Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

BIOS consortium; i2QTL Consortium

doi:10.1038/s41588-021-00913-z

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

BIOS consortium
, i2QTL Consortium

University of Groningen
Estonian Biocentre
European Molecular Biology Laboratory
Utrecht University
Georgia Institute of Technology
Leipzig University
Johns Hopkins University
University of Cambridge
NHS Blood and Transplant
Garvan Institute of Medical Research
Ontario Institute for Cancer Research
Nantes Université
University of Washington
Tampere University
The University of Chicago
University of Greifswald
German Centre for Cardiovascular Research
Helmholtz Zentrum München - German Research Center for Environmental Health
University Hospital Munich
University of Bristol
Erasmus University Rotterdam
University of Exeter Medical School
University of Westminster
Luleå University of Technology
University of Lausanne
Swiss Institute of Bioinformatics
Universite de Geneve Faculte de Medecine
University of Dundee
University of Oulu
Finnish Institute for Health and Welfare, Helsinki, Finland
Agency for Science, Technology and Research, Singapore
University of Queensland
Leiden University
University of Liege
University of Oxford
Menzies Research Institute, University of Tasmania, Hobart, TAS, Australia
University of Melbourne
Icahn School of Medicine at Mount Sinai
Basque Research and Technology Alliance (BRTA)
Basque Foundation for Science
Laboratory for Genotyping Development, Japan
Ludwig Maximilian University of Munich
VU University Medical Hospital
Stanford University
University of Turku
Maastricht University Medical Center and Cardiovascular Research Institute Maastricht (CARIM)
Karolinska Institutet
Radboud University Nijmegen
University of Helsinki
Broad Institute
University of Geneva
Technical University of Munich
Human Genetics, United Kingdom
National Center for Tumor Diseases Heidelberg
Westlake University
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
University of New South Wales

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Abstract

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.

Original language	English
Pages (from-to)	1300-1310
Number of pages	11
Journal	Nature genetics
Volume	53
Issue number	9
DOIs	https://doi.org/10.1038/s41588-021-00913-z
Publication status	Published - 1 Sept 2021

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10.1038/s41588-021-00913-z

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title = "Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression",

abstract = "Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88\% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37\% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13\% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.",

author = "Urmo V{\~o}sa and Annique Claringbould and Harm-Jan Westra and Bonder, \{Marc Jan\} and Patrick Deelen and Biao Zeng and Holger Kirsten and Ashis Saha and Roman Kreuzhuber and Seyhan Yazar and Harm Brugge and Roy Oelen and \{de Vries\}, \{Dylan H.\} and \{van der Wijst\}, \{Monique G. P.\} and Silva Kasela and Natalia Pervjakova and Isabel Alves and Marie-Julie Fav{\'e} and Mawuss{\'e} Agbessi and Christiansen, \{Mark W.\} and Rick Jansen and Ilkka Sepp{\"a}l{\"a} and Lin Tong and Alexander Teumer and Katharina Schramm and Gibran Hemani and Joost Verlouw and Hanieh Yaghootkar and \{S{\"o}nmez Flitman\}, Reyhan and Andrew Brown and Viktorija Kukushkina and Anette Kalnapenkis and Sina R{\"u}eger and Eleonora Porcu and Jaanika Kronberg and Johannes Kettunen and Bernett Lee and Futao Zhang and Ting Qi and Hernandez, \{Jose Alquicira\} and Wibowo Arindrarto and Frank Beutner and Julia Dmitrieva and Mahmoud Elansary and Fairfax, \{Benjamin P.\} and Michel Georges and Heijmans, \{Bastiaan T.\} and Hewitt, \{Alex W.\} and Mika K{\"a}h{\"o}nen and Yungil Kim and Knight, \{Julian C.\} and Peter Kovacs and Knut Krohn and Shuang Li and Markus Loeffler and Marigorta, \{Urko M.\} and Hailang Mei and Yukihide Momozawa and Martina M{\"u}ller-Nurasyid and Matthias Nauck and Nivard, \{Michel G.\} and Penninx, \{Brenda W. J. H.\} and Pritchard, \{Jonathan K.\} and Raitakari, \{Olli T.\} and Olaf Rotzschke and Slagboom, \{Eline P.\} and Stehouwer, \{Coen D. A.\} and Michael Stumvoll and Patrick Sullivan and \{'t Hoen\}, \{Peter A. C.\} and Joachim Thiery and Anke T{\"o}njes and \{van Dongen\}, Jenny and \{van Iterson\}, Maarten and Veldink, \{Jan H.\} and Uwe V{\"o}lker and Robert Warmerdam and Cisca Wijmenga and Morris Swertz and Anand Andiappan and Montgomery, \{Grant W.\} and Samuli Ripatti and Markus Perola and Zoltan Kutalik and Emmanouil Dermitzakis and Sven Bergmann and Timothy Frayling and \{van Meurs\}, Joyce and Holger Prokisch and Habibul Ahsan and Pierce, \{Brandon L.\} and Terho Lehtim{\"a}ki and Boomsma, \{Dorret I.\} and Psaty, \{Bruce M.\} and Gharib, \{Sina A.\} and Philip Awadalla and Lili Milani and Ouwehand, \{Willem H.\} and Kate Downes and Oliver Stegle and Alexis Battle and Visscher, \{Peter M.\} and \{BIOS consortium\} and Jian Yang and Markus Scholz and \{i2QTL Consortium\} and Joseph Powell and Greg Gibson and Esko, \{T. nu\} and Lude Franke",

note = "Publisher Copyright: {\textcopyright} 2021. The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine",

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month = sep,

day = "1",

doi = "10.1038/s41588-021-00913-z",

language = "English",

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T1 - Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

AU - Võsa, Urmo

AU - Claringbould, Annique

AU - Westra, Harm-Jan

AU - Bonder, Marc Jan

AU - Deelen, Patrick

AU - Zeng, Biao

AU - Kirsten, Holger

AU - Saha, Ashis

AU - Kreuzhuber, Roman

AU - Yazar, Seyhan

AU - Brugge, Harm

AU - Oelen, Roy

AU - de Vries, Dylan H.

AU - van der Wijst, Monique G. P.

AU - Kasela, Silva

AU - Pervjakova, Natalia

AU - Alves, Isabel

AU - Favé, Marie-Julie

AU - Agbessi, Mawussé

AU - Christiansen, Mark W.

AU - Jansen, Rick

AU - Seppälä, Ilkka

AU - Tong, Lin

AU - Teumer, Alexander

AU - Schramm, Katharina

AU - Hemani, Gibran

AU - Verlouw, Joost

AU - Yaghootkar, Hanieh

AU - Sönmez Flitman, Reyhan

AU - Brown, Andrew

AU - Kukushkina, Viktorija

AU - Kalnapenkis, Anette

AU - Rüeger, Sina

AU - Porcu, Eleonora

AU - Kronberg, Jaanika

AU - Kettunen, Johannes

AU - Lee, Bernett

AU - Zhang, Futao

AU - Qi, Ting

AU - Hernandez, Jose Alquicira

AU - Arindrarto, Wibowo

AU - Beutner, Frank

AU - Dmitrieva, Julia

AU - Elansary, Mahmoud

AU - Fairfax, Benjamin P.

AU - Georges, Michel

AU - Heijmans, Bastiaan T.

AU - Hewitt, Alex W.

AU - Kähönen, Mika

AU - Kim, Yungil

AU - Knight, Julian C.

AU - Kovacs, Peter

AU - Krohn, Knut

AU - Li, Shuang

AU - Loeffler, Markus

AU - Marigorta, Urko M.

AU - Mei, Hailang

AU - Momozawa, Yukihide

AU - Müller-Nurasyid, Martina

AU - Nauck, Matthias

AU - Nivard, Michel G.

AU - Penninx, Brenda W. J. H.

AU - Pritchard, Jonathan K.

AU - Raitakari, Olli T.

AU - Rotzschke, Olaf

AU - Slagboom, Eline P.

AU - Stehouwer, Coen D. A.

AU - Stumvoll, Michael

AU - Sullivan, Patrick

AU - 't Hoen, Peter A. C.

AU - Thiery, Joachim

AU - Tönjes, Anke

AU - van Dongen, Jenny

AU - van Iterson, Maarten

AU - Veldink, Jan H.

AU - Völker, Uwe

AU - Warmerdam, Robert

AU - Wijmenga, Cisca

AU - Swertz, Morris

AU - Andiappan, Anand

AU - Montgomery, Grant W.

AU - Ripatti, Samuli

AU - Perola, Markus

AU - Kutalik, Zoltan

AU - Dermitzakis, Emmanouil

AU - Bergmann, Sven

AU - Frayling, Timothy

AU - van Meurs, Joyce

AU - Prokisch, Holger

AU - Ahsan, Habibul

AU - Pierce, Brandon L.

AU - Lehtimäki, Terho

AU - Boomsma, Dorret I.

AU - Psaty, Bruce M.

AU - Gharib, Sina A.

AU - Awadalla, Philip

AU - Milani, Lili

AU - Ouwehand, Willem H.

AU - Downes, Kate

AU - Stegle, Oliver

AU - Battle, Alexis

AU - Visscher, Peter M.

AU - BIOS consortium

AU - Yang, Jian

AU - Scholz, Markus

AU - i2QTL Consortium

AU - Powell, Joseph

AU - Gibson, Greg

AU - Esko, T. nu

AU - Franke, Lude

N1 - Publisher Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine

PY - 2021/9/1

Y1 - 2021/9/1

N2 - Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.

AB - Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.

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U2 - 10.1038/s41588-021-00913-z

DO - 10.1038/s41588-021-00913-z

M3 - Article

C2 - 34475573

SN - 1061-4036

VL - 53

SP - 1300

EP - 1310

JO - Nature genetics

JF - Nature genetics

IS - 9

ER -

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

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