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Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression |
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| Author: | Vosa, Urmo1,2; Claringbould, Annique1,3,4; Westra, Harm-Jan1,3; |
| Organizations: |
1Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. 2Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia. 3Oncode Inst, Amsterdam, Netherlands.
4European Mol Biol Lab, Struct & Computat Biol Unit, Heidelberg, Germany.
5European Mol Biol Lab, Genome Biol Unit, Heidelberg, Germany. 6Univ Med Ctr Groningen, Genom Coordinat Ctr, Groningen, Netherlands. 7Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands. 8Georgia Tech, Sch Biol Sci, Atlanta, GA USA. 9Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. 10Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany. 11Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA. 12Univ Cambridge, Dept Haematol, Cambridge, England. 13NHS Blood & Transplant, Cambridge Biomed Campus, Cambridge, England. 14European Mol Biol Lab, European Bioinformat Inst, Wellcome Genome Campus, Hinxton, England. 15Garvan Weizmann Ctr Cellular Genom, Garvan Inst Med Res, Sydney, NSW, Australia. 16Ontario Inst Canc Res, Computat Biol, Toronto, ON, Canada. 17CHU Nantes, CNRS, INSERM, Inst Thorax, Nantes, France. 18Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. 19Vrije Univ Amsterdam, Dept Psychiat, Amsterdam UMC, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands. 20Amsterdam Neurosci, Amsterdam, Netherlands. 21Tampere Univ, Fac Med & Hlth Technol, Fimlab Labs, Dept Clin Chem, Tampere, Finland. 22Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland. 23Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA. 24Univ Med Greifswald, Inst Community Med, Greifswald, Germany. 25DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany. 26Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany. 27Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany. 28Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England. 29Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. 30Univ Exeter Med Sch, Royal Devon & Exeter Hosp, Genet Complex Traits, Exeter, Devon, England. 31Univ Westminster, Coll Liberal Arts & Sci, Sch Life Sci, London, England. 32Lulea Univ Technol, Dept Hlth Sci, Div Med Sci, Lulea, Sweden. 33Univ Lausanne, Dept Computat Biol, Lausanne, Switzerland. 34Swiss Inst Bioinformat, Lausanne, Switzerland. 35Univ Geneva, Dept Genet Med & Dev, Med Sch, Geneva, Switzerland. 36Univ Dundee, Populat Hlth & Genom, Dundee, Scotland. 37Lausanne Univ Hosp, Lausanne, Switzerland. 38Univ Oulu, Fac Med, Computat Med, Oulu, Finland. 39Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland. 40Univ Oulu, Bioctr Oulu, Oulu, Finland. 41Finnish Inst Hlth & Welf, Helsinki, Finland. 42Agcy Sci Technol & Res, Singapore Immunol Network, Singapore, Singapore. 43Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia. 44Leiden Univ Med Ctr, Leiden, Netherlands. 45Univ Leipzig, Heart Ctr Leipzig, Leipzig, Germany. 46Univ Liege, GIGA R, Unit Anim Genom, WELBIO, Liege, Belgium. 47Univ Liege, Fac Vet Med, Liege, Belgium. 48Univ Oxford, Wellcome Ctr Human Genet, Oxford, England. 49Univ Tasmania, Sch Med, Menzies Inst Med Res, Hobart, Tas, Australia. 50Univ Melbourne, Ctr Eye Res Australia, Dept Surg, Melbourne, Vic, Australia. 51Tampere Univ, Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. 52Tampere Univ, Fac Med & Hlth Technol, Tampere, Finland. 53Icahn Sch Med Mt Sinai, Genet & Genom Sci Dept, New York, NY 10029 USA. 54Univ Leipzig, IFB Adipos Dis, Leipzig, Germany. 55Univ Leipzig, Interdisciplinary Ctr Clin Res, Fac Med, Leipzig, Germany. 56Basque Res & Technol Alliance BRTA, Integrat Genom Lab, CIC BioGUNE, Bizkaia Sci & Technol Pk, Derio, Spain. 57Basque Fdn Sci, Ikerbasque, Bilbao, Spain. 58Leiden Univ Med Ctr, Dept Med Stat & Bioinformat, Leiden, Netherlands. 59RIKEN Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. 60Ludwig Maximilians Univ Munchen, Fac Med, IBE, Munich, Germany. 61Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. 62Vrije Univ, Fac Behav & Movement Sci, Dept Biol Psychol, Amsterdam, Netherlands. 63Stanford Univ, Dept Biol, Stanford, CA 94305 USA. 64Stanford Univ, Dept Genet, Stanford, CA 94305 USA. 65Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. 66Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland. 67Univ Turku, Ctr Populat Hlth Res, Turku, Finland. 68Turku Univ Hosp, Turku, Finland. 69Maastricht Univ Med Ctr, Dept Internal Med, Maastricht, Netherlands. 70Maastricht Univ Med Ctr, Sch Cardiovasc Dis CARIM, Maastricht, Netherlands. 71Univ Leipzig, Dept Med, Leipzig, Germany. 72Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. 73Univ Leipzig, Inst Lab Med, LIFE Leipzig Res Ctr Civilizat Dis, Leipzig, Germany. 74Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Dept Biol Psychol, Netherlands Twin Register, Amsterdam, Netherlands. 75Univ Utrecht, Univ Med Ctr Utrecht, UMC Utrecht Brain Ctr, Dept Neurol, Utrecht, Netherlands. 76Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. 77Univ Helsinki, Inst Mol Med Finland FIMM, HiLIFE, Helsinki, Finland. 78Univ Helsinki, Fac Med, Publ Hlth, Helsinki, Finland. 79Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. 80Univ Helsinki, Natl Inst Hlth & Welf, Helsinki, Finland. 81Univ Lausanne, Ctr Primary Care & Publ Hlth, Lausanne, Switzerland. 82Univ Geneva, Inst Genet & Genom Geneva iGE3, Geneva, Switzerland. 83Helmholtz Zentrum Munchen, Inst Neurogen, Neuherberg, Germany. 84Tech Univ Munich, Inst Human Genet, Munich, Germany. 85Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. 86Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. 87Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. 88Univ Washington, Dept Med, Seattle, WA USA. 89Wellcome Sanger Inst, Human Genet, Wellcome Genome Campus, Hinxton, England. 90German Canc Res Ctr, Div Computat Genom & Syst Genet, Heidelberg, Germany. 91Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. 92Westlake Univ, Sch Life Sci, Hangzhou, Peoples R China. 93Westlake Lab Life Sci & Biomed, Hangzhou, Peoples R China. 94Univ New South Wales, UNSW Cellular Genom Futures Inst, Sydney, NSW, Australia. |
| Format: | article |
| Version: | accepted version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 3.6 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe2022030422046 |
| Language: | English |
| Published: |
Springer Nature,
2021
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| Publish Date: | 2022-03-04 |
| Description: |
AbstractTrait-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. see all
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| Series: |
Nature genetics |
| ISSN: | 1061-4036 |
| ISSN-E: | 1546-1718 |
| ISSN-L: | 1061-4036 |
| Volume: | 53 |
| Issue: | 9 |
| Pages: | 1300 - 1310 |
| DOI: | 10.1038/s41588-021-00913-z |
| OADOI: | https://oadoi.org/10.1038/s41588-021-00913-z |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3111 Biomedicine 3121 General medicine, internal medicine and other clinical medicine |
| Subjects: | |
| Funding: |
The cohorts participating in this study list their acknowledgements in the cohort-specific sections of the Supplementary Note. This work is supported by a grant from the European Research Council (ERC, ERC Starting Grant agreement number 637640 ImmRisk), a VIDI grant Scientific Research (NWO) to L.F. This work has been supported by the European Regional Development Fund and the program Mobilitas Pluss Lichten'grants 849200011 and 531003014 from the Netherlands Organisation for Health Research and Development, a VENI grant from the NWO funded by a Diabetes UK RD Lawrence fellowship (17/0005594). This project received funding from the ERC under the European Union's Horizon 2020 research and innovation program (grant agreement no. 772376 Research Council grant PRG (PRG1291). A.Battle was supported by NIH grant R01MH109905, NIH grant R01HG008150 (NHGRI; Non-Coding Variants Program) and NIH grant R01MH101814 (NIH Common Fund; GTEx Program). M.G.P.v.d.W. was funded by the Nederlandse Organisatie voor Wetenschappelijk onderzoek, NWO-Veni 192.029. This work was supported by NIH grants R21ES024834 (B.Pierce), R01ES020506 (B.Pierce), R01ES023834 supported by the Sigrid Juselius Foundation (J.Kettunen) and funds from the Academy of Finland (grant numbers 297338 and 307247) (J.Kettunen) and the Novo Nordisk Foundation (grant number NNF17OC0026062) of Excellence in Complex Disease Genetics (grant no. 312062). M.G. was supported by EU Horizon 2020 (grant 733100 for SYSCID) and a grant from the Excellence of Science (FNRS and FWO) (grant no. 30770923). We acknowledge support from the BBMRI-NL (Biobanking and Biomolecular Resources Research Infrastructure 184.021.007 and 184.033.111), Spinozapremie (NWO 56-46414192), the ERC (ERC Advanced 230374) and the KNAW Academy Professor Award (PAH/6635) to D.I.B. G.H. works in a unit that receives funding from the UK MRC (MC_UU_12013/1&2&5) and the University of Bristol. S.B. was supported by the Swiss National Science Foundation (310030-152724). B.M.P. was supported by CHARGE infrastructure grant number HJ105756 for the HVH cohort. This work was supported by the German Federal Ministry of Education and Research Diseases), Universitat Leipzig (which is funded by the European Union, by the European Regional Development Fund and by the Free State of Saxony within the framework of the excellence initiative to H.K. and M.Scholz). We thank the UMCG Genomics Coordination Center, the MOLGENIS team, the UG Center for Information Technology and the UMCG research IT program and their sponsors, in particular the BBMRI-NL for data storage, high-performance computing and web hosting infrastructure. The BBMRI-NL is a research infrastructure financed by the NWO (grant number 184.033.111). We thank K. McIntyre for editing the manuscript text. |
| Academy of Finland Grant Number: |
297338 307247 |
| Detailed Information: |
297338 (Academy of Finland Funding decision) 307247 (Academy of Finland Funding decision) |
| Copyright information: |
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2021. This is a post-peer-review, pre-copyedit version of an article published in Nat Genet. The final authenticated version is available online at https://doi.org/10.1038/s41588-021-00913-z. |