical frameworks for joint analysis of gene expression across tissues combined with simultaneous analysis of multiple genetic variants have been developed to date. Here, we propose Sparse Bayesian Regression models for mapping eQTLs within individual tissues and simultaneously across tissues. Testing these on a set of 2,000 genes in four tissues, we demonstrate that our methods are more powerful than traditional approaches in revealing the true complexity of the eQTL landscape at the systems-level. Highlighting the power of our method, we identified a two-eQTL model (cis/trans) for the Hopx gene that was experimentally validated and was not detected by conventional approaches. We showed common genetic regulation of gene expression across four tissues for approximately 27% of transcripts, providing >5 fold increase in eQTLs detection when compared with single tissue analyses at 5% FDR level. These findings provide a new opportunity to uncover complex genetic regulatory mechanisms controlling global gene expression while the generality of our modelling approach makes it adaptable to other model systems and humans, with broad application to analysis of multiple intermediate and whole-body phenotypes.

SUBMITTER: Petretto E

PROVIDER: S-EPMC2851562 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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New insights into the genetic control of gene expression using a Bayesian multi-tissue approach.

Petretto Enrico E Bottolo Leonardo L Langley Sarah R SR Heinig Matthias M McDermott-Roe Chris C Sarwar Rizwan R Pravenec Michal M Hübner Norbert N Aitman Timothy J TJ Cook Stuart A SA Richardson Sylvia S

PLoS computational biology 20100408 4

The majority of expression quantitative trait locus (eQTL) studies have been carried out in single tissues or cell types, using methods that ignore information shared across tissues. Although global analysis of RNA expression in multiple tissues is now feasible, few integrated statistical frameworks for joint analysis of gene expression across tissues combined with simultaneous analysis of multiple genetic variants have been developed to date. Here, we propose Sparse Bayesian Regression models f ...[more]

PMID: 20386736

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Project description:The clinical beliefs (expectations and demands) of veterinarians regarding herd-level strategies to control mastitis, lameness, and Johne's disease were quantified in a numerical format; 94 veterinarians working in England (UK) were randomly selected and, during interviews, a statistical technique called probabilistic elicitation was used to capture their clinical expectations as probability distributions. The results revealed that markedly different clinical expectations existed for all 3 diseases, and many pairs of veterinarians had expectations with nonoverlapping 95% Bayesian credible intervals. For example, for a 3-yr lameness intervention, the most pessimistic veterinarian was centered at an 11% population mean reduction in lameness prevalence (95% credible interval: 0-21%); the most enthusiastic veterinarian was centered at a 58% reduction (95% credible interval: 38-78%). This suggests that a major change in beliefs would be required to achieve clinical agreement. Veterinarians' clinical expectations were used as priors in Bayesian models where they were combined with synthetic data (from randomized clinical trials of different sizes) to explore the effect of new evidence on current clinical opinion. The mathematical models make predictions based on the assumption that veterinarians will update their beliefs logically. For example, for the lameness intervention, a 200-farm clinical trial that estimated a 30% mean reduction in lameness prevalence was predicted to be reasonably convincing to the most pessimist veterinarian; that is, in light of this data, they were predicted to believe there would be a 0.92 probability of exceeding the median clinical demand of this sample of veterinarians, which was a 20% mean reduction in lameness. Currently, controversy exists over the extent to which veterinarians update their beliefs logically, and further research on this is needed. This study has demonstrated that probabilistic elicitation and a Bayesian framework are useful for evaluating the diversity and strength of veterinarians' clinical beliefs. The wide variations observed have implications for designing future projects. Although many factors influence disease control, nonetheless the heterogeneity in beliefs also raises concern over the extent to which a broadly consistent approach is currently being achieved; it supports the argument for more randomized clinical trials and for national programs to control nonstatutory endemic diseases.

Dataset Information

New insights into the genetic control of gene expression using a Bayesian multi-tissue approach.

Publications

New insights into the genetic control of gene expression using a Bayesian multi-tissue approach.

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