F-SNP: computationally predicted functional SNPs for disease association studies

Abstract

The Functional Single Nucleotide Polymorphism (F-SNP) database integrates information obtained from 16 bioinformatics tools and databases about the functional effects of SNPs. These effects are predicted and indicated at the splicing, transcriptional, translational and post-translational level. As such, the database helps identify and focus on SNPs with potential deleterious effect to human health. In particular, users can retrieve SNPs that disrupt genomic regions known to be functional, including splice sites and transcriptional regulatory regions. Users can also identify non-synonymous SNPs that may have deleterious effects on protein structure or function, interfere with protein translation or impede post-translational modification. A web interface enables easy navigation for obtaining information through multiple starting points and exploration routes (e.g. starting from SNP identifier, genomic region, gene or target disease). The F-SNP database is available at http://compbio.cs.queensu.ca/F-SNP/.

Figure 1.

Decision procedure for functional SNP assessment. Each SNP is examined for deleterious effects with respect to each functional category (i.e. protein coding, splicing regulation, transcriptional regulation and post-translation—as shown in the top part of the figure). For each category, a series of tests is executed to determine whether the SNP has a functional impact. First the type (coding, intronic, etc.) of the genomic region is identified, using data from dbSNP (3) and Ensembl (4). Once this is determined, other tests are performed. For example, to assess if a SNP has a deleterious effect on protein coding, it first must be located on a coding region. Ensembl (4) is used to examine if this is a nonsense mutation, in which case the SNP is considered to be deleterious. Otherwise—if the SNP is a missense mutation, it is further tested by five different tools [PolyPhen (6), SIFT (7), SNPeffect (8), SNPs3D (9) and LS-SNP (10)] to check if the non-synonymous substitution is deleterious. A majority vote among these tools concludes the process, and identifies the SNP as either having a potentially deleterious functional impact (denoted ‘functional’ in the figure) or not.

Figure 2.

Example of an F-SNP search session. (a) The initial search page is displayed, where the user selected the disease type to be Cancers, and the specific disease to be Breast cancer (Search by disease). (b) Results obtained after clicking the Submit button in panel (a), namely a list of genes associated with Breast cancer along with their associated chromosome location, known related disorders, and links to OMIM. The BRCA1 link (circled) is selected and clicked. (c) A detailed description of SNPs associated with BRCA1 is produced (demonstrating results of Search by gene). The SNP whose identifier is rs28897699 (circled)—indicated by a ‘+’ mark to have associated functional information—is selected and clicked. (d) Information about the SNP rs28897699 is presented (demonstrating results of Search by SNP ID).