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

当前位置： X-MOL 学术 › Nat. Genet. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression
Nature Genetics ( IF 30.8 ) Pub Date : 2021-09-02 , DOI: 10.1038/s41588-021-00913-z
Urmo Võsa _{1,

2} , Annique Claringbould _{1,

3,

4} , Harm-Jan Westra _{1,

3} , Marc Jan Bonder _{1,

5} , Patrick Deelen _{1,

3,

6,

7} , Biao Zeng ₈ , Holger Kirsten _{9,

10} , Ashis Saha ₁₁ , Roman Kreuzhuber _{12,

13,

14} , Seyhan Yazar ₁₅ , Harm Brugge _{1,

3} , Roy Oelen _{1,

3} , Dylan H de Vries _{1,

3} , Monique G P van der Wijst _{1,

3} , Silva Kasela ₂ , Natalia Pervjakova ₂ , Isabel Alves _{16,

17} , Marie-Julie Favé ₁₆ , Mawussé Agbessi ₁₆ , Mark W Christiansen ₁₈ , Rick Jansen ₁₉ , Ilkka Seppälä ₂₀ , Lin Tong ₂₁ , Alexander Teumer _{22,

23} , Katharina Schramm _{24,

25} , Gibran Hemani ₂₆ , Joost Verlouw ₂₇ , Hanieh Yaghootkar _{28,

29,

30} , Reyhan Sönmez Flitman _{31,

32} , Andrew Brown _{33,

34} , Viktorija Kukushkina ₂ , Anette Kalnapenkis ₂ , Sina Rüeger ₃₅ , Eleonora Porcu ₃₅ , Jaanika Kronberg ₂ , Johannes Kettunen _{36,

37,

38,

39} , Bernett Lee ₄₀ , Futao Zhang ₄₁ , Ting Qi ₄₁ , Jose Alquicira Hernandez ₁₅ , Wibowo Arindrarto ₄₂ , Frank Beutner ₄₃ , , , Julia Dmitrieva ₄₄ , Mahmoud Elansary ₄₄ , Benjamin P Fairfax ₄₅ , Michel Georges ₄₄ , Bastiaan T Heijmans ₄₂ , Alex W Hewitt _{46,

47} , Mika Kähönen ₄₈ , Yungil Kim _{11,

49} , Julian C Knight ₄₅ , Peter Kovacs ₅₀ , Knut Krohn ₅₁ , Shuang Li _{1,

6} , Markus Loeffler _{9,

10} , Urko M Marigorta _{8,

52,

53} , Hailang Mei ₅₄ , Yukihide Momozawa _{44,

55} , Martina Müller-Nurasyid _{24,

25,

56} , Matthias Nauck _{23,

57} , Michel G Nivard ₅₈ , Brenda W J H Penninx ₁₉ , Jonathan K Pritchard _{59,

60} , Olli T Raitakari _{61,

62,

63} , Olaf Rotzschke ₄₀ , Eline P Slagboom ₄₂ , Coen D A Stehouwer ₆₄ , Michael Stumvoll ₆₅ , Patrick Sullivan ₆₆ , Peter A C 't Hoen ₆₇ , Joachim Thiery _{10,

68} , Anke Tönjes ₆₅ , Jenny van Dongen ₆₉ , Maarten van Iterson ₄₂ , Jan H Veldink ₇₀ , Uwe Völker ₇₁ , Robert Warmerdam _{1,

3} , Cisca Wijmenga ₁ , Morris Swertz ₆ , Anand Andiappan ₄₀ , Grant W Montgomery ₄₁ , Samuli Ripatti _{72,

73,

74} , Markus Perola ₇₅ , Zoltan Kutalik ₇₆ , Emmanouil Dermitzakis _{32,

33,

77} , Sven Bergmann _{31,

32} , Timothy Frayling ₂₈ , Joyce van Meurs ₂₇ , Holger Prokisch _{78,

79} , Habibul Ahsan ₂₁ , Brandon L Pierce ₂₁ , Terho Lehtimäki ₂₀ , Dorret I Boomsma ₆₉ , Bruce M Psaty ₈₀ , Sina A Gharib _{18,

81} , Philip Awadalla ₁₆ , Lili Milani ₂ , Willem H Ouwehand _{12,

13,

82} , Kate Downes _{12,

13} , Oliver Stegle _{5,

14,

83} , Alexis Battle _{11,

84} , Peter M Visscher ₄₁ , Jian Yang _{41,

85,

86} , Markus Scholz _{9,

10} , Joseph Powell _{15,

87} , Greg Gibson ₈ , Tõnu Esko ₂ , Lude Franke _{1,

3}

Affiliation

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Oncode Institute, Amsterdam, the Netherlands.
Structural & Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Genomics Coordination Center, University Medical Centre Groningen, Groningen, the Netherlands.
Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
School of Biological Sciences, Georgia Tech, Atlanta, GA, USA.
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.
Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics, Sydney, New South Wales, Australia.
Computational Biology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
L'institut du thorax, Université de Nantes, CHU Nantes, INSERM, CNRS, Nantes, France.
Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Amsterdam, the Netherlands.
Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany.
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Department of Medicine I, University Hospital Munich, Ludwig Maximilian's University, Munich, Germany.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, United Kingdom.
School of Life Sciences, College of Liberal Arts and Science, University of Westminster, London, United Kingdom.
Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden.
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Population Health and Genomics, University of Dundee, Dundee, United Kingdom.
Lausanne University Hospital, Lausanne, Switzerland.
Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
Biocenter Oulu, University of Oulu, Oulu, Finland.
Finnish Institute for Health and Welfare, Helsinki, Finland.
Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Leiden University Medical Center, Leiden, the Netherlands.
Heart Center Leipzig, Universität Leipzig, Leipzig, Germany.
Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
Centre for Eye Research Australia, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia.
Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Genetics and Genomic Science Department, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany.
Interdisciplinary Center for Clinical Research, Faculty of Medicine, Universität Leipzig, Leipzig, Germany.
Integrative Genomics Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, Derio, Spain.
IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Department of Biological Psychology, Faculty of Behaviour and Movement Sciences, Vrije Universiteit, Amsterdam, the Netherlands.
Department of Biology, Stanford University, Stanford, CA, USA.
Department of Genetics, Stanford University, Stanford, CA, USA.
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.
Department of Medicine, Universität Leipzig, Leipzig, Germany.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands.
Institute for Laboratory Medicine, LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany.
Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Amsterdam, the Netherlands.
UMC Utrecht Brain Center, University Medical Center Utrecht, Department of Neurology, Utrecht University, Utrecht, the Netherlands.
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland.
Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland.
Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland.
Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
Institute of Human Genetics, Technical University Munich, Munich, Germany.
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
Department of Medicine, University of Washington, Seattle, WA, USA.
Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
Division of Computational Genomics and Systems Genetics, German Cancer Research Center, Heidelberg, Germany.
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
School of Life Sciences, Westlake University, Hangzhou, China.
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, New South Wales, Australia.

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.

中文翻译：

大规模的 cis- 和 trans-eQTL 分析确定了数千个调节血液基因表达的基因位点和多基因评分

性状相关的遗传变异主要通过转录组的调控机制影响复杂的表型。为了研究基因表达的遗传学，我们通过 eQTLGen 联盟使用来自 31,684 名个体的血液衍生表达进行了顺式和反式表达数量性状基因座 (eQTL) 分析。我们检测到88% 的基因的cis -eQTL，这些在许多组织中都是可复制的。远端反式-eQTL（在 10,317 个测试的性状相关变体中检测到 37%）显示出较低的复制率，部分原因是复制能力低和细胞类型组成的混杂。然而，单细胞 RNA-seq 数据中的复制分析优先考虑细胞内trans - eQTL。Trans -eQTL 通过多种机制发挥作用，主要是通过转录因子的调节。13% 的基因表达与 1,263 种表型的多基因评分相关，从而确定了这些性状的潜在驱动因素。总之，这项工作代表了一个庞大的 eQTL 资源，其结果可作为深入解释复杂表型的起点。

更新日期：2021-09-02

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南

全部期刊列表>>