Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.,Molecular Psychiatry

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Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.
Molecular Psychiatry ( IF 11.0 ) Pub Date : 2019-12-06 , DOI: 10.1038/s41380-019-0605-z
Tianye Jia _{1,

2,

3} , Congying Chu ₁ , Yun Liu ₄ , Jenny van Dongen ₅ , Evangelos Papastergios ₁ , Nicola J Armstrong ₆ , Mark E Bastin ₇ , Tania Carrillo-Roa ₈ , Anouk den Braber ₅ , Mathew Harris ₉ , Rick Jansen ₁₀ , Jingyu Liu ₁₁ , Michelle Luciano ₁₂ , Anil P S Ori ₁₃ , Roberto Roiz Santiañez _{14,

15} , Barbara Ruggeri ₁ , Daniil Sarkisyan ₁₆ , Jean Shin ₁₇ , Kim Sungeun _{18,

19} , Diana Tordesillas Gutiérrez _{14,

20} , Dennis Van't Ent ₅ , David Ames _{21,

22} , Eric Artiges _{23,

24,

25} , Georgy Bakalkin ₁₆ , Tobias Banaschewski ₂₆ , Arun L W Bokde ₂₇ , Henry Brodaty _{28,

29} , Uli Bromberg ₃₀ , Rachel Brouwer ₃₁ , Christian Büchel ₃₀ , Erin Burke Quinlan ₁ , Wiepke Cahn ₃₁ , Greig I de Zubicaray ₃₂ , Stefan Ehrlich ₃₃ , Tomas J Ekström ₃₄ , Herta Flor _{35,

36} , Juliane H Fröhner ₃₇ , Vincent Frouin ₃₈ , Hugh Garavan ₃₉ , Penny Gowland ₄₀ , Andreas Heinz _{41,

42} , Jacqueline Hoare ₄₃ , Bernd Ittermann ₄₄ , Neda Jahanshad ₄₅ , Jiyang Jiang ₂₈ , John B Kwok _{46,

47} , Nicholas G Martin ₄₈ , Jean-Luc Martinot _{23,

24,

49} , Karen A Mather _{28,

50} , Katie L McMahon ₅₁ , Allan F McRae ₅₂ , Frauke Nees _{26,

35} , Dimitri Papadopoulos Orfanos ₃₈ , Tomáš Paus ₅₃ , Luise Poustka ₅₄ , Philipp G Sämann ₈ , Peter R Schofield _{50,

55} , Michael N Smolka ₃₇ , Dan J Stein _{43,

56} , Lachlan T Strike ₅₇ , Jalmar Teeuw _{13,

31} , Anbupalam Thalamuthu _{28,

50} , Julian Trollor _{28,

58} , Henrik Walter _{41,

42} , Joanna M Wardlaw _{59,

60} , Wei Wen ₂₈ , Robert Whelan ₆₁ , Liana G Apostolova _{62,

63,

64,

65} , Elisabeth B Binder ₈ , Dorret I Boomsma ₅ , Vince Calhoun _{11,

66} , Benedicto Crespo-Facorro ₁₄ , Ian J Deary ₁₂ , Hilleke Hulshoff Pol ₃₁ , Roel A Ophoff _{31,

67} , Zdenka Pausova ₁₇ , Perminder S Sachdev _{28,

68} , Andrew Saykin ₆₉ , Margaret J Wright ₄₈ , Paul M Thompson ₄₅ , Gunter Schumann ₁ , Sylvane Desrivières ₁

Affiliation

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.
MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Shanghai, China.
MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
Vrije Universiteit, Amsterdam, Dept Biological Psychology, Van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.
Mathematics and Statistics, Murdoch University, Perth, WA, Australia.
Brain Research Imaging Centre, Centre for Clinical Brain Sciences, and Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh (MEB), Edinburgh, UK.
Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Kraepelinstr, 2-10 80804, Munich, Germany.
Centre for Clinical Brain Sciences and Edinburgh Imaging, University of Edinburgh, Edinburgh, UK.
Department of Psychiatry, VU University Medical Centre, Amsterdam, The Netherlands.
Department of Electrical Engineering, University of New Mexico, Albuquerque, NM, USA.
Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
UCLA Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria, Santander, Spain.
Centro Investigación Biomédica en Red de Salud Mental, Santander, Spain.
Box 591, Uppsala biomedicinska centrum BMC, Husarg. 3, 751 24, Uppsala, Sweden.
Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
Neuroimaging Unit, Technological Facilities. Valdecilla Biomedical Research Institute IDIVAL, Santander, Cantabria, Spain.
National Ageing Research Institute, Parkville, VIC, Australia.
Academic Unit for Psychiatry of Old Age, University of Melbourne, St George's Hospital, Kew, VIC, Australia.
Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 "Neuroimaging & Psychiatry", University Paris Sud-Paris Saclay, University Paris Descartes, Orsay, France.
DIGITEO Labs, Gif sur Yvette, France.
GH Nord Essonne Psychiatry Department 91G16, Orsay, France.
Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159, Mannheim, Germany.
Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
Dementia Centre for Research Collaboration, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
University Medical Centre Hamburg-Eppendorf, House W34, 3.OG, Martinistr. 52, 20246, Hamburg, Germany.
Department of Psychiatry and Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Germany.
Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany.
Department of Psychology, School of Social Sciences, University of Mannheim, 68131, Mannheim, Germany.
Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.
NeuroSpin, CEA, Université Paris-Saclay, F-91191, Gif-sur-Yvette, France.
Departments of Psychiatry and Psychology, University of Vermont, 05405, Burlington, VT, USA.
Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, UK.
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Berlin Institute of Health, Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charitéplatz 1, Berlin, Germany.
Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
Physikalisch-Technische Bundesanstalt (PTB), Braunschweig and Berlin, Berlin, Germany.
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of the University of Southern California, Marina del Rey, CA, USA.
Central Clinical School-Brain and Mind Centre, The University of Sydney, Camperdown, NSW, 2050, Australia.
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Maison de Solenn, Cochin Hospital, Paris, France.
Neuroscience Research Australia, Sydney, NSW, Australia.
Herston Imaging Research Facility, School of Clinical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital and Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, M6A 2E1, Canada.
Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, von-Siebold-Str. 5, 37075, Göttingen, Germany.
Faculty of Medicine, University of New South Wales, Sydney, Australia.
SAMRC Unit on Risk & Resilience in Mental Disorders, Cape Town, South Africa.
Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
Brain Research Imaging Centre, Centre for Clinical Brain Sciences, Edinburgh Dementia Research Centre, and Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
UK Dementia Research Institute at the University of Edinburgh, Edinburgh, UK.
School of Psychology and Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Emory University, 30303, Atlanta, GA, USA.
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, NSW, Australia.
Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

中文翻译：

血液 DNA 甲基化的全表观基因组荟萃分析及其与皮层下体积的关联：来自 ENIGMA 表观遗传学工作组的发现。

受遗传因素和环境暴露调节的 DNA 甲基化可能提供独特的机会来发现与疾病相关的大脑表型的新生物标志物，即使在大脑以外的其他组织（如血液）中进行测量也是如此。一些小样本研究揭示了血液 DNA 甲基化与神经精神病理学之间的关联，然而，需要大规模表观基因组范围的关联研究 (EWAS) 来研究 DNA 甲基化分析作为大脑外周标记的效用。在这里，在对 11 个国际队列（共 3337 人）的分析中，我们报告了血液 DNA 甲基化与海马体积的表观基因组范围的荟萃分析，丘脑和伏隔核 (NAcc) - 三个皮层下区域因其与疾病和遗传力以及体积变异性的关联而被选中。对单个 CpG 的分析揭示了全基因组与两个位点的海马体积显着相关。对于丘脑和伏隔核体积的分析没有发现显着关联。基于聚类的分析揭示了与海马体积相关的其他差异甲基化区域 (DMR)。这些位点的 DNA 甲基化影响了参与学习和记忆、干细胞维持和分化、脂肪酸代谢和 2 型糖尿病的近端基因的表达。这些DNA甲基化标记，

更新日期：2019-12-06

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