We found numerous examples of biologically plausible pathways discovered by Pascal that were not found by a standard binary enrichment analysis (Fig 6, S2 Table). For insulin resistance[34] we found the REACTOME pathway insulin signal attenuation to be genome-wide significant. Notably, none of the genes in this pathway was found to contain a genome-wide significant SNP in the original publication. Another example is bone mineral density in women (LS-BMD)[35]. We found the Hedgehog and Wnt pathways to be significant, both of which are known to be involved in osteoblast biology[36]. Again, standard binary enrichment did not reach genome-wide significance. For smoking behaviour (measured in cigarettes per day)[37], we found pathways related to nicotinic acetylcholine receptors. For macular degeneration, we found lipoprotein and complement system involvement, which both have support in the literature[38,39]. These examples illustrate that the improvements made by Pascal not only lead to better performance on benchmarks, but may also have a dramatic impact on the interpretation of GWAS results in practice.
