Our interactive burden test on Gene pages, powered by the Genetic Association Analysis Tool (GAIT), allows you to do all that and more. The burden test considers a gene as the unit of inquiry, including all the variants it contains in a statistical test of disease association. We described the basics of the burden test and GAIT in a recent blog post. Now, we’ve added some options for selecting variants in the interactive burden test that make this tool even more versatile.
The variant selection step of the burden test on a Gene page is pre-populated with all of the variants present in the selected dataset that are located within the gene and its 100 kb up- and downstream flanking regions. You can create a specific subset of these by checking or un-checking individual variants. The table may be sorted by multiple criteria in order to find variants of interest: chromosomal coordinate; minor allele count; predictions of the effect allele’s impact on the encoded protein; and the protein change or type of mutation caused by the effect allele.
|Section of the interactive burden test interface showing the default list of variants for the SLC30A8 gene. Options for customizing the list are located above the variant table.|
The table of variants may be filtered so that the test considers only certain categories of variants, with varying predicted impacts on the encoded protein. Previously, the burden test offered filters based on an unpublished method. Now, we have replaced those filters with the set that was used in a recent major publication: The genetic architecture of type 2 diabetes, by Fuchsberger, Flannick, Teslovich, Mahajan, Agarwala, Gaulton, et al.
|Variant filters in the interactive burden test|
All coding variants--selects variants within the coding sequence, from the dataset that was initially selected for the burden test
Protein-truncating + missense with MAF<1%--selects variants in both of these categories:
- protein-truncating (predicted to cause a truncated protein to be generated, either by creating a premature stop codon or by causing a frameshift)
- cause a missense mutation AND have minor allele frequency (MAF) of less than 1%. The MAF limit eliminates common variants, which would not be expected to have very deleterious effects.
Protein-truncating + possibly deleterious missense with MAF<1%--selects variants in both of these categories:
- cause a missense mutation AND are predicted to be deleterious by at least one of 5 algorithms (LRT, MutationTaster, PolyPhen2-HumDiv, PolyPhen2-HumVar, or SIFT) AND have MAF < 1%
Protein-truncating + probably deleterious missense--selects variants in both of these categories:
- cause a missense mutation AND are predicted to be deleterious by all 5 algorithms (LRT, MutationTaster, PolyPhen2-HumDiv, PolyPhen2-HumVar, and SIFT)
Protein-truncating only--selects variants predicted to cause a truncated protein to be generated, either by creating a premature stop codon or by causing a frameshift.
Using these filters, you can tailor the list of variants to those with specific impact on the encoded protein. If you would like to customize the list even further by adding variants that were not present in the default list, there is now an option to add single or multiple variants, using dbSNP IDs (e.g., rs112881768) or identifiers in the format “chromosome_coordinate_reference-nucleotide_variant-nucleotide” (e.g., 8_112881768_G_A).
When “single variant” is selected, once you begin typing, variant IDs that match your entry are suggested. When “multiple” is selected, you may type or paste in a list of variant IDs, separated by commas or returns. Note that any added variants are not subject to the filters, which act only on the default list of variants for a gene.
Our GAIT User Guide (download PDF) that summarizes all the details of the interface has been updated with the latest changes. Please check out our new, improved interactive burden test and let us know if you have comments or suggestions.