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

Urmo Võsa; Annique Claringbould; Harm-Jan Westra; Marc Jan Bonder; Patrick Deelen; Biao Zeng; Holger Kirsten; Ashis Saha; Roman Kreuzhuber; Seyhan Yazar; Harm Brugge; Roy Oelen; Dylan H. de Vries; Monique G. P. van der Wijst; Silva Kasela; Natalia Pervjakova; Isabel Alves; Marie-Julie Favé; Mawussé Agbessi; Mark W. Christiansen; Rick Jansen; Ilkka Seppälä; Lin Tong; Alexander Teumer; Katharina Schramm; Gibran Hemani; Joost Verlouw; Hanieh Yaghootkar; Reyhan Sönmez Flitman; Andrew Brown; Viktorija Kukushkina; Anette Kalnapenkis; Sina Rüeger; Eleonora Porcu; Jaanika Kronberg; Johannes Kettunen; Bernett Lee; Futao Zhang; Ting Qi; Jose Alquicira Hernandez; Wibowo Arindrarto; Frank Beutner; Julia Dmitrieva; Mahmoud Elansary; Benjamin P. Fairfax; Michel Georges; Bastiaan T. Heijmans; Alex W. Hewitt; Mika Kähönen; Yungil Kim

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

,
, Urmo Võsa (Lead / Corresponding author)
, Annique Claringbould (Lead / Corresponding author)
, Harm-Jan Westra
, Marc Jan Bonder
, Patrick Deelen
, Biao Zeng
, Holger Kirsten
, Ashis Saha
, Roman Kreuzhuber
, Seyhan Yazar
, Harm Brugge
, Roy Oelen
, Dylan H. de Vries
, Monique G. P. van der Wijst
, Silva Kasela
, Natalia Pervjakova
, Isabel Alves
, Marie-Julie Favé

Mawussé Agbessi, Mark W. Christiansen, Rick Jansen, Ilkka Seppälä, Lin Tong, Alexander Teumer, Katharina Schramm, Gibran Hemani, Joost Verlouw, Hanieh Yaghootkar, Reyhan Sönmez Flitman, Andrew Brown, Viktorija Kukushkina, Anette Kalnapenkis, Sina Rüeger, Eleonora Porcu, Jaanika Kronberg, Johannes Kettunen, Bernett Lee, Futao Zhang, Ting Qi, Jose Alquicira Hernandez, Wibowo Arindrarto, Frank Beutner, Julia Dmitrieva, Mahmoud Elansary, Benjamin P. Fairfax, Michel Georges, Bastiaan T. Heijmans, Alex W. Hewitt, Mika Kähönen, Yungil Kim

Population Health and Genomics

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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
Early online date	2 Sept 2021
DOIs	https://doi.org/10.1038/s41588-021-00913-z
Publication status	Published - Sept 2021

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Gene expression
Gene regulation
Genome-wide association studies

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10.1038/s41588-021-00913-z

Author Accepted ManuscriptAccepted author manuscript, 2.48 MB

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, Võsa, U., Claringbould, A., Westra, H.-J., Bonder, M. J., Deelen, P., Zeng, B., Kirsten, H., Saha, A., Kreuzhuber, R., Yazar, S., Brugge, H., Oelen, R., de Vries, D. H., van der Wijst, M. G. P., Kasela, S., Pervjakova, N., Alves, I., ... Kim, Y. (2021). Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nature Genetics, 53, 1300-1310. https://doi.org/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.",

keywords = "Gene expression, Gene regulation, Genome-wide association studies",

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",

note = "{\textcopyright} 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = sep,

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

language = "English",

volume = "53",

pages = "1300--1310",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

}

Võsa, U, Claringbould, A, Westra, H-J, Bonder, MJ, Deelen, P, Zeng, B, Kirsten, H, Saha, A, Kreuzhuber, R, Yazar, S, Brugge, H, Oelen, R, de Vries, DH, van der Wijst, MGP, Kasela, S, Pervjakova, N, Alves, I, Favé, M-J, Agbessi, M, Christiansen, MW, Jansen, R, Seppälä, I, Tong, L, Teumer, A, Schramm, K, Hemani, G, Verlouw, J, Yaghootkar, H, Sönmez Flitman, R, Brown, A, Kukushkina, V, Kalnapenkis, A, Rüeger, S, Porcu, E, Kronberg, J, Kettunen, J, Lee, B, Zhang, F, Qi, T, Hernandez, JA, Arindrarto, W, Beutner, F, Dmitrieva, J, Elansary, M, Fairfax, BP, Georges, M, Heijmans, BT & Hewitt, AW & Kähönen, M & Kim, Y 2021, 'Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression', Nature Genetics, vol. 53, pp. 1300-1310. https://doi.org/10.1038/s41588-021-00913-z

TY - JOUR

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

PY - 2021/9

Y1 - 2021/9

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.

KW - Gene expression

KW - Gene regulation

KW - Genome-wide association studies

UR - https://www.scopus.com/pages/publications/85115732255

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

ER -

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

Abstract

UN SDGs

Keywords

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