Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression
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 individua...
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| Vydané v: | Nature genetics Ročník 53; číslo 9; s. 1300 - 1310 |
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| Médium: | Journal Article |
| Jazyk: | English |
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New York
Nature Publishing Group US
01.09.2021
Nature Publishing Group |
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| ISSN: | 1061-4036, 1546-1718, 1546-1718 |
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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.
Analyses of expression profiles from whole blood of 31,684 individuals identify
cis
-expression quantitative trait loci (eQTL) effects for 88% of genes and
trans
-eQTL effects for 37% of trait-associated variants. |
|---|---|
| AbstractList | 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. 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.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. 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-eQTLs for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTLs (detected for 37% out 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-eQTLs. Trans-eQTLs exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores (PGS) 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. 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. Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants. 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. Analyses of expression profiles from whole blood of 31,684 individuals identify cis -expression quantitative trait loci (eQTL) effects for 88% of genes and trans -eQTL effects for 37% of trait-associated variants. |
| Audience | Academic |
| Author | Veldink, Jan H. Hewitt, Alex W. Thiery, Joachim van Dongen, Jenny Psaty, Bruce M. Kirsten, Holger Lee, Bernett Porcu, Eleonora Qi, Ting Ahsan, Habibul Kasela, Silva Kettunen, Johannes Schramm, Katharina Christiansen, Mark W. Verlouw, Joost Fairfax, Benjamin P. Tong, Lin Mei, Hailang Brown, Andrew Dermitzakis, Emmanouil Boomsma, Dorret I. Esko, Tõnu Kovacs, Peter Kalnapenkis, Anette Claringbould, Annique Dmitrieva, Julia Arindrarto, Wibowo Wijmenga, Cisca Battle, Alexis Kähönen, Mika Hemani, Gibran Frayling, Timothy Saha, Ashis Tönjes, Anke Kukushkina, Viktorija Powell, Joseph Võsa, Urmo Gharib, Sina A. Kutalik, Zoltan Alves, Isabel Perola, Markus Heijmans, Bastiaan T. Knight, Julian C. Agbessi, Mawussé Oelen, Roy Yazar, Seyhan Slagboom, Eline P. Müller-Nurasyid, Martina Pervjakova, Natalia Stehouwer, Coen D. A. Deelen, Patrick t Hoen, Peter A. C. Zhang, Futao Sullivan, Patrick Loeffler, Markus Hernandez, Jose Alquicira Beutner, Frank Marigorta, Urko M. Georges, Michel Montgomery, Grant W. Pritchard, Jonathan K. Seppälä, Ilkka Yaghootkar, Hanieh Ro |
| AuthorAffiliation | 17. l’institut du thorax, Université de Nantes, CHU Nantes, INSERM, CNRS, Nantes, France 23. DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany 1. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 6. Genomics Coordination Center, University Medical Centre Groningen, Groningen, The Netherlands 87. School of Life Sciences, Westlake University, Hangzhou, China 16. Computational Biology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada 79. Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland 46. Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom 33. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland 86. Departments of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America 10. LIFE Research Center for Civilization Di |
| AuthorAffiliation_xml | – name: 83. Department of Medicine, University of Washington, Seattle, Washington, United States of America – name: 63. Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland – name: 28. Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, United Kingdom – name: 65. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland – name: 44. Heart Center Leipzig, Universität Leipzig, Leipzig, Germany – name: 69. Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands – name: 88. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China – name: 19. Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Amsterdam, The Netherlands – name: 71. Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam Public Health research institute and Amsterdam Neuroscience, Amsterdam, the Netherlands – name: 3. Oncode Institute, Amsterdam, The Netherlands – name: 1. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands – name: 34. Population Health and Genomics, University of Dundee, Dundee, United Kingdom – name: 47. Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia – name: 84. Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom – name: 58. IBE, Faculty of Medicine, LMU Munich, Munich, Germany – name: 80. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany – name: 77. National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland – name: 11. Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, United States of America – name: 2. Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia – name: 76. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America – name: 15. Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics, Sydney, New South Wales, Australia – name: 37. Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland – name: 38. Biocenter Oulu, University of Oulu, Oulu, Finland – name: 17. l’institut du thorax, Université de Nantes, CHU Nantes, INSERM, CNRS, Nantes, France – name: 25. Department of Medicine I, University Hospital Munich, Ludwig Maximilian’s University, Munich, Germany – name: 74. Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Finland – name: 18. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America – name: 64. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland – name: 27. Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands – name: 49. Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland – name: 45. Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liege, Liège, Belgium – name: 14. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom – name: 73. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany – name: 40. Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore – name: 5. European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany – name: 41. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia – name: 57. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan – name: 75. Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland – name: 22. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany – name: 4. European Molecular Biology Laboratory, Structural & Computational Biology Unit, Heidelberg, Germany – name: 24. Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany – name: 51. IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany – name: 53. School of Biological Sciences, Georgia Tech, Atlanta, Georgia, United States of America – name: 23. DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany – name: 68. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden – name: 81. Institute of Human Genetics, Technical University Munich, Munich, Germany – name: 85. Division of Computational Genomics and Systems Genetics, German Cancer Research Center, Heidelberg, Germany – name: 86. Departments of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America – name: 33. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland – name: 56. Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands – name: 78. Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland – name: 7. Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands – name: 43. Leiden University Medical Center, Leiden, The Netherlands – name: 52. Interdisciplinary Center for Clinical Research, Faculty of Medicine, Universität Leipzig, Leipzig, Germany – name: 66. Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands – name: 10. LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany – name: 36. Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland – name: 13. NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom – name: 35. Lausanne University Hospital, Lausanne, Switzerland – name: 8. School of Biological Sciences, Georgia Tech, Atlanta, United States of America – name: 21. Department of Public Health Sciences, University of Chicago, Chicago, Illinois, United States of America – name: 16. Computational Biology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada – name: 12. Department of Haematology, University of Cambridge, Cambridge, United Kingdom – name: 79. Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland – name: 20. Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland – name: 31. Department of Computational Biology, University of Lausanne, Lausanne, Switzerland – name: 50. Genetics and Genomic Science Department, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America – name: 70. Institute for Laboratory Medicine, LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany – name: 29. School of Life Sciences, College of Liberal Arts and Science, University of Westminster, London, United Kingdom – name: 48. Centre for Eye Research Australia, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia – name: 6. Genomics Coordination Center, University Medical Centre Groningen, Groningen, The Netherlands – name: 72. UMC Utrecht Brain Center, University Medical Center Utrecht, Department of Neurology, Utrecht University, Utrecht, The Netherlands – name: 87. School of Life Sciences, Westlake University, Hangzhou, China – name: 89. UNSW Cellular genomics Futures Institute, University of New South Wales, Sydney, New South Wales, Australia – name: 9. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany – name: 67. Department of Medicine, Universität Leipzig, Leipzig, Germany – name: 26. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom – name: 42. Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics, Sydney, Australia – name: 61. Department of Biology, Stanford University, Stanford, California, United States of America – name: 39. Finnish Institute for Health and Welfare, Helsinki, Finland – name: 60. Department of Biological Psychology, Faculty of Behaviour and Movement Sciences, VU, Amsterdam, The Netherlands – name: 82. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA – name: 32. Swiss Institute of Bioinformatics, Lausanne, Switzerland – name: 54. Integrative Genomics Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, Derio, Bizkaia, Basque Country, Spain – name: 30. Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden – name: 46. Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom – name: 55. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain – name: 59. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany – name: 62. Department of Genetics, Stanford University, Stanford, California, United States of America |
| Author_xml | – sequence: 2 givenname: Annique orcidid: 0000-0002-9201-6557 surname: Claringbould fullname: Claringbould, Annique email: anniqueclaringbould@gmail.com organization: Department of Genetics, University of Groningen, University Medical Center Groningen, Oncode Institute, Structural & Computational Biology Unit, European Molecular Biology Laboratory – sequence: 3 givenname: Harm-Jan orcidid: 0000-0001-7038-567X surname: Westra fullname: Westra, Harm-Jan organization: Department of Genetics, University of Groningen, University Medical Center Groningen, Oncode Institute – sequence: 4 givenname: Marc Jan surname: Bonder fullname: Bonder, Marc Jan organization: Department of Genetics, University of Groningen, University Medical Center Groningen, Genome Biology Unit, European Molecular Biology Laboratory – sequence: 5 givenname: Patrick orcidid: 0000-0002-5654-3966 surname: Deelen fullname: Deelen, Patrick organization: Department of Genetics, University of Groningen, University Medical Center Groningen, Oncode Institute, Genomics Coordination Center, University Medical Centre Groningen, Department of Genetics, University Medical Centre Utrecht – sequence: 7 givenname: Holger orcidid: 0000-0002-3126-7950 surname: Kirsten fullname: Kirsten, Holger organization: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, LIFE Research Center for Civilization Diseases, University of Leipzig – sequence: 8 givenname: Ashis surname: Saha fullname: Saha, Ashis organization: Department of Computer Science, Johns Hopkins University – sequence: 10 givenname: Seyhan surname: Yazar fullname: Yazar, Seyhan organization: Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics – sequence: 11 givenname: Harm surname: Brugge fullname: Brugge, Harm organization: Department of Genetics, University of Groningen, University Medical Center Groningen, Oncode Institute – sequence: 12 givenname: Roy orcidid: 0000-0002-5026-6531 surname: Oelen fullname: Oelen, Roy organization: Department of Genetics, University of Groningen, University Medical Center Groningen, Oncode Institute – sequence: 13 givenname: Dylan H. orcidid: 0000-0002-0953-0257 surname: de Vries fullname: de Vries, Dylan H. organization: Department of Genetics, University of Groningen, University Medical Center Groningen, Oncode Institute – sequence: 14 givenname: Monique G. 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University, IBE, Faculty of Medicine, LMU Munich – sequence: 62 givenname: Matthias orcidid: 0000-0002-6678-7964 surname: Nauck fullname: Nauck, Matthias organization: DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald – sequence: 63 givenname: Michel G. orcidid: 0000-0003-2015-1888 surname: Nivard fullname: Nivard, Michel G. organization: Department of Biological Psychology, Faculty of Behaviour and Movement Sciences, Vrije Universiteit – sequence: 64 givenname: Brenda W. J. H. surname: Penninx fullname: Penninx, Brenda W. J. H. organization: Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute and Amsterdam Neuroscience – sequence: 65 givenname: Jonathan K. orcidid: 0000-0002-8828-5236 surname: Pritchard fullname: Pritchard, Jonathan K. organization: Department of Biology, Stanford University, Department of Genetics, Stanford University – sequence: 66 givenname: Olli T. surname: Raitakari fullname: Raitakari, Olli T. organization: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Centre for Population Health Research, University of Turku and Turku University Hospital – sequence: 67 givenname: Olaf surname: Rotzschke fullname: Rotzschke, Olaf organization: Singapore Immunology Network, Agency for Science, Technology and Research – sequence: 68 givenname: Eline P. orcidid: 0000-0002-2875-4723 surname: Slagboom fullname: Slagboom, Eline P. organization: Leiden University Medical Center – sequence: 69 givenname: Coen D. A. surname: Stehouwer fullname: Stehouwer, Coen D. A. organization: Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center – sequence: 70 givenname: Michael surname: Stumvoll fullname: Stumvoll, Michael organization: Department of Medicine, Universität Leipzig – sequence: 71 givenname: Patrick surname: Sullivan fullname: Sullivan, Patrick organization: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet – sequence: 72 givenname: Peter A. C. orcidid: 0000-0003-4450-3112 surname: ’t Hoen fullname: ’t Hoen, Peter A. C. organization: Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center Nijmegen – sequence: 73 givenname: Joachim surname: Thiery fullname: Thiery, Joachim organization: LIFE Research Center for Civilization Diseases, University of Leipzig, Institute for Laboratory Medicine, LIFE—Leipzig Research Center for Civilization Diseases, Universität Leipzig – sequence: 74 givenname: Anke surname: Tönjes fullname: Tönjes, Anke organization: Department of Medicine, Universität Leipzig – sequence: 75 givenname: Jenny orcidid: 0000-0003-2063-8741 surname: van Dongen fullname: van Dongen, Jenny organization: Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute and Amsterdam Neuroscience – sequence: 76 givenname: Maarten surname: van Iterson fullname: van Iterson, Maarten organization: Leiden University Medical Center – sequence: 77 givenname: Jan H. orcidid: 0000-0001-5572-9657 surname: Veldink fullname: Veldink, Jan H. organization: UMC Utrecht Brain Center, University Medical Center Utrecht, Department of Neurology, Utrecht University – sequence: 78 givenname: Uwe orcidid: 0000-0002-5689-3448 surname: Völker fullname: Völker, Uwe organization: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald – sequence: 79 givenname: Robert orcidid: 0000-0001-8691-0053 surname: Warmerdam fullname: Warmerdam, Robert organization: Department of Genetics, University of Groningen, University Medical Center Groningen, Oncode Institute – sequence: 80 givenname: Cisca orcidid: 0000-0002-5635-1614 surname: Wijmenga fullname: Wijmenga, Cisca organization: Department of Genetics, University of Groningen, University Medical Center Groningen – sequence: 81 givenname: Morris orcidid: 0000-0002-0979-3401 surname: Swertz fullname: Swertz, Morris organization: Genomics Coordination Center, University Medical Centre Groningen – sequence: 82 givenname: Anand orcidid: 0000-0002-8442-1544 surname: Andiappan fullname: Andiappan, Anand organization: Singapore Immunology Network, Agency for Science, Technology and Research – sequence: 83 givenname: Grant W. orcidid: 0000-0002-4140-8139 surname: Montgomery fullname: Montgomery, Grant W. organization: Institute for Molecular Bioscience, University of Queensland – sequence: 84 givenname: Samuli orcidid: 0000-0002-0504-1202 surname: Ripatti fullname: Ripatti, Samuli organization: Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Public Health, Faculty of Medicine, University of Helsinki, Broad Institute of MIT and Harvard – sequence: 85 givenname: Markus surname: Perola fullname: Perola, Markus organization: National Institute for Health and Welfare, University of Helsinki – sequence: 86 givenname: Zoltan surname: Kutalik fullname: Kutalik, Zoltan organization: Center for Primary Care and Public Health, University of Lausanne – sequence: 87 givenname: Emmanouil orcidid: 0000-0002-9302-6490 surname: Dermitzakis fullname: Dermitzakis, Emmanouil organization: Swiss Institute of Bioinformatics, Department of Genetic Medicine and Development, University of Geneva Medical School, Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva – sequence: 88 givenname: Sven orcidid: 0000-0002-6785-9034 surname: Bergmann fullname: Bergmann, Sven organization: Department of Computational Biology, University of Lausanne, Swiss Institute of Bioinformatics – sequence: 90 givenname: Joyce surname: van Meurs fullname: van Meurs, Joyce organization: Department of Internal Medicine, Erasmus Medical Center – sequence: 91 givenname: Holger orcidid: 0000-0003-2379-6286 surname: Prokisch fullname: Prokisch, Holger organization: Institute of Neurogenomics, Helmholtz Zentrum München, Institute of Human Genetics, Technical University Munich – sequence: 92 givenname: Habibul surname: Ahsan fullname: Ahsan, Habibul organization: Department of Public Health Sciences, University of Chicago – sequence: 93 givenname: Brandon L. surname: Pierce fullname: Pierce, Brandon L. organization: Department of Public Health Sciences, University of Chicago – sequence: 94 givenname: Terho surname: Lehtimäki fullname: Lehtimäki, Terho organization: Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center—Tampere, Faculty of Medicine and Health Technology, Tampere University – sequence: 96 givenname: Bruce M. orcidid: 0000-0002-7278-2190 surname: Psaty fullname: Psaty, Bruce M. organization: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington – sequence: 97 givenname: Sina A. orcidid: 0000-0002-2480-4367 surname: Gharib fullname: Gharib, Sina A. organization: Cardiovascular Health Research Unit, University of Washington, Department of Medicine, University of Washington – sequence: 98 givenname: Philip surname: Awadalla fullname: Awadalla, Philip organization: Computational Biology, Ontario Institute for Cancer Research – sequence: 99 givenname: Lili orcidid: 0000-0002-5323-3102 surname: Milani fullname: Milani, Lili organization: Estonian Genome Centre, Institute of Genomics, University of Tartu – sequence: 100 givenname: Willem H. orcidid: 0000-0002-7744-1790 surname: Ouwehand fullname: Ouwehand, Willem H. organization: Department of Haematology, University of Cambridge, NHS Blood and Transplant, Cambridge Biomedical Campus, Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus – sequence: 101 givenname: Kate surname: Downes fullname: Downes, Kate organization: Department of Haematology, University of Cambridge, NHS Blood and Transplant, Cambridge Biomedical Campus – sequence: 102 givenname: Oliver orcidid: 0000-0002-8818-7193 surname: Stegle fullname: Stegle, Oliver organization: Genome Biology Unit, European Molecular Biology Laboratory, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Division of Computational Genomics and Systems Genetics, German Cancer Research Center – sequence: 103 givenname: Alexis surname: Battle fullname: Battle, Alexis organization: Department of Computer Science, Johns Hopkins University, Department of Biomedical Engineering, Johns Hopkins University – sequence: 104 givenname: Peter M. orcidid: 0000-0002-2143-8760 surname: Visscher fullname: Visscher, Peter M. organization: Institute for Molecular Bioscience, University of Queensland – sequence: 105 givenname: Jian orcidid: 0000-0003-2001-2474 surname: Yang fullname: Yang, Jian organization: Institute for Molecular Bioscience, University of Queensland, School of Life Sciences, Westlake University, Westlake Laboratory of Life Sciences and Biomedicine – sequence: 107 givenname: Joseph surname: Powell fullname: Powell, Joseph organization: Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics, UNSW Cellular Genomics Futures Institute, University of New South Wales – sequence: 108 givenname: Greg orcidid: 0000-0002-5352-5877 surname: Gibson fullname: Gibson, Greg organization: School of Biological Sciences, Georgia Tech – sequence: 109 givenname: Tõnu orcidid: 0000-0003-1982-6569 surname: Esko fullname: Esko, Tõnu organization: Estonian Genome Centre, Institute of Genomics, University of Tartu – sequence: 110 givenname: Lude orcidid: 0000-0002-5159-8802 surname: Franke fullname: Franke, Lude email: lude@ludesign.nl organization: Department of Genetics, University of Groningen, University Medical Center Groningen, Oncode Institute |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34475573$$D View this record in MEDLINE/PubMed https://urn.kb.se/resolve?urn=urn:nbn:se:ltu:diva-86989$$DView record from Swedish Publication Index http://kipublications.ki.se/Default.aspx?queryparsed=id:147555701$$DView record from Swedish Publication Index (Karolinska Institutet) |
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| Copyright | The Author(s), under exclusive licence to Springer Nature America, Inc. 2021 2021. The Author(s), under exclusive licence to Springer Nature America, Inc. COPYRIGHT 2021 Nature Publishing Group Copyright Nature Publishing Group Sep 2021 |
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| GrantInformation_xml | – fundername: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). – fundername: This work was supported through The Sigrid Juselius Foundation (J.Ke.) and funds from the Academy of Finland [grant numbers 297338 and 307247] (J.Ke.) and Novo Nordisk Foundation [grant number NNF17OC0026062] (J.Ke.). – fundername: HVH was supported in part by grants R01 HL085251 and R01 HL073410 from the National Heart, Lung, and Blood Institute (NHLBI). The provision of genomic data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Research Center. – fundername: EGCUT analyses were funded by EU H2020 grant 692145, Estonian Research Council Grant IUT20-60, IUT24-6, and European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012GENTRANSMED. – fundername: Research in the Ouwehand laboratory receives funding from the British Heart Foundation, European Commission (TrainMALTA), International Society on Thrombosis and Haemostasis, National Institute for Health Research England, Medical Research Council, NHS Blood and Transplant and the Rosetrees Trust. – fundername: This work is supported by a grant from the European Research Council (ERC, ERC Starting Grant agreement number 637640 ImmRisk), a VIDI grant (917.14.374) and VICI grant from the Netherlands Organisation for Scientific Research (NWO) to L.F. – fundername: S.B was supported by the Swiss National Science Foundation (310030-152724). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. – fundername: H.Y. is funded by a Diabetes UK RD Lawrence fellowship (17/0005594). – fundername: M.v.d.W was funded by Nederlandse Organisatie voor Wetenschappelijk onderzoek, NWO-Veni 192.029. – fundername: T.E. was supported by the Estonian Research Council grant PRG (PRG1291). – fundername: NIMH NIH HHS grantid: R01 MH109905 – fundername: Wellcome Trust grantid: 201488/Z/16/Z – fundername: NIGMS NIH HHS grantid: R01 GM108711 – fundername: NIA NIH HHS grantid: P30 AG073104 – fundername: NIEHS NIH HHS grantid: R01 ES023834 – fundername: NIEHS NIH HHS grantid: R21 ES024834 – fundername: NHLBI NIH HHS grantid: R01 HL105756 – fundername: NIEHS NIH HHS grantid: R35 ES028379 – fundername: NIMH NIH HHS grantid: R01 MH101814 – fundername: NHGRI NIH HHS grantid: R01 HG008150 |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 scopus-id:2-s2.0-85115732255 info:eu-repo/grantAgreement/EC/H2020/733100 These authors jointly supervised U.V. and A.C. coordinated the consortium analyses, ran the meta-analyses, interpreted the data, performed downstream analyses, drafted and revised the manuscript. H-J.W., MJ.B. and P.D. developed the software used in the analyses, did downstream analyses, participated in manuscript writing and revisions. L.F. and T.E. conceived the study. L.F. supervised the project, ran downstream analyses, participated in the manuscript writing and revisions. B.Z., H.K., A.S., S.K., N.P., I.A., M-J.F., M.A., M.W.C., R.J., I.S., L.T., A.T., K.S., J.V., H.Y., V.K., A.K., J.Ke., J.P., B.L. ran consortium analyses in their respective cohorts. A.S., R.K., S.K., G.H., R.S., A.Br. ran replication analyses in their respective cohorts. A.A., G.W.M., S.Ri., M.P., E.D., S.B., T.F., J.v.M, H.P., H.A., B.P., T.L., D.I.B., B.M.P., S.A.G., P.A., L.M., W.H.O., K.D., O.S., A.Ba., M.Sc., G.G., T.E., W.A., F.B., J.D., M.E., B.P.F, M.G., B.T.H., M.K., Y.K., J.C.K, P.K., K.K., M.L., U.M.M., H.M., Y.M., M.M-N., M.Na., M.G.N., B.WJH.P., O.T.R., O.Ro., E.P.S, C.D.A.S., M.St., P.S., P.A.C.’tH, J.T., A.Tö., J.v.D., M.v.I., J.H.V., U.Vö., C.W. provided the data used in the study. B.Z., H.K., Z.K., J.Kr., S.Rü., E.P., S.L., J.Y., F.Z., P.M.V., J.P., T.Q., R.W., H.K, M.Sc. and G.G. participated in downstream analyses. S.Y., H.B., R.O., D.d.V. and M.v.d.W. ran replication analyses in scRNA-seq cohorts. A.H., JA.H. and J.P. generated scRNA-seq replication data. H.K., A.T., M.G., M.G.N., J.P., Z.K., J.Y., P.M.V., M.Sc., G.G., J.P., S.A.G. and P.A.C.’tH. contributed to writing and revising the manuscript. J.K.P. provided Supplementary Equations for interpretation of results. H.B. and M.Sw. created the website to host the results. U.V. and A.C. contributed equally to this work. H-J.W, MJ.B. and P.D. contributed equally to this work. L.F., T.E., G.G. and J.P. jointly supervised this work. BIOS Consortium contributed with the subset of the whole blood data, used in discovery analyses. i2QTL Consortium contributed with trans-eQTL and eQTS replication analyses in iPSCs. A list of authors and their affiliations appears at the end of the paper. Full list for consortium members appears in Supplementary Note These authors contributed equally Author contributions |
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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 |
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