Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation,Nature Genetics

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Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation
Nature Genetics ( IF 30.8 ) Pub Date : 2021-09-06 , DOI: 10.1038/s41588-021-00923-x
Josine L Min _{1,

2} , Gibran Hemani _{1,

2} , Eilis Hannon ₃ , Koen F Dekkers ₄ , Juan Castillo-Fernandez ₅ , René Luijk ₄ , Elena Carnero-Montoro _{5,

6} , Daniel J Lawson _{1,

2} , Kimberley Burrows _{1,

2} , Matthew Suderman _{1,

2} , Andrew D Bretherick ₇ , Tom G Richardson _{1,

2} , Johanna Klughammer ₈ , Valentina Iotchkova ₉ , Gemma Sharp _{1,

2} , Ahmad Al Khleifat ₁₀ , Aleksey Shatunov ₁₀ , Alfredo Iacoangeli _{10,

11} , Wendy L McArdle ₂ , Karen M Ho ₂ , Ashish Kumar _{12,

13,

14} , Cilla Söderhäll ₁₅ , Carolina Soriano-Tárraga ₁₆ , Eva Giralt-Steinhauer ₁₆ , Nabila Kazmi _{1,

2} , Dan Mason ₁₇ , Allan F McRae ₁₈ , David L Corcoran ₁₉ , Karen Sugden _{19,

20} , Silva Kasela ₂₁ , Alexia Cardona _{22,

23} , Felix R Day ₂₂ , Giovanni Cugliari _{24,

25} , Clara Viberti _{24,

25} , Simonetta Guarrera _{24,

25} , Michael Lerro ₂₆ , Richa Gupta _{27,

28} , Sailalitha Bollepalli _{27,

28} , Pooja Mandaviya ₂₉ , Yanni Zeng _{7,

30,

31} , Toni-Kim Clarke ₃₂ , Rosie M Walker _{33,

34} , Vanessa Schmoll ₃₅ , Darina Czamara ₃₅ , Carlos Ruiz-Arenas _{36,

37,

38} , Faisal I Rezwan ₃₉ , Riccardo E Marioni _{33,

34} , Tian Lin ₁₈ , Yvonne Awaloff ₃₅ , Marine Germain ₄₀ , Dylan Aïssi ₄₁ , Ramona Zwamborn ₄₂ , Kristel van Eijk ₄₂ , Annelot Dekker ₄₂ , Jenny van Dongen ₄₃ , Jouke-Jan Hottenga ₄₃ , Gonneke Willemsen ₄₃ , Cheng-Jian Xu _{44,

45} , Guillermo Barturen ₆ , Francesc Català-Moll ₄₆ , Martin Kerick ₄₇ , Carol Wang ₄₈ , Phillip Melton _{49,

50,

51} , Hannah R Elliott _{1,

2} , Jean Shin ₅₂ , Manon Bernard ₅₂ , Idil Yet _{5,

53} , Melissa Smart ₅₄ , Tyler Gorrie-Stone ₅₅ , , Chris Shaw _{10,

56} , Ammar Al Chalabi _{10,

56,

57} , Susan M Ring _{1,

2} , Göran Pershagen ₁₂ , Erik Melén _{12,

58} , Jordi Jiménez-Conde ₁₆ , Jaume Roquer ₁₆ , Deborah A Lawlor _{1,

2} , John Wright ₁₇ , Nicholas G Martin ₅₉ , Grant W Montgomery ₁₈ , Terrie E Moffitt _{19,

20,

60,

61} , Richie Poulton ₆₂ , Tõnu Esko _{21,

63} , Lili Milani ₂₁ , Andres Metspalu ₂₁ , John R B Perry ₂₂ , Ken K Ong ₂₂ , Nicholas J Wareham ₂₂ , Giuseppe Matullo _{24,

25} , Carlotta Sacerdote _{25,

64} , Salvatore Panico ₆₅ , Avshalom Caspi _{19,

20,

60,

61} , Louise Arseneault ₆₁ , France Gagnon ₂₆ , Miina Ollikainen _{27,

28} , Jaakko Kaprio _{27,

28} , Janine F Felix _{66,

67} , Fernando Rivadeneira ₂₉ , Henning Tiemeier _{68,

69} , Marinus H van IJzendoorn _{70,

71} , André G Uitterlinden ₂₉ , Vincent W V Jaddoe _{66,

67} , Chris Haley ₇ , Andrew M McIntosh _{32,

34} , Kathryn L Evans _{33,

34} , Alison Murray ₇₂ , Katri Räikkönen ₇₃ , Jari Lahti ₇₃ , Ellen A Nohr _{74,

75} , Thorkild I A Sørensen _{1,

2,

76,

77} , Torben Hansen ₇₆ , Camilla S Morgen _{76,

78} , Elisabeth B Binder _{35,

79} , Susanne Lucae ₃₅ , Juan Ramon Gonzalez _{36,

37,

38} , Mariona Bustamante _{36,

37,

38,

80} , Jordi Sunyer _{36,

37,

38,

81} , John W Holloway _{82,

83} , Wilfried Karmaus ₈₄ , Hongmei Zhang ₈₄ , Ian J Deary ₃₄ , Naomi R Wray _{18,

85} , John M Starr _{34,

86} , Marian Beekman ₄ , Diana van Heemst ₈₇ , P Eline Slagboom ₄ , Pierre-Emmanuel Morange ₈₈ , David-Alexandre Trégouët ₄₀ , Jan H Veldink ₄₂ , Gareth E Davies ₈₉ , Eco J C de Geus ₄₃ , Dorret I Boomsma ₄₃ , Judith M Vonk ₉₀ , Bert Brunekreef _{91,

92} , Gerard H Koppelman ₄₄ , Marta E Alarcón-Riquelme _{6,

12} , Rae-Chi Huang ₉₃ , Craig E Pennell ₄₈ , Joyce van Meurs ₂₉ , M Arfan Ikram ₉₄ , Alun D Hughes ₉₅ , Therese Tillin ₉₅ , Nish Chaturvedi ₉₅ , Zdenka Pausova ₅₂ , Tomas Paus ₉₆ , Timothy D Spector ₅ , Meena Kumari ₅₄ , Leonard C Schalkwyk ₅₅ , Peter M Visscher _{18,

85} , George Davey Smith _{1,

2} , Christoph Bock _{8,

97} , Tom R Gaunt _{1,

2} , Jordana T Bell ₅ , Bastiaan T Heijmans ₄ , Jonathan Mill ₃ , Caroline L Relton _{1,

2}

Affiliation

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Pfizer-University of Granada-Andalusian Government Center for Genomics and Oncological Research, Granada, Spain.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
MRC Weatherall Institute of Molecular Medicine, Oxford, UK.
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK.
Department of Biostatistics and Health Informatics, King's College London, London, UK.
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Chronic Disease Epidemiology unit, Swiss Tropical and Public Health Institute, Basel, Switzerland.
University of Basel, Basel, Switzerland.
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Neurology Department, Hospital del Mar, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.
Bradford Institute for Health Research, Bradford, UK.
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
MRC Epidemiology Unit, School of Clinical Medicine, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Department of Genetics, University of Cambridge, Cambridge, UK.
Department of Medical Sciences, University of Turin, Turin, Italy.
Italian Institute for Genomic Medicine, Turin, Italy.
Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK.
Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany.
ISGlobal, Barcelona Global Health Institute, Barcelona, Spain.
Universitat Pompeu Fabra, Barcelona, Spain.
CIBER Epidemiología y Salud Pública, Madrid, Spain.
Department of Computer Science, Aberystwyth University, Aberystwyth, UK.
INSERM UMR_S 1219, Bordeaux Population Health Center, University of Bordeaux, Bordeaux, France.
Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute Groningen, Groningen, the Netherlands.
CiiM and TWINCORE, Hannover Medical School and Helmholtz Centre for Infection Research, Hannover, Germany.
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, Barcelona, Spain.
Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, Australia.
Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, Australia.
School of Global Population Health, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia.
School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, Australia.
The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Department of Bioinformatics, Institute of Health Sciences, Hacettepe University, Ankara, Turkey.
Institute for Social and Economic Research, University of Essex, Colchester, UK.
School of Life Sciences, University of Essex, Colchester, UK.
Department of Neurology, King's College Hospital, London, UK.
United Kingdom Dementia Research Institute, King's College London, London, UK.
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, NC, USA.
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Dunedin Multidisciplinary Health and Development Research Unit, Department of Psychology, University of Otago, Dunedin, New Zealand.
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Piemonte Centre for Cancer Prevention, Turin, Italy.
Dipartimento Di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy.
The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, the Netherlands.
Department of Social and Behavioral Science, Harvard TH Chan School of Public Health, Boston, MA, USA.
Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, the Netherlands.
Department of Clinical, Educational and Health Psychology, Division on Psychology and Language Sciences, Faculty of Brain Sciences, University College London, London, UK.
Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Research Unit for Gynaecology and Obstetrics, Institute of Clinical research, University of Southern Denmark, Odense, Denmark.
Centre of Women's, Family and Child Health, University of South-Eastern Norway, Kongsberg, Norway.
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Public Health (Section of Epidemiology), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
Center for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
Hospital del Mar Medical Research Institute, Barcelona, Spain.
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Division of Epidemiology, Biostatistics, and Environmental Health Sciences, School of Public Health, University of Memphis, Memphis, TN, USA.
Queensland Brain Institute, University of Queensland, Brisbane, Australia.
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
C2VN, Aix-Marseille University, INSERM, INRAE, Marseille, France.
Avera Institute for Human Genetics, Sioux Falls, SD, USA.
University of Groningen, University Medical Center Groningen, Department of Epidemiology, GRIAC Research Institute Groningen, Groningen, the Netherlands.
Institute for Risk Assessment Sciences, Universiteit Utrecht, Utrecht, the Netherlands.
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
Telethon Kids Institute, University of Western Australia, Perth, Australia.
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
UCL Institute of Cardiovascular Science, London, UK.
Departments of Psychology and Psychiatry, University of Toronto, Toronto, Canada.
Institute of Artificial Intelligence and Decision Support, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated.

中文翻译：

从遗传对 DNA 甲基化的影响图谱中获得的基因组和表型见解

表征遗传对 DNA 甲基化 (DNAm) 的影响为了解支持基因调控和疾病的机制提供了机会。在本研究中，我们描述了 32,851 名参与者的 DNAm 数量性状位点 (mQTL) 分析结果，确定了血液中 420,509 个 DNAm 位点与 DNAm 相关的遗传变异。我们提供了一个包含 >270,000 个独立 mQTL 的数据库，其中 8.5% 包含远程（反式））协会。已识别的 mQTL 关联解释了 DNAm 的加性遗传变异的 15-17%。我们表明 DNAm 水平的遗传结构是高度多基因的。使用远端 DNAm 位点之间的共享遗传控制，我们构建了网络，识别了 405 个离散的基因组群落，这些群落丰富了基因组注释和复杂性状。共享遗传变异与 DNAm 水平和复杂疾病相关，但仅在少数情况下，这些关联反映了 DNAm 与性状之间的因果关系，反之亦然，表明基因型 - 表型图比先前预期的更为复杂。

更新日期：2021-09-06

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