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Its input is gene-level P-values from any source, including omicsWAS, aggregation of genome-wide association studies P-values, CRISPR screens, or differential expression analysis. It is based on the idea that genes whose P-values are low purely by chance are distributed randomly across networks and functions, so genes with suggestive P-values that cluster in densely connected subnetworks and share common functions are less likely to reflect chance and more likely to replicate. FISHNET combines network and function analysis with permutation-based P-value thresholds to identify a small set of exceptional genes that we call FISHNET genes. Applied to 11 cardiovascular risk traits, FISHNET identified 19 gene-trait relationships that missed genome-wide significance thresholds but, nonetheless, replicated in an independent cohort. The replication rate of FISHNET genes matched that of genes with lower P-values. FISHNET identified a novel association between RUNX1 expression and HDL that is supported by experimental evidence that RUNX1 promotes white fat browning, which increases HDL cholesterol levels. FISHNET also identified an association between LTB expression and BMI that is supported by experimental evidence that higher LTB expression increases BMI via activation of the LT\u03b2R pathway. Both associations failed genome-wide significance thresholds, highlighting FISHNET\u2019s ability to uncover meaningful relationships missed by traditional methods. FISHNET software is freely available at https:\/\/brentlab.github.io\/fishnet\/.<\/jats:p>","DOI":"10.1093\/bib\/bbag061","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:40:12Z","timestamp":1769604012000},"source":"Crossref","is-referenced-by-count":0,"title":["Finding Significant Hits in Networks: a network-based tool for analyzing gene-level\n                    <i>P<\/i>\n                    -values to identify significant genes missed by standard methods"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8046-0688","authenticated-orcid":false,"given":"Sandeep","family":"Acharya","sequence":"first","affiliation":[{"name":"Division of Computational and Data Sciences, Washington University , 1 Brookings Dr, St. Louis, MO 63130 ,","place":["United States"]}]},{"given":"Vaha Akbary","family":"Moghaddam","sequence":"additional","affiliation":[{"name":"Division of Statistical Genomics, Washington University 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