Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.
Pubmed ID: 29494619 RIS Download
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Database as central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms. Distinguishes report of how to assay SNP from use of that SNP with individuals and populations. This separation simplifies some issues of data representation. However, these initial reports describing how to assay SNP will often be accompanied by SNP experiments measuring allele occurrence in individuals and populations. Community can contribute to this resource.
View all literature mentionsCombines collections of genetic variants (GVs) from GWAS and their comprehensive functional annotations, as well as disease classifications. Used to maximize utilility of GWAS data to gain biological insights through integrative, multi-dimensional functional annotation portal. In addition to all GVs annotated in NHGRI GWAS Catalog, we manually curate GVs that are marginally significant (P value < 10-3) by looking into supplementary materials of each original publication and provide extensive functional annotations for these GVs. GVs are manually classified by diseases according to Disease Ontology Lite and HPO (Human Phenotype Ontology) for easy access. Database can also conduct gene based pathway enrichment and PPI network association analysis for those diseases with sufficient variants. SOAP services are available. You may Download GWASdb SNP. (This file contains all of the significant SNP in GWASdb. In the pvalue column, 0 means this P-value is not reported in the study but it is significant SNP. In the source column, GWAS:A represents the original data in GWAS catalog, while GWAS:B is our curation data which P-value < 10-3)
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