The PWAS Portal – Protein Function Based Association between Genes and Diseases

We present the PWAS portal, a framework for discovery and visualization of the combined effect of variants in human coding genes, given sex-specific cohorts from the UK-Biobank (UKBB). The underlying notion behind PWAS is the ability to quantify the effect of any genetic variation on protein function. An underlying functional inference tool, called FIRM, estimates the combined damaging effect of variants for each individual. The gene effect from FIRM was successfully implemented on the FABRIC cancer portal (fabric-cancer.huji.ac.il) whose goal was to identify cancer driver genes. Similar to FABRIC, the set of known variants is permuted at each site over all possible nucleotides to create all permissible deviations from the reference genome. PWAS then runs a search of each such configuration against the desired phenotype in a case-control setting. This precomputed result is displayed on the website along with multi-dimensional metrics that present a model for dominant vs. recessive inheritance, a configurations for sub-populations of male vs. female (vs. both sexes), and the degenerative capacity of each gene—whether the significant variants increase or decrease the risk of carrying the phenotype. The display gives the statistical significance of each gene’s damaging status along with the effect size and statistical confidence adjusted for multiple testing experiments. The portal can be utilized as hypothesis generator tool for human disorders. Several novel results can be visualized on the portal. For example, a gender-dependent genetic effect of males vs. females on hypertension, emphasizing the substantial gender-specific genetics. The PWAS portal is available at pwas.huji.ac.il.