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Fast and Rigorous Computation of Gene and Pathway Scores from SNP-Based Summary Statistics

Fig 6

Examples of pathway enrichments comparing Pascal (chi-squared method) to the hypergeometric method.

Displayed are results for four phenotypes showing improvement when using Pascal instead of the hypergeometric (binary) enrichment strategy at the 5% threshold level. Underlying gene scores were calculated using the sum method. Dashed lines refer to the Bonferroni significance level when correcting for the number of pathways (1077). Besides from few cancer-related pathways, all pathways highlighted by this analysis have been implied by prior research (see main text). (a) For the trait insulin resistance, Pascal scored the pathway insulin signal attenuation first, followed by two other trait-relevant pathways (PI3K AKT activation and insulin receptor signaling), while the hypergeometric test did not find any significant pathways. (b) For smoking amount (number of cigarettes per day), Pascal revealed three significant pathways related to nicotinic acetylcholine receptors. (c) For osteoporosis, two cancer-related pathways scored significant using both Pascal and the hypergeometric test, but only Pascal revealed the WNT and Hedgehog signaling pathways, which are known to be involved in osteoblast biology. (d) For macular degeneration, Pascal found three significant, trait-relevant pathways related to lipoproteins and the complement system.

Fig 6