The Human Genetic Evidence Calculator can help you evaluate the extent to which human genetic evidence supports a hypothesis about the role of a gene in a disease or trait.
The figure below gives an overview of the HuGE Calculator:
The HuGE Calculator is implemented in the Knowledge Portals in two ways:
- It is implemented in the portals' backend Aggregator and is run across all genes and phenotypes to generate a pre-computed HuGE score for each gene-phenotype combination, displayed on Gene pages.
- It is also available as a standalone, customizable interface.
Note that because the method that powers the standalone HuGE Calculator interface differs slightly from the HuGE Calculator method run across all genes and phenotypes in the portals' backend Aggregator, the HuGE scores displayed on the Gene page may not be exactly the same as those generated on the fly by the interface.
The data that are input for the HuGE Calculator include:
- Common variant associations: bottom-line genetic associations generated by overlap-aware meta-analysis of all genetic associations in the Knowledge Portals.
- Rare variant associations from the following datasets:
- AMP T2D-GENES T2D exome sequence analysis (T2D associations), published in Flannick et al. 2019.
- AMP T2D-GENES quantitative trait exome sequence analysis (23 cardiometabolic traits), published in Dornbos et al. 2022.
- A pre-publication study (Jurgens SJ, Wang X, et al., Submitted, 2023) of rare-variant gene-level associations for 601 diseases (expressed as PheCode terms) across more than 600,000 individuals, based on exome and whole-genome sequence data. Rare variant associations are only included for PheCodes that map exactly to Knowledge Portal phenotypes.
- Rare variant associations from the Genebass resource, for 189 phenotypes that map exactly to Knowledge Portal phenotypes.
The HuGE Calculator first searches for rare variant associations from the first 2 datasets listed, and if found, uses those as input. If there are no rare variant associations for a phenotype in those datasets, the Jurgens et al. dataset is searched next. If a phenotype match is not found there, the Calculator next searches the Genebass phenotypes.
The reference for the HuGE Calculator is:
Evaluating human genetic support for hypothesized metabolic disease genes.
Dornbos P, et al.
Cell Metab. 2022 May 3;34(5):661-666. doi: 10.1016/j.cmet.2022.03.011.
PMID: 35421386
Full documentation is available in this whitepaper.
For a detailed overview of the HuGE Calculator and the science behind it, see this video of a webinar presented on March 11, 2021 by Jason Flannick and Peter Dornbos.