Timothy D Arthur, Jennifer P Nguyen, Benjamin A Henson, Agnieszka D'Antonio-Chronowska, Jeffrey Jaureguy, Nayara Silva, Athanasia D Panopoulos, Juan Carlos Izpisua Belmonte, Matteo D'Antonio, Graham McVicker, Kelly A Frazer
{"title":"多组QTL定位揭示了GWAS基因座的表型复杂性，并优先考虑假定的因果变异。","authors":"Timothy D Arthur, Jennifer P Nguyen, Benjamin A Henson, Agnieszka D'Antonio-Chronowska, Jeffrey Jaureguy, Nayara Silva, Athanasia D Panopoulos, Juan Carlos Izpisua Belmonte, Matteo D'Antonio, Graham McVicker, Kelly A Frazer","doi":"10.1016/j.xgen.2025.100775","DOIUrl":null,"url":null,"abstract":"<p><p>Most GWAS loci are presumed to affect gene regulation; however, only ∼43% colocalize with expression quantitative trait loci (eQTLs). To address this colocalization gap, we map eQTLs, chromatin accessibility QTLs (caQTLs), and histone acetylation QTLs (haQTLs) using molecular samples from three early developmental-like tissues. Through colocalization, we annotate 10.4% (n = 540) of GWAS loci in 15 traits by QTL phenotype, temporal specificity, and complexity. We show that integration of chromatin QTLs results in a 2.3-fold higher annotation rate of GWAS loci because they capture distal GWAS loci missed by eQTLs, and that 5.4% (n = 13) of GWAS colocalizing eQTLs are early developmental specific. Finally, we utilize the iPSCORE multiomic QTLs to prioritize putative causal variants overlapping transcription factor motifs to elucidate the potential genetic underpinnings of 296 GWAS-QTL colocalizations.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100775"},"PeriodicalIF":11.1000,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960542/pdf/","citationCount":"0","resultStr":"{\"title\":\"Multiomic QTL mapping reveals phenotypic complexity of GWAS loci and prioritizes putative causal variants.\",\"authors\":\"Timothy D Arthur, Jennifer P Nguyen, Benjamin A Henson, Agnieszka D'Antonio-Chronowska, Jeffrey Jaureguy, Nayara Silva, Athanasia D Panopoulos, Juan Carlos Izpisua Belmonte, Matteo D'Antonio, Graham McVicker, Kelly A Frazer\",\"doi\":\"10.1016/j.xgen.2025.100775\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Most GWAS loci are presumed to affect gene regulation; however, only ∼43% colocalize with expression quantitative trait loci (eQTLs). To address this colocalization gap, we map eQTLs, chromatin accessibility QTLs (caQTLs), and histone acetylation QTLs (haQTLs) using molecular samples from three early developmental-like tissues. Through colocalization, we annotate 10.4% (n = 540) of GWAS loci in 15 traits by QTL phenotype, temporal specificity, and complexity. We show that integration of chromatin QTLs results in a 2.3-fold higher annotation rate of GWAS loci because they capture distal GWAS loci missed by eQTLs, and that 5.4% (n = 13) of GWAS colocalizing eQTLs are early developmental specific. Finally, we utilize the iPSCORE multiomic QTLs to prioritize putative causal variants overlapping transcription factor motifs to elucidate the potential genetic underpinnings of 296 GWAS-QTL colocalizations.</p>\",\"PeriodicalId\":72539,\"journal\":{\"name\":\"Cell genomics\",\"volume\":\" \",\"pages\":\"100775\"},\"PeriodicalIF\":11.1000,\"publicationDate\":\"2025-03-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960542/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell genomics\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.xgen.2025.100775\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/2/21 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell genomics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.xgen.2025.100775","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/21 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Multiomic QTL mapping reveals phenotypic complexity of GWAS loci and prioritizes putative causal variants.
Most GWAS loci are presumed to affect gene regulation; however, only ∼43% colocalize with expression quantitative trait loci (eQTLs). To address this colocalization gap, we map eQTLs, chromatin accessibility QTLs (caQTLs), and histone acetylation QTLs (haQTLs) using molecular samples from three early developmental-like tissues. Through colocalization, we annotate 10.4% (n = 540) of GWAS loci in 15 traits by QTL phenotype, temporal specificity, and complexity. We show that integration of chromatin QTLs results in a 2.3-fold higher annotation rate of GWAS loci because they capture distal GWAS loci missed by eQTLs, and that 5.4% (n = 13) of GWAS colocalizing eQTLs are early developmental specific. Finally, we utilize the iPSCORE multiomic QTLs to prioritize putative causal variants overlapping transcription factor motifs to elucidate the potential genetic underpinnings of 296 GWAS-QTL colocalizations.
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