{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T20:16:31Z","timestamp":1776543391283,"version":"3.51.2"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009563","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000}}],"reference-count":58,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100011541","name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute","doi-asserted-by":"crossref","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100011541","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Expression QTL (eQTL) analyses have suggested many genes mediating genome-wide association study (GWAS) signals but most GWAS signals still lack compelling explanatory genes. We have leveraged an adipose-specific gene regulatory network to infer expression regulator activities and phenotypic master regulators (MRs), which were used to detect activity QTLs (aQTLs) at cardiometabolic trait GWAS loci. Regulator activities were inferred with the VIPER algorithm that integrates enrichment of expected expression changes among a regulator\u2019s target genes with confidence in their regulator-target network interactions and target overlap between different regulators (i.e., pleiotropy). Phenotypic MRs were identified as those regulators whose activities were most important in predicting their respective phenotypes using random forest modeling. While eQTLs were typically more significant than aQTLs in <jats:italic>cis<\/jats:italic>, the opposite was true among candidate MRs in <jats:italic>trans<\/jats:italic>. Several GWAS loci colocalized with MR <jats:italic>trans<\/jats:italic>-eQTLs\/aQTLs in the absence of colocalized <jats:italic>cis<\/jats:italic>-QTLs. Intriguingly, at the 1p36.1 BMI GWAS locus the <jats:italic>EPHB2 cis<\/jats:italic>-aQTL was stronger than its <jats:italic>cis<\/jats:italic>-eQTL and colocalized with the GWAS signal and 35 BMI MR <jats:italic>trans<\/jats:italic>-aQTLs, suggesting the GWAS signal may be mediated by effects on <jats:italic>EPHB2<\/jats:italic> activity and its downstream effects on a network of BMI MRs. These MR and aQTL analyses represent systems genetic methods that may be broadly applied to supplement standard eQTL analyses for suggesting molecular effects mediating GWAS signals.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009563","type":"journal-article","created":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T19:04:33Z","timestamp":1637262273000},"page":"e1009563","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Inferred expression regulator activities suggest genes mediating cardiometabolic genetic signals"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6944-1996","authenticated-orcid":true,"given":"Jason W.","family":"Hoskins","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles 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