medRxiv : the preprint server for health sciences · 2026

Trans-eQTLs reveal the architecture of human gene regulatory networks.

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Warmerdam C A Robert, Westra Harm-Jan, van der Graaf Adriaan, Bonder Marc Jan, Deelen Patrick, van Lieshout Tijs, Landman Anke Jannie, Jesse Mihkel, Strober Benjamin J, Boltz Toni, Lapinska Sandra, Nagpal Sini, Xie Manke, Tay Darwin, Kirsten Holger, Naeem Haroon, Raghavan Venket, Farzeen Aiman, Teumer Alexander, Favé Marie-Julie, Persyn Elodie, Tokolyi Alex, Pool René, Hottenga Jouke Jan, Rodríguez Ruth D, Rivas-Torrubia María, Mishra Binisha Hamal, Pierce Brandon, Tong Lin, Wang Qingbo S, Hasegawa Takanori, Chhetri Surya B, Dutta Diptavo, Weiss Stefan, Dupuis Théo, Lyytikäinen Leo-Pekka, Mishra Pashupati P, Wood Andrew R, Burnham Katie L, Wen Jia, Cheruiyot Evans, Boahen Collins K, Jansen Rick, Krohn Knut, Thiery Joachim, IMI DIRECT Consortium, Daida Kensuke, Gibbs J Raphael, Verlouw Joost, Kukushkina Viktorija, Mägi Reedik, Budde John, Johnson Matt, Sanford Jessie, Slagboom Eline, Beutner Frank, Loeffler Markus, PRECISESADS Clinical Consortium, Martin Javier, Raitoharju Emma, Kibriya Muhammad G, Jasmine Farzana, Nauck Matthias, HELIOS Study Team, Souto Juan Carlos, Martinez-Perez Angel, Ikram M Arfan, Mykkänen Juha, Pahkala Katja, Rovio Suvi P, Raffield Laura M, van Greevenbroek Marleen, van der Kallen Carla J H, Schalkwijk Casper G, Veldink Jan, Freimann Krista, Vochteloo Martijn, Kooijmans Anoek, Ouadah Lilia, Claringbould Annique, Huang Yunfeng, Bryois Julien, Tsai Ellen A, Heinig Matthias, van der Wijst Monique G P, Estonian Biobank Research Team, sc-eQTLGen Consortium, Kumar Vinod, Visscher Peter M, McRae Allan F, Montgomery Grant W, Li Yun, Knight Julian C, Singleton Andrew, Ferrucci Luigi, Frayling Timothy M, Brown Andrew, Soria José Manuel, Völker Uwe, Battle Alexis, Okada Yukinori, Fukunaga Koichi, Namkoong Ho, Ahsan Habibul, Lehtimäki Terho, Kähönen Mika, Raitakari Olli T, Alarcón-Riquelme Marta E, Barturen Guillermo, Penninx Brenda W J H, Paul Dirk S, Inouye Michael, Awadalla Philip, Sung Yun Ju, Cruchaga Carlos, van Meurs Joyce, Prokisch Holger, Peters Annette, Gieger Christian, Blauwendraat Cornelis, Mokrab Younes, Davenport Emma E, Scholz Markus, Loh Marie, Chambers John, Gibson Greg, Boomsma Dorret I, Viñuela Ana, Pasaniuc Bogdan, Ophoff Roel, Price Alkes L, Alasoo Kaur, Kutalik Zoltan, Esko Tõnu, Franke Lude H, Võsa Urmo

Аннотация

Many non-coding variants influence complex traits and diseases through gene regulation, yet the mechanisms linking these variants to downstream biology remain poorly understood. Here, we present eQTLGen Phase 2, a comprehensive genome-wide analysis of gene expression quantitative trait loci (eQTLs) in 43,301 blood samples from 52 datasets. Beyond local ciseffects, this sample size enabled the first systematic mapping of trans-eQTLs at scale. We identify cis-eQTLs for nearly all expressed genes (94.7%) and trans-eQTLs for over half (56.2%). Second, by colocalizing cis-eQTLs with trans-eQTLs, we infer a directed gene regulatory network comprising 47,554 directed gene regulatory relationships. These networks reveal how genetic perturbations in upstream regulators produce dose-dependent downstream effects, supported by Perturb-seq and ChIP-seq data. Third, integrating this network with 87 genome-wide association studies allows us to systematically prioritize trait-relevant pathways and candidate genes. Variants exerting both cis- and trans-effects are markedly more likely to colocalize with trait associations than cis-only variants, delineating a subset of functionally active cis-eQTLs from a large group with limited downstream impact. This distinction provides a conceptual framework for identifying regulatory variants that truly mediate complex trait biology. Together, these results provide a publicly available resource of cis- and trans-eQTLs and an in vivo scaffold for human gene-regulatory networks, elucidating how propagation of cis-effects modulates complex disease.

Trans-eQTLs reveal the architecture of human gene regulatory networks.

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