41
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

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

      research-article
      1 , 2 , # , 1 , 3 , 4 , # , 1 , 3 , 1 , 5 , 1 , 3 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 1 , 3 , 1 , 3 , 1 , 3 , 1 , 3 , 2 , 2 , 16 , 17 , 16 , 16 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 2 , 2 , 35 , 35 , 2 , 36 , 37 , 38 , 39 , 40 , 41 , 41 , 42 , 43 , 44 , BIOS Consortium, i2QTL Consortium, 45 , 45 , 46 , 45 , 43 , 47 , 48 , 49 , 50 , 11 , 46 , 51 , 52 , 1 , 6 , 9 , 10 , 53 , 54 , 55 , 56 , 45 , 57 , 24 , 25 , 58 , 23 , 59 , 60 , 19 , 61 , 62 , 63 , 64 , 65 , 40 , 43 , 66 , 67 , 68 , 69 , 70 , 10 , 67 , 71 , 43 , 72 , 73 , 1 , 3 , 1 , 6 , 40 , 41 , 74 , 75 , 76 , 77 , 78 , 32 , 33 , 79 , 31 , 32 , 28 , 27 , 80 , 81 , 21 , 21 , 20 , 71 , 82 , 18 , 83 , 16 , 2 , 12 , 13 , 84 , 12 , 13 , 5 , 14 , 85 , 11 , 86 , 41 , 41 , 87 , 88 , 9 , 10 , 15 , 89 , 53 , 2 , 1 , 3 , #
      Nature genetics

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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-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.

          Related collections

          Most cited references77

          • Record: found
          • Abstract: not found
          • Article: not found

          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            STAR: ultrafast universal RNA-seq aligner.

            Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              clusterProfiler: an R package for comparing biological themes among gene clusters.

              Increasing quantitative data generated from transcriptomics and proteomics require integrative strategies for analysis. Here, we present an R package, clusterProfiler that automates the process of biological-term classification and the enrichment analysis of gene clusters. The analysis module and visualization module were combined into a reusable workflow. Currently, clusterProfiler supports three species, including humans, mice, and yeast. Methods provided in this package can be easily extended to other species and ontologies. The clusterProfiler package is released under Artistic-2.0 License within Bioconductor project. The source code and vignette are freely available at http://bioconductor.org/packages/release/bioc/html/clusterProfiler.html.
                Bookmark

                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat Genet
                Nature genetics
                1061-4036
                1546-1718
                15 August 2021
                02 September 2021
                September 2021
                02 March 2022
                : 53
                : 9
                : 1300-1310
                Affiliations
                [1. ] Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
                [2. ] Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
                [3. ] Oncode Institute, Amsterdam, The Netherlands
                [4. ] European Molecular Biology Laboratory, Structural & Computational Biology Unit, Heidelberg, Germany
                [5. ] European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
                [6. ] Genomics Coordination Center, University Medical Centre Groningen, Groningen, The Netherlands
                [7. ] Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
                [8. ] School of Biological Sciences, Georgia Tech, Atlanta, United States of America
                [9. ] Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
                [10. ] LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
                [11. ] Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, United States of America
                [12. ] Department of Haematology, University of Cambridge, Cambridge, United Kingdom
                [13. ] NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom
                [14. ] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
                [15. ] Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics, Sydney, New South Wales, Australia
                [16. ] Computational Biology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
                [17. ] l’institut du thorax, Université de Nantes, CHU Nantes, INSERM, CNRS, Nantes, France
                [18. ] Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America
                [19. ] Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Amsterdam, The Netherlands
                [20. ] Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
                [21. ] Department of Public Health Sciences, University of Chicago, Chicago, Illinois, United States of America
                [22. ] Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
                [23. ] DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany
                [24. ] Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
                [25. ] Department of Medicine I, University Hospital Munich, Ludwig Maximilian’s University, Munich, Germany
                [26. ] MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
                [27. ] Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
                [28. ] Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, United Kingdom
                [29. ] School of Life Sciences, College of Liberal Arts and Science, University of Westminster, London, United Kingdom
                [30. ] Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden
                [31. ] Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
                [32. ] Swiss Institute of Bioinformatics, Lausanne, Switzerland
                [33. ] Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
                [34. ] Population Health and Genomics, University of Dundee, Dundee, United Kingdom
                [35. ] Lausanne University Hospital, Lausanne, Switzerland
                [36. ] Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
                [37. ] Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
                [38. ] Biocenter Oulu, University of Oulu, Oulu, Finland
                [39. ] Finnish Institute for Health and Welfare​, Helsinki, Finland
                [40. ] Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore
                [41. ] Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
                [42. ] Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics, Sydney, Australia
                [43. ] Leiden University Medical Center, Leiden, The Netherlands
                [44. ] Heart Center Leipzig, Universität Leipzig, Leipzig, Germany
                [45. ] Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liege, Liège, Belgium
                [46. ] Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
                [47. ] Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia
                [48. ] Centre for Eye Research Australia, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
                [49. ] Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
                [50. ] Genetics and Genomic Science Department, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [51. ] IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany
                [52. ] Interdisciplinary Center for Clinical Research, Faculty of Medicine, Universität Leipzig, Leipzig, Germany
                [53. ] School of Biological Sciences, Georgia Tech, Atlanta, Georgia, United States of America
                [54. ] Integrative Genomics Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, Derio, Bizkaia, Basque Country, Spain
                [55. ] IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
                [56. ] Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
                [57. ] Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
                [58. ] IBE, Faculty of Medicine, LMU Munich, Munich, Germany
                [59. ] Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
                [60. ] Department of Biological Psychology, Faculty of Behaviour and Movement Sciences, VU, Amsterdam, The Netherlands
                [61. ] Department of Biology, Stanford University, Stanford, California, United States of America
                [62. ] Department of Genetics, Stanford University, Stanford, California, United States of America
                [63. ] Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
                [64. ] Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
                [65. ] Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
                [66. ] Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands
                [67. ] Department of Medicine, Universität Leipzig, Leipzig, Germany
                [68. ] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
                [69. ] Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands
                [70. ] Institute for Laboratory Medicine, LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
                [71. ] Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam Public Health research institute and Amsterdam Neuroscience, Amsterdam, the Netherlands
                [72. ] UMC Utrecht Brain Center, University Medical Center Utrecht, Department of Neurology, Utrecht University, Utrecht, The Netherlands
                [73. ] Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
                [74. ] Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Finland
                [75. ] Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland
                [76. ] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
                [77. ] National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland
                [78. ] Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland
                [79. ] Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland
                [80. ] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
                [81. ] Institute of Human Genetics, Technical University Munich, Munich, Germany
                [82. ] Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA
                [83. ] Department of Medicine, University of Washington, Seattle, Washington, United States of America
                [84. ] Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
                [85. ] Division of Computational Genomics and Systems Genetics, German Cancer Research Center, Heidelberg, Germany
                [86. ] Departments of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
                [87. ] School of Life Sciences, Westlake University, Hangzhou, China
                [88. ] Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
                [89. ] UNSW Cellular genomics Futures Institute, University of New South Wales, Sydney, New South Wales, Australia
                Author notes
                [*]

                These authors contributed equally

                [**]

                These authors jointly supervised

                [†]

                A list of authors and their affiliations appears at the end of the paper. Full list for consortium members appears in Supplementary Note

                Author contributions

                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.

                [# ] Correspondence to: Urmo Võsa ( urmo.vosa@ 123456gmail.com ), Annique Claringbould ( anniqueclaringbould@ 123456gmail.com ) and Lude Franke ( lude@ 123456ludesign.nl )
                Article
                NIHMS1723987
                10.1038/s41588-021-00913-z
                8432599
                34475573
                64e6b990-4ed6-41ab-a6c4-8f7a79db96b9

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms

                History
                Categories
                Article

                Genetics
                Genetics

                Comments

                Comment on this article