Dataset Information

Using gene expression data to identify causal pathways between genotype and phenotype in a complex disease: application to Genetic Analysis Workshop 19.

ABSTRACT: We explore causal relationships between genotype, gene expression and phenotype in the Genetic Analysis Workshop 19 data. We compare the use of structural equation modeling and a Bayesian unified framework approach to infer the most likely causal models that gave rise to the data. Testing an exhaustive set of causal relationships between each single-nucleotide polymorphism, gene expression probe, and phenotype would be computationally infeasible, thus a filtering step is required. In addition to filtering based on pairwise associations, we consider weighted gene correlation network analysis as a method of clustering genes with similar function into a small number of modules. These modules capture the key functional mechanisms of genes while greatly reducing the number of relationships to test for in causal modeling.

SUBMITTER: Ainsworth HF

PROVIDER: S-EPMC5133478 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Using gene expression data to identify causal pathways between genotype and phenotype in a complex disease: application to Genetic Analysis Workshop 19.

Ainsworth Holly F HF Cordell Heather J HJ

BMC proceedings 20161018 Suppl 7

We explore causal relationships between genotype, gene expression and phenotype in the Genetic Analysis Workshop 19 data. We compare the use of structural equation modeling and a Bayesian unified framework approach to infer the most likely causal models that gave rise to the data. Testing an exhaustive set of causal relationships between each single-nucleotide polymorphism, gene expression probe, and phenotype would be computationally infeasible, thus a filtering step is required. In addition to ...[more]

PMID: 27980615

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Project description:The coupling of electronic medical records (EMR) with genetic data has created the potential for implementing reverse genetic approaches in humans, whereby the function of a gene is inferred from the shared pattern of morbidity among homozygotes of a genetic variant. We explored the feasibility of this approach to identify phenotypes associated with low frequency variants using Vanderbilt's EMR-based BioVU resource. We analyzed 1,658 low frequency non-synonymous SNPs (nsSNPs) with a minor allele frequency (MAF)<10% collected on 8,546 subjects. For each nsSNP, we identified diagnoses shared by at least 2 minor allele homozygotes and with an association p<0.05. The diagnoses were reviewed by a clinician to ascertain whether they may share a common mechanistic basis. While a number of biologically compelling clinical patterns of association were observed, the frequency of these associations was identical to that observed using genotype-permuted data sets, indicating that the associations were likely due to chance. To refine our analysis associations, we then restricted the analysis to 711 nsSNPs in genes with phenotypes in the On-line Mendelian Inheritance in Man (OMIM) or knock-out mouse phenotype databases. An initial comparison of the EMR diagnoses to the known in vivo functions of the gene identified 25 candidate nsSNPs, 19 of which had significant genotype-phenotype associations when tested using matched controls. Twleve of the 19 nsSNPs associations were confirmed by a detailed record review. Four of 12 nsSNP-phenotype associations were successfully replicated in an independent data set: thrombosis (F5,rs6031), seizures/convulsions (GPR98,rs13157270), macular degeneration (CNGB3,rs3735972), and GI bleeding (HGFAC,rs16844401). These analyses demonstrate the feasibility and challenges of using reverse genetics approaches to identify novel gene-phenotype associations in human subjects using low frequency variants. As increasing amounts of rare variant data are generated from modern genotyping and sequence platforms, model organism data may be an important tool to enable discovery.

Dataset Information

Using gene expression data to identify causal pathways between genotype and phenotype in a complex disease: application to Genetic Analysis Workshop 19.

Publications

Using gene expression data to identify causal pathways between genotype and phenotype in a complex disease: application to Genetic Analysis Workshop 19.

Similar Datasets

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