Linking disease associations with regulatory information in the human genome

Abstract

Genome-wide association studies have been successful in identifying single nucleotide polymorphisms (SNPs) associated with a large number of phenotypes. However, an associated SNP is likely part of a larger region of linkage disequilibrium. This makes it difficult to precisely identify the SNPs that have a biological link with the phenotype. We have systematically investigated the association of multiple types of ENCODE data with disease-associated SNPs and show that there is significant enrichment for functional SNPs among the currently identified associations. This enrichment is strongest when integrating multiple sources of functional information and when highest confidence disease-associated SNPs are used. We propose an approach that integrates multiple types of functional data generated by the ENCODE Consortium to help identify ''functional SNPs'' that may be associated with the disease phenotype. Our approach generates putative functional annotations for up to 80% of all previously reported associations. We show that for most associations, the functional SNP most strongly supported by experimental evidence is a SNP in linkage disequilibrium with the reported association rather than the reported SNP itself. Our results show that the experimental data sets generated by the ENCODE Consortium can be successfully used to suggest functional hypotheses for variants associated with diseases and other phenotypes.

Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits

“…3 In addition, fewer than 5% of GWAS SNPs are non-synonymous substitutions, while the remainder are located within non-coding regions. 2,6 This suggests that instead of directly altering the amino acid sequence of proteins, SNPs can affect phenotypes by other mechanisms, such as regulation of gene transcription levels.…”

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

“…Previous studies have demonstrated enrichment of disease‐associated variants (for numerous diseases) with functional genomic annotations, including DNase I hypersensitive sites, transcription factor binding sites, histone modifications, and expression quantitative trait loci (eQTLs) 4, 5, 6, 7. These annotations vary depending on cell/tissue type.…”

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…These functional annotations involve biological or chemical events typically identified via high throughput techniques (Schaub, Boyle, Kundaje, Batzoglou, & Snyder, 2012). For example in the hypothetical locus displayed in Figure 5, six SNPs are in strong LD as demonstrated by an r 2 close to 1.…”

“…Thus if we were to follow systematic approach we could prioritize polymorphisms in this region from the 'most functional' to 'least functional'. As in this example, Schaub et al report that in the majority of associations the SNP most strongly supported by functional annotation is not the sentinel SNP from GWAS but a SNP in LD with the sentinel SNP (Schaub et al, 2012). There are numerous possible regulatory features and patterns of gene regulation which are both cell type specific and can vary at different stages of development.…”

“…Schaub et al has shown that TF binding (as demonstrated by ChIP-seq) is the most enriched functional element in GWAS loci when compared to the rest of investigated regulatory elements (Schaub et al, 2012). …”