New Results
Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis
View ORCID ProfileUrmo Võsa, View ORCID ProfileAnnique Claringbould, Harm-Jan Westra, Marc Jan Bonder, Patrick Deelen, Biao Zeng, Holger Kirsten, Ashis Saha, Roman Kreuzhuber, Silva Kasela, Natalia Pervjakova, Isabel Alvaes, Marie-Julie Fave, Mawusse Agbessi, Mark Christiansen, Rick Jansen, Ilkka Seppälä, Lin Tong, Alexander Teumer, Katharina Schramm, Gibran Hemani, Joost Verlouw, Hanieh Yaghootkar, Reyhan Sönmez, Andrew Brown, Viktorija Kukushkina, Anette Kalnapenkis, Sina Rüeger, Eleonora Porcu, Jaanika Kronberg-Guzman, Johannes Kettunen, Joseph Powell, Bernett Lee, Futao Zhang, Wibowo Arindrarto, Frank Beutner, BIOS Consortium, Harm Brugge, i2QTL Consortium, Julia Dmitreva, Mahmoud Elansary, Benjamin P. Fairfax, Michel Georges, Bastiaan T. Heijmans, Mika Kähönen, Yungil Kim, Julian C. Knight, Peter Kovacs, Knut Krohn, Shuang Li, Markus Loeffler, Urko M. Marigorta, Hailang Mei, Yukihide Momozawa, Martina Müller-Nurasyid, Matthias Nauck, Michel Nivard, Brenda Penninx, Jonathan Pritchard, Olli Raitakari, Olaf Rotzchke, Eline P. Slagboom, Coen D.A. Stehouwer, Michael Stumvoll, Patrick Sullivan, Peter A.C. ‘t Hoen, Joachim Thiery, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Jan Veldink, Uwe Völker, Cisca Wijmenga, Morris Swertz, Anand Andiappan, Grant W. Montgomery, Samuli Ripatti, Markus Perola, Zoltan Kutalik, Emmanouil Dermitzakis, Sven Bergmann, Timothy Frayling, Joyce van Meurs, Holger Prokisch, Habibul Ahsan, Brandon Pierce, Terho Lehtimäki, Dorret Boomsma, Bruce M. Psaty, Sina A. Gharib, Philip Awadalla, Lili Milani, Willem Ouwehand, Kate Downes, Oliver Stegle, Alexis Battle, Jian Yang, Peter M. Visscher, Markus Scholz, Gregory Gibson, Tõnu Esko, View ORCID ProfileLude Franke
doi: https://doi.org/10.1101/447367
Urmo Võsa
1
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
2
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia
Annique Claringbould
1
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
Harm-Jan Westra
1
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
Marc Jan Bonder
1
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
Patrick Deelen
1
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
3
Genomics Coordination Center, University Medical Centre Groningen, Groningen, The Netherlands
Biao Zeng
4
School of Biological Sciences, Georgia Tech, Atlanta, United States of America
Holger Kirsten
5
Institut für Medizinische InformatiK, Statistik und Epidemiologie, LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
Ashis Saha
6
Department of Computer Science, Johns Hopkins University, Baltimore, United States of America
Roman Kreuzhuber
7
Department of Haematology, University of Cambridge and NHS Blood and Transplant Cambridge Biomedical Campus, Cambridge, United Kingdom
8
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom
Silva Kasela
2
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia
Natalia Pervjakova
2
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia
Isabel Alvaes
9
Computational Biology, Ontario Institute for Cancer Research, Toronto, Canada
Marie-Julie Fave
9
Computational Biology, Ontario Institute for Cancer Research, Toronto, Canada
Mawusse Agbessi
9
Computational Biology, Ontario Institute for Cancer Research, Toronto, Canada
Mark Christiansen
10
Cardiovascular Health Research Unit, University of Washington, Seattle, United States of America
Rick Jansen
11
Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Ilkka Seppälä
12
Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
Lin Tong
13
Department of Public Health Sciences, University of Chicago, Chicago, United States of America
Alexander Teumer
14
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
Katharina Schramm
15
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
16
Department of Medicine I, University Hospital Munich, Ludwig Maximilian’s University, München, Germany
Gibran Hemani
17
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
Joost Verlouw
18
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
Hanieh Yaghootkar
19
Exeter Medical School, University of Exeter, Exeter, United Kingdom
Reyhan Sönmez
20
Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland
21
Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Andrew Brown
22
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
23
Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland
21
Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Viktorija Kukushkina
2
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia
Anette Kalnapenkis
2
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia
Sina Rüeger
24
Lausanne University Hospital, Lausanne, Switzerland
Eleonora Porcu
24
Lausanne University Hospital, Lausanne, Switzerland
Jaanika Kronberg-Guzman
2
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia
Johannes Kettunen
25
University of Helsinki, Helsinki, Finland
Joseph Powell
26
Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics, Sydney, Australia
Bernett Lee
27
Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore
Futao Zhang
28
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
Wibowo Arindrarto
29
Leiden University Medical Center, Leiden, The Netherlands
Frank Beutner
30
Heart Center Leipzig, Universität Leipzig, Leipzig, Germany
Harm Brugge
1
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
Julia Dmitreva
31
Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liege, 1 Avenue de l’Hôpital, Liège 4000, Belgium
Mahmoud Elansary
31
Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liege, 1 Avenue de l’Hôpital, Liège 4000, Belgium
Benjamin P. Fairfax
32
Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
Michel Georges
31
Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liege, 1 Avenue de l’Hôpital, Liège 4000, Belgium
Bastiaan T. Heijmans
29
Leiden University Medical Center, Leiden, The Netherlands
Mika Kähönen
33
Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
Yungil Kim
34
Department of Computer Science, Johns Hopkins University, Baltimore, United States of America
35
Genetics and Genomic Science Department, Icahn School of Medicine at Mount Sinai, New York, United States of America
Julian C. Knight
32
Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
Peter Kovacs
36
IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany
Knut Krohn
37
Interdisciplinary Center for Clinical Research, Faculty of Medicine, Universität Leipzig, Leipzig, Germany
Shuang Li
1
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
Markus Loeffler
5
Institut für Medizinische InformatiK, Statistik und Epidemiologie, LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
Urko M. Marigorta
4
School of Biological Sciences, Georgia Tech, Atlanta, United States of America
Hailang Mei
38
Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
Yukihide Momozawa
31
Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liege, 1 Avenue de l’Hôpital, Liège 4000, Belgium
39
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan
Martina Müller-Nurasyid
15
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
16
Department of Medicine I, University Hospital Munich, Ludwig Maximilian’s University, München, Germany
40
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
Matthias Nauck
41
Institute of Clinical Chemistry and Laboratory Medicine, Greifswald University Hospital, Greifswald, Germany
Michel Nivard
42
Faculty of Genes, Behavior and Health, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Brenda Penninx
11
Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Jonathan Pritchard
43
Stanford University, Stanford, United States of America
Olli Raitakari
44
Turku University Hospital and University of Turku, Turku, Finland
Olaf Rotzchke
27
Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore
Eline P. Slagboom
29
Leiden University Medical Center, Leiden, The Netherlands
Coen D.A. Stehouwer
45
Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
Michael Stumvoll
46
Department of Medicine, Universität Leipzig, Leipzig, Germany
Patrick Sullivan
47
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Peter A.C. ‘t Hoen
48
Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands
Joachim Thiery
49
Institute for Laboratory Medicine, LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
Anke Tönjes
46
Department of Medicine, Universität Leipzig, Leipzig, Germany
Jenny van Dongen
11
Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Maarten van Iterson
29
Leiden University Medical Center, Leiden, The Netherlands
Jan Veldink
50
University Medical Center Utrecht, Utrecht, The Netherlands
Uwe Völker
51
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
Cisca Wijmenga
1
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
Morris Swertz
3
Genomics Coordination Center, University Medical Centre Groningen, Groningen, The Netherlands
Anand Andiappan
27
Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore
Grant W. Montgomery
52
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
Samuli Ripatti
53
Statistical and Translational Genetics, University of Helsinki, Helsinki, Finland
Markus Perola
54
National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland
Zoltan Kutalik
24
Lausanne University Hospital, Lausanne, Switzerland
Emmanouil Dermitzakis
22
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
23
Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland
21
Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Sven Bergmann
20
Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland
21
Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Timothy Frayling
19
Exeter Medical School, University of Exeter, Exeter, United Kingdom
Joyce van Meurs
18
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
Holger Prokisch
55
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
56
Institute of Human Genetics, Technical University Munich, Munich, Germany.
Habibul Ahsan
13
Department of Public Health Sciences, University of Chicago, Chicago, United States of America
Brandon Pierce
13
Department of Public Health Sciences, University of Chicago, Chicago, United States of America
Terho Lehtimäki
12
Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
Dorret Boomsma
11
Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Bruce M. Psaty
10
Cardiovascular Health Research Unit, University of Washington, Seattle, United States of America
57
Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States of America
Sina A. Gharib
58
Department of Medicine, University of Washington, Seattle, United States of America
10
Cardiovascular Health Research Unit, University of Washington, Seattle, United States of America
Philip Awadalla
9
Computational Biology, Ontario Institute for Cancer Research, Toronto, Canada
Lili Milani
2
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia
Willem Ouwehand
7
Department of Haematology, University of Cambridge and NHS Blood and Transplant Cambridge Biomedical Campus, Cambridge, United Kingdom
59
Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton Cambridge, United Kingdom
Kate Downes
7
Department of Haematology, University of Cambridge and NHS Blood and Transplant Cambridge Biomedical Campus, Cambridge, United Kingdom
Oliver Stegle
8
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom
60
Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
61
Division of Computational Genomics and Systems Genetics, German Cancer Research Center, 69120 Heidelberg, Germany
Alexis Battle
62
Departments of Biomedical Engineering and Computer Science, Johns Hopkins University, Baltimore, United States of America
Jian Yang
28
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
63
Institute for Advanced Research, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
Peter M. Visscher
28
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
Markus Scholz
5
Institut für Medizinische InformatiK, Statistik und Epidemiologie, LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
Gregory Gibson
4
School of Biological Sciences, Georgia Tech, Atlanta, United States of America
Tõnu Esko
2
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia
Lude Franke
1
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
Abstract
Summary While many disease-associated variants have been identified through genome-wide association studies, their downstream molecular consequences remain unclear.
To identify these effects, we performed cis- and trans-expression quantitative trait locus (eQTL) analysis in blood from 31,684 individuals through the eQTLGen Consortium.
We observed that cis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting our ability to use cis-eQTLs to pinpoint causal genes within susceptibility loci.
In contrast, trans-eQTLs (detected for 37% of 10,317 studied trait-associated variants) were more informative. Multiple unlinked variants, associated to the same complex trait, often converged on trans-genes that are known to play central roles in disease etiology.
We observed the same when ascertaining the effect of polygenic scores calculated for 1,263 genome-wide association study (GWAS) traits. Expression levels of 13% of the studied genes correlated with polygenic scores, and many resulting genes are known to drive these traits.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Posted October 19, 2018.
Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis
Urmo Võsa, Annique Claringbould, Harm-Jan Westra, Marc Jan Bonder, Patrick Deelen, Biao Zeng, Holger Kirsten, Ashis Saha, Roman Kreuzhuber, Silva Kasela, Natalia Pervjakova, Isabel Alvaes, Marie-Julie Fave, Mawusse Agbessi, Mark Christiansen, Rick Jansen, Ilkka Seppälä, Lin Tong, Alexander Teumer, Katharina Schramm, Gibran Hemani, Joost Verlouw, Hanieh Yaghootkar, Reyhan Sönmez, Andrew Brown, Viktorija Kukushkina, Anette Kalnapenkis, Sina Rüeger, Eleonora Porcu, Jaanika Kronberg-Guzman, Johannes Kettunen, Joseph Powell, Bernett Lee, Futao Zhang, Wibowo Arindrarto, Frank Beutner, BIOS Consortium, Harm Brugge, i2QTL Consortium, Julia Dmitreva, Mahmoud Elansary, Benjamin P. Fairfax, Michel Georges, Bastiaan T. Heijmans, Mika Kähönen, Yungil Kim, Julian C. Knight, Peter Kovacs, Knut Krohn, Shuang Li, Markus Loeffler, Urko M. Marigorta, Hailang Mei, Yukihide Momozawa, Martina Müller-Nurasyid, Matthias Nauck, Michel Nivard, Brenda Penninx, Jonathan Pritchard, Olli Raitakari, Olaf Rotzchke, Eline P. Slagboom, Coen D.A. Stehouwer, Michael Stumvoll, Patrick Sullivan, Peter A.C. ‘t Hoen, Joachim Thiery, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Jan Veldink, Uwe Völker, Cisca Wijmenga, Morris Swertz, Anand Andiappan, Grant W. Montgomery, Samuli Ripatti, Markus Perola, Zoltan Kutalik, Emmanouil Dermitzakis, Sven Bergmann, Timothy Frayling, Joyce van Meurs, Holger Prokisch, Habibul Ahsan, Brandon Pierce, Terho Lehtimäki, Dorret Boomsma, Bruce M. Psaty, Sina A. Gharib, Philip Awadalla, Lili Milani, Willem Ouwehand, Kate Downes, Oliver Stegle, Alexis Battle, Jian Yang, Peter M. Visscher, Markus Scholz, Gregory Gibson, Tõnu Esko, Lude Franke
bioRxiv 447367; doi: https://doi.org/10.1101/447367
Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis
Urmo Võsa, Annique Claringbould, Harm-Jan Westra, Marc Jan Bonder, Patrick Deelen, Biao Zeng, Holger Kirsten, Ashis Saha, Roman Kreuzhuber, Silva Kasela, Natalia Pervjakova, Isabel Alvaes, Marie-Julie Fave, Mawusse Agbessi, Mark Christiansen, Rick Jansen, Ilkka Seppälä, Lin Tong, Alexander Teumer, Katharina Schramm, Gibran Hemani, Joost Verlouw, Hanieh Yaghootkar, Reyhan Sönmez, Andrew Brown, Viktorija Kukushkina, Anette Kalnapenkis, Sina Rüeger, Eleonora Porcu, Jaanika Kronberg-Guzman, Johannes Kettunen, Joseph Powell, Bernett Lee, Futao Zhang, Wibowo Arindrarto, Frank Beutner, BIOS Consortium, Harm Brugge, i2QTL Consortium, Julia Dmitreva, Mahmoud Elansary, Benjamin P. Fairfax, Michel Georges, Bastiaan T. Heijmans, Mika Kähönen, Yungil Kim, Julian C. Knight, Peter Kovacs, Knut Krohn, Shuang Li, Markus Loeffler, Urko M. Marigorta, Hailang Mei, Yukihide Momozawa, Martina Müller-Nurasyid, Matthias Nauck, Michel Nivard, Brenda Penninx, Jonathan Pritchard, Olli Raitakari, Olaf Rotzchke, Eline P. Slagboom, Coen D.A. Stehouwer, Michael Stumvoll, Patrick Sullivan, Peter A.C. ‘t Hoen, Joachim Thiery, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Jan Veldink, Uwe Völker, Cisca Wijmenga, Morris Swertz, Anand Andiappan, Grant W. Montgomery, Samuli Ripatti, Markus Perola, Zoltan Kutalik, Emmanouil Dermitzakis, Sven Bergmann, Timothy Frayling, Joyce van Meurs, Holger Prokisch, Habibul Ahsan, Brandon Pierce, Terho Lehtimäki, Dorret Boomsma, Bruce M. Psaty, Sina A. Gharib, Philip Awadalla, Lili Milani, Willem Ouwehand, Kate Downes, Oliver Stegle, Alexis Battle, Jian Yang, Peter M. Visscher, Markus Scholz, Gregory Gibson, Tõnu Esko, Lude Franke
bioRxiv 447367; doi: https://doi.org/10.1101/447367
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