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

IMI DIRECT Consortium; C A Robert Warmerdam; Harm-Jan Westra; Adriaan van der Graaf; Marc Jan Bonder; Patrick Deelen; Tijs van Lieshout; Anke Jannie Landman; Mihkel Jesse; Benjamin J Strober; Toni Boltz; Sandra Lapinska; Sini Nagpal; Manke Xie; Darwin Tay; Holger Kirsten; Haroon Naeem; Venket Raghavan; Aiman Farzeen; Alexander Teumer; Marie-Julie Favé; Elodie Persyn; Alex Tokolyi; René Pool; Jouke Jan Hottenga; Ruth D Rodríguez; María Rivas-Torrubia; Binisha Hamal Mishra; Brandon Pierce; Lin Tong; Qingbo S Wang; Takanori Hasegawa; Surya B Chhetri; Diptavo Dutta; Stefan Weiss; Théo Dupuis; Leo-Pekka Lyytikäinen; Pashupati P Mishra; Katie L Burnham; Jia Wen; Evans Cheruiyot; Collins K Boahen; Rick Jansen; Knut Krohn; Joachim Thiery; Kensuke Daida; J Raphael Gibbs; Joost Verlouw; Vinod Kumar; Andrew Brown; Ana Viñuela

doi:10.64898/2026.02.04.26343575

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

IMI DIRECT Consortium
, C A Robert Warmerdam
, Harm-Jan Westra
, Adriaan van der Graaf
, Marc Jan Bonder
, Patrick Deelen
, Tijs van Lieshout
, Anke Jannie Landman
, Mihkel Jesse
, Benjamin J Strober
, Toni Boltz
, Sandra Lapinska
, Sini Nagpal
, Manke Xie
, Darwin Tay
, Holger Kirsten
, Haroon Naeem
, Venket Raghavan
, Aiman Farzeen
, Alexander Teumer

Marie-Julie Favé, Elodie Persyn, Alex Tokolyi, René Pool, Jouke Jan Hottenga, Ruth D Rodríguez, María Rivas-Torrubia, Binisha Hamal Mishra, Brandon Pierce, Lin Tong, Qingbo S Wang, Takanori Hasegawa, Surya B Chhetri, Diptavo Dutta, Stefan Weiss, Théo Dupuis, Leo-Pekka Lyytikäinen, Pashupati P Mishra, Katie L Burnham, Jia Wen, Evans Cheruiyot, Collins K Boahen, Rick Jansen, Knut Krohn, Joachim Thiery, Kensuke Daida, J Raphael Gibbs, Joost Verlouw, Vinod Kumar, Andrew Brown, Ana Viñuela

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Abstract

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.

Original language	English
Publisher	medRxiv
Number of pages	58
DOIs	https://doi.org/10.64898/2026.02.04.26343575
Publication status	Published - 5 Feb 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

genetic and genomic medicine
eQTL mapping
cis-eQTLs
gene regulatory networks
fine-mapping
colocalization analysis
complex traits
population genetics

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10.64898/2026.02.04.26343575Licence: CC BY-NC-ND

PreprintSubmitted manuscript, 3.11 MBLicence: CC BY-NC-ND

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IMI DIRECT Consortium, Warmerdam, C. A. R., Westra, H.-J., van der Graaf, A., Bonder, M. J., Deelen, P., van Lieshout, T., Landman, A. J., Jesse, M., Strober, B. J., Boltz, T., Lapinska, S., Nagpal, S., Xie, M., Tay, D., Kirsten, H., Naeem, H., Raghavan, V., Farzeen, A., ... Viñuela, A. (2026). Trans-eQTLs reveal the architecture of human gene regulatory networks. medRxiv. https://doi.org/10.64898/2026.02.04.26343575

@techreport{980d46ae7406412284cbbe271bcb267b,

title = "Trans-eQTLs reveal the architecture of human gene regulatory networks.",

abstract = "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. ",

keywords = "genetic and genomic medicine, eQTL mapping, cis-eQTLs, gene regulatory networks, fine-mapping, colocalization analysis, complex traits, population genetics",

author = "\{IMI DIRECT Consortium\} and Warmerdam, \{C A Robert\} and Harm-Jan Westra and \{van der Graaf\}, Adriaan and Bonder, \{Marc Jan\} and Patrick Deelen and \{van Lieshout\}, Tijs and Landman, \{Anke Jannie\} and Mihkel Jesse and Strober, \{Benjamin J\} and Toni Boltz and Sandra Lapinska and Sini Nagpal and Manke Xie and Darwin Tay and Holger Kirsten and Haroon Naeem and Venket Raghavan and Aiman Farzeen and Alexander Teumer and Marie-Julie Fav{\'e} and Elodie Persyn and Alex Tokolyi and Ren{\'e} Pool and Hottenga, \{Jouke Jan\} and Rodr{\'i}guez, \{Ruth D\} and Mar{\'i}a Rivas-Torrubia and Mishra, \{Binisha Hamal\} and Brandon Pierce and Lin Tong and Wang, \{Qingbo S\} and Takanori Hasegawa and Chhetri, \{Surya B\} and Diptavo Dutta and Stefan Weiss and Th{\'e}o Dupuis and Leo-Pekka Lyytik{\"a}inen and Mishra, \{Pashupati P\} and Burnham, \{Katie L\} and Jia Wen and Evans Cheruiyot and Boahen, \{Collins K\} and Rick Jansen and Knut Krohn and Joachim Thiery and Kensuke Daida and Gibbs, \{J Raphael\} and Joost Verlouw and Vinod Kumar and Andrew Brown and Ana Vi{\~n}uela",

year = "2026",

month = feb,

day = "5",

doi = "10.64898/2026.02.04.26343575",

language = "English",

publisher = "medRxiv",

type = "WorkingPaper",

institution = "medRxiv",

}

IMI DIRECT Consortium, Warmerdam, CAR, Westra, H-J, van der Graaf, A, Bonder, MJ, Deelen, P, van Lieshout, T, Landman, AJ, Jesse, M, Strober, BJ, Boltz, T, Lapinska, S, Nagpal, S, Xie, M, Tay, D, Kirsten, H, Naeem, H, Raghavan, V, Farzeen, A, Teumer, A, Favé, M-J, Persyn, E, Tokolyi, A, Pool, R, Hottenga, JJ, Rodríguez, RD, Rivas-Torrubia, M, Mishra, BH, Pierce, B, Tong, L, Wang, QS, Hasegawa, T, Chhetri, SB, Dutta, D, Weiss, S, Dupuis, T, Lyytikäinen, L-P, Mishra, PP, Burnham, KL, Wen, J, Cheruiyot, E, Boahen, CK, Jansen, R, Krohn, K, Thiery, J, Daida, K, Gibbs, JR, Verlouw, J, Kumar, V, Brown, A & Viñuela, A 2026 'Trans-eQTLs reveal the architecture of human gene regulatory networks.' medRxiv. https://doi.org/10.64898/2026.02.04.26343575

TY - UNPB

T1 - Trans-eQTLs reveal the architecture of human gene regulatory networks.

AU - IMI DIRECT Consortium

AU - Warmerdam, C A Robert

AU - Westra, Harm-Jan

AU - van der Graaf, Adriaan

AU - Bonder, Marc Jan

AU - Deelen, Patrick

AU - van Lieshout, Tijs

AU - Landman, Anke Jannie

AU - Jesse, Mihkel

AU - Strober, Benjamin J

AU - Boltz, Toni

AU - Lapinska, Sandra

AU - Nagpal, Sini

AU - Xie, Manke

AU - Tay, Darwin

AU - Kirsten, Holger

AU - Naeem, Haroon

AU - Raghavan, Venket

AU - Farzeen, Aiman

AU - Teumer, Alexander

AU - Favé, Marie-Julie

AU - Persyn, Elodie

AU - Tokolyi, Alex

AU - Pool, René

AU - Hottenga, Jouke Jan

AU - Rodríguez, Ruth D

AU - Rivas-Torrubia, María

AU - Mishra, Binisha Hamal

AU - Pierce, Brandon

AU - Tong, Lin

AU - Wang, Qingbo S

AU - Hasegawa, Takanori

AU - Chhetri, Surya B

AU - Dutta, Diptavo

AU - Weiss, Stefan

AU - Dupuis, Théo

AU - Lyytikäinen, Leo-Pekka

AU - Mishra, Pashupati P

AU - Burnham, Katie L

AU - Wen, Jia

AU - Cheruiyot, Evans

AU - Boahen, Collins K

AU - Jansen, Rick

AU - Krohn, Knut

AU - Thiery, Joachim

AU - Daida, Kensuke

AU - Gibbs, J Raphael

AU - Verlouw, Joost

AU - Kumar, Vinod

AU - Brown, Andrew

AU - Viñuela, Ana

PY - 2026/2/5

Y1 - 2026/2/5

N2 - 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.

AB - 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.

KW - genetic and genomic medicine

KW - eQTL mapping

KW - cis-eQTLs

KW - gene regulatory networks

KW - fine-mapping

KW - colocalization analysis

KW - complex traits

KW - population genetics

U2 - 10.64898/2026.02.04.26343575

DO - 10.64898/2026.02.04.26343575

M3 - Preprint

C2 - 42051578

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

PB - medRxiv

ER -

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

Abstract

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Keywords

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