What is Transcript Variant Set Analysis?
An overview of Variant Set Association (VSAS) analysis and how the Transcript Variant Set Analysis tool explores these summary statistics.
Explore variant-set association (VSAS) analysis summary statistics with the Transcript Variant Set Analysis tool.
A VSAS analysis is similar to a genome-wide association study (GWAS), but instead of reporting statistical associations between a genotype at a single variant and a phenotype of interest, we instead collapse the genotypes at multiple variants into a single value (a ‘variant set’). This boosts statistical power by aggregating information across variants, particularly in the case of rare variants, and reduces the burden of multiple testing by performing fewer tests.
There are multiple ways to collapse variants for a VSAS analysis. At launch, the app contains predicted loss-of-function (pLoF) variant burden analysis in the UK Biobank whole-exome sequencing data, restricted to European ancestry individuals. These analyses collapse all rare (minor allele frequency <1%) protein-coding variants that are predicted to cause loss-of-function in a gene into a single pLoF burden value. This value captures whether or not an individual is expected to have lost function in one or more copies of a given gene.
Because the effect of a variant depends on the transcript (as a loss-of-function variant may fall in an excluded exon depending on how a gene is transcribed), these results are reported per transcript, rather than per gene. We then test these burden scores against phenotypes in UK Biobank to identify any phenotypes linked to loss-of-function in the gene.