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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

      research-article
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      Molecular Psychiatry
      Nature Publishing Group UK
      Genetics, Molecular biology, Neuroscience

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          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

          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.

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          An Integrated Encyclopedia of DNA Elements in the Human Genome

          Summary The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provides new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research.
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            Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays.

            The recently released Infinium HumanMethylation450 array (the '450k' array) provides a high-throughput assay to quantify DNA methylation (DNAm) at ∼450 000 loci across a range of genomic features. Although less comprehensive than high-throughput sequencing-based techniques, this product is more cost-effective and promises to be the most widely used DNAm high-throughput measurement technology over the next several years. Here we describe a suite of computational tools that incorporate state-of-the-art statistical techniques for the analysis of DNAm data. The software is structured to easily adapt to future versions of the technology. We include methods for preprocessing, quality assessment and detection of differentially methylated regions from the kilobase to the megabase scale. We show how our software provides a powerful and flexible development platform for future methods. We also illustrate how our methods empower the technology to make discoveries previously thought to be possible only with sequencing-based methods. http://bioconductor.org/packages/release/bioc/html/minfi.html. khansen@jhsph.edu; rafa@jimmy.harvard.edu Supplementary data are available at Bioinformatics online.
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              A genome-wide association study identifies novel risk loci for type 2 diabetes.

              Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
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                Author and article information

                Contributors
                sylvane.desrivieres@kcl.ac.uk
                Journal
                Mol Psychiatry
                Mol Psychiatry
                Molecular Psychiatry
                Nature Publishing Group UK (London )
                1359-4184
                1476-5578
                6 December 2019
                6 December 2019
                2021
                : 26
                : 8
                : 3884-3895
                Affiliations
                [1 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, , Psychology & Neuroscience, King’s College London, ; London, UK
                [2 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Institute of Science and Technology for Brain-Inspired Intelligence, , Fudan University, ; Shanghai, China
                [3 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, , Fudan University, ; Shanghai, China
                [4 ]GRID grid.413087.9, ISNI 0000 0004 1755 3939, 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
                [5 ]GRID grid.12380.38, ISNI 0000 0004 1754 9227, Vrije Universiteit, Amsterdam, Dept Biological Psychology, ; Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands
                [6 ]GRID grid.1025.6, ISNI 0000 0004 0436 6763, Mathematics and Statistics, , Murdoch University, ; Perth, WA Australia
                [7 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Brain Research Imaging Centre, Centre for Clinical Brain Sciences, and Centre for Cognitive Ageing and Cognitive Epidemiology, , University of Edinburgh (MEB), ; Edinburgh, UK
                [8 ]GRID grid.419548.5, ISNI 0000 0000 9497 5095, Department of Translational Research in Psychiatry, , Max-Planck Institute of Psychiatry, Kraepelinstr, ; 2-10 80804 Munich, Germany
                [9 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Clinical Brain Sciences and Edinburgh Imaging, , University of Edinburgh, ; Edinburgh, UK
                [10 ]GRID grid.16872.3a, ISNI 0000 0004 0435 165X, Department of Psychiatry, , VU University Medical Centre, ; Amsterdam, The Netherlands
                [11 ]GRID grid.266832.b, ISNI 0000 0001 2188 8502, Department of Electrical Engineering, , University of New Mexico, ; Albuquerque, NM USA
                [12 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, , University of Edinburgh, ; Edinburgh, UK
                [13 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, UCLA Center for Neurobehavioral Genetics, , University of California, Los Angeles, ; Los Angeles, CA USA
                [14 ]GRID grid.7821.c, ISNI 0000 0004 1770 272X, Department of Psychiatry, University Hospital Marqués de Valdecilla, , School of Medicine, University of Cantabria, ; Santander, Spain
                [15 ]GRID grid.469673.9, ISNI 0000 0004 5901 7501, Centro Investigación Biomédica en Red de Salud Mental, ; Santander, Spain
                [16 ]Box 591, Uppsala biomedicinska centrum BMC, Husarg. 3, 751 24, Uppsala, Sweden
                [17 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Hospital for Sick Children, , University of Toronto, ; Toronto, ON Canada
                [18 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Center for Neuroimaging, Department of Radiology and Imaging Sciences, , Indiana University School of Medicine, ; Indianapolis, IN USA
                [19 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Center for Computational Biology and Bioinformatics, , Indiana University School of Medicine, ; Indianapolis, IN USA
                [20 ]GRID grid.484299.a, Neuroimaging Unit, , Technological Facilities. Valdecilla Biomedical Research Institute IDIVAL, ; Santander, Cantabria Spain
                [21 ]GRID grid.429568.4, ISNI 0000 0004 0382 5980, National Ageing Research Institute, ; Parkville, VIC Australia
                [22 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Academic Unit for Psychiatry of Old Age, , University of Melbourne, St George’s Hospital, ; Kew, VIC Australia
                [23 ]GRID grid.508487.6, ISNI 0000 0004 7885 7602, 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
                [24 ]GRID grid.484074.b, ISNI 0000 0004 5906 5503, DIGITEO Labs, ; Gif sur Yvette, France
                [25 ]GH Nord Essonne Psychiatry Department 91G16, Orsay, France
                [26 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, , Heidelberg University, Square J5, ; 68159 Mannheim, Germany
                [27 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, , Trinity College Dublin, ; Dublin, Ireland
                [28 ]GRID grid.1005.4, ISNI 0000 0004 4902 0432, Centre for Healthy Brain Ageing, School of Psychiatry, , University of New South Wales, ; Sydney, NSW Australia
                [29 ]GRID grid.1005.4, ISNI 0000 0004 4902 0432, Dementia Centre for Research Collaboration, School of Psychiatry, , University of New South Wales, ; Sydney, NSW Australia
                [30 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, University Medical Centre Hamburg-Eppendorf, House W34, ; 3.OG, Martinistr. 52, 20246 Hamburg, Germany
                [31 ]GRID grid.7692.a, ISNI 0000000090126352, Department of Psychiatry and Brain Center Rudolf Magnus, , University Medical Center Utrecht, ; Utrecht, The Netherlands
                [32 ]GRID grid.1024.7, ISNI 0000000089150953, Faculty of Health, Institute of Health and Biomedical Innovation, , Queensland University of Technology, ; Brisbane, QLD Australia
                [33 ]GRID grid.4488.0, ISNI 0000 0001 2111 7257, Division of Psychological and Social Medicine and Developmental Neurosciences, , Faculty of Medicine, ; TU Dresden, Germany
                [34 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, , Karolinska University Hospital, ; Stockholm, Sweden
                [35 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, , Heidelberg University, Square J5, ; Mannheim, Germany
                [36 ]GRID grid.5601.2, ISNI 0000 0001 0943 599X, Department of Psychology, School of Social Sciences, , University of Mannheim, ; 68131 Mannheim, Germany
                [37 ]GRID grid.4488.0, ISNI 0000 0001 2111 7257, Department of Psychiatry and Neuroimaging Center, , Technische Universität Dresden, ; Dresden, Germany
                [38 ]GRID grid.457334.2, NeuroSpin, CEA, Université Paris-Saclay, ; F-91191 Gif-sur-Yvette, France
                [39 ]GRID grid.59062.38, ISNI 0000 0004 1936 7689, Departments of Psychiatry and Psychology, , University of Vermont, ; 05405 Burlington, VT USA
                [40 ]GRID grid.4563.4, ISNI 0000 0004 1936 8868, Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, , University of Nottingham, University Park, ; Nottingham, UK
                [41 ]GRID grid.7468.d, ISNI 0000 0001 2248 7639, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, , Humboldt-Universität zu Berlin, ; Berlin, Germany
                [42 ]GRID grid.484013.a, Berlin Institute of Health, Department of Psychiatry and Psychotherapy, , Campus Charité Mitte, Charitéplatz 1, ; Berlin, Germany
                [43 ]GRID grid.7836.a, ISNI 0000 0004 1937 1151, Department of Psychiatry and Neuroscience Institute, , University of Cape Town, ; Cape Town, South Africa
                [44 ]GRID grid.4764.1, ISNI 0000 0001 2186 1887, Physikalisch-Technische Bundesanstalt (PTB), , Braunschweig and Berlin, ; Berlin, Germany
                [45 ]GRID grid.42505.36, ISNI 0000 0001 2156 6853, 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
                [46 ]GRID grid.1013.3, ISNI 0000 0004 1936 834X, Central Clinical School—Brain and Mind Centre, , The University of Sydney, ; Camperdown, NSW 2050 Australia
                [47 ]GRID grid.1005.4, ISNI 0000 0004 4902 0432, School of Medical Sciences, , University of New South Wales, ; Sydney, NSW Australia
                [48 ]GRID grid.1049.c, ISNI 0000 0001 2294 1395, Genetic Epidemiology, QIMR Berghofer Medical Research Institute, ; Brisbane, QLD Australia
                [49 ]GRID grid.411784.f, ISNI 0000 0001 0274 3893, Maison de Solenn, , Cochin Hospital, ; Paris, France
                [50 ]GRID grid.250407.4, ISNI 0000 0000 8900 8842, Neuroscience Research Australia, ; Sydney, NSW Australia
                [51 ]GRID grid.1024.7, ISNI 0000000089150953, Herston Imaging Research Facility, School of Clinical Sciences, , Queensland University of Technology, ; Brisbane, QLD Australia
                [52 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, Institute for Molecular Bioscience, , University of Queensland, ; Brisbane, QLD Australia
                [53 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital and Departments of Psychology and Psychiatry, , University of Toronto, ; Toronto, ON M6A 2E1 Canada
                [54 ]GRID grid.411984.1, ISNI 0000 0001 0482 5331, Department of Child and Adolescent Psychiatry and Psychotherapy, , University Medical Centre Göttingen, von-Siebold-Str. 5, ; 37075 Göttingen, Germany
                [55 ]GRID grid.1005.4, ISNI 0000 0004 4902 0432, Faculty of Medicine, , University of New South Wales, ; Sydney, Australia
                [56 ]GRID grid.415021.3, ISNI 0000 0000 9155 0024, SAMRC Unit on Risk & Resilience in Mental Disorders, ; Cape Town, South Africa
                [57 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, Queensland Brain Institute, , University of Queensland, ; Brisbane, QLD Australia
                [58 ]GRID grid.1005.4, ISNI 0000 0004 4902 0432, Department of Developmental Disability Neuropsychiatry, School of Psychiatry, , University of New South Wales, ; Sydney, NSW Australia
                [59 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, 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
                [60 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, UK Dementia Research Institute at the University of Edinburgh, ; Edinburgh, UK
                [61 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, School of Psychology and Global Brain Health Institute, , Trinity College Dublin, ; Dublin, Ireland
                [62 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Department of Neurology, , Indiana University School of Medicine, ; Indianapolis, IN USA
                [63 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Department of Radiology and Imaging Sciences, , Indiana University School of Medicine, ; Indianapolis, IN USA
                [64 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Department of Medical and Molecular Genetics, , Indiana University School of Medicine, ; Indianapolis, IN USA
                [65 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Indiana Alzheimer Disease Center, Indiana University School of Medicine, ; Indianapolis, IN USA
                [66 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), , Emory University, ; 30303, Atlanta, GA USA
                [67 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Semel Institute for Neuroscience and Human Behavior, , University of California, Los Angeles, ; Los Angeles, CA USA
                [68 ]GRID grid.415193.b, Neuropsychiatric Institute, , Prince of Wales Hospital, ; Sydney, NSW Australia
                [69 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Radiology and Imaging Sciences, , Indiana University School of Medicine, ; Indianapolis, IN 46202 USA
                Author information
                http://orcid.org/0000-0001-5399-2953
                http://orcid.org/0000-0001-5753-1265
                http://orcid.org/0000-0003-2063-8741
                http://orcid.org/0000-0002-1135-4141
                http://orcid.org/0000-0002-3333-6737
                http://orcid.org/0000-0002-1724-7523
                http://orcid.org/0000-0002-7306-3008
                http://orcid.org/0000-0001-7353-5178
                http://orcid.org/0000-0003-4595-1144
                http://orcid.org/0000-0001-9487-6617
                http://orcid.org/0000-0003-4974-971X
                http://orcid.org/0000-0003-2927-1632
                http://orcid.org/0000-0002-0482-8759
                http://orcid.org/0000-0003-4506-0579
                http://orcid.org/0000-0001-9360-6623
                http://orcid.org/0000-0003-4401-8950
                http://orcid.org/0000-0002-2147-6302
                http://orcid.org/0000-0002-6357-615X
                http://orcid.org/0000-0001-5286-5485
                http://orcid.org/0000-0002-1242-8990
                http://orcid.org/0000-0003-2967-9662
                http://orcid.org/0000-0001-5398-5569
                http://orcid.org/0000-0002-9403-6121
                http://orcid.org/0000-0002-9812-6642
                http://orcid.org/0000-0001-7088-6618
                http://orcid.org/0000-0002-7099-7972
                http://orcid.org/0000-0001-9058-0747
                http://orcid.org/0000-0002-9595-3220
                http://orcid.org/0000-0002-1376-8532
                http://orcid.org/0000-0001-7133-4970
                http://orcid.org/0000-0002-7740-6469
                Article
                605
                10.1038/s41380-019-0605-z
                8550939
                31811260
                899164d1-a91b-4a8d-9594-a358b97bf6d7
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 March 2019
                : 9 November 2019
                : 12 November 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100009187, RCUK | MRC | Medical Research Foundation;
                Award ID: MR/R00465X/1
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000265, RCUK | Medical Research Council (MRC);
                Award ID: MR/R00465X/1
                Award ID: MR/N000390/1
                Award ID: MR/N027558/1
                Award ID: MR/N000390/1
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                Funded by: National Institutes of Health (NIH) USA- U54 EB020403
                Funded by: FundRef https://doi.org/10.13039/501100011002, National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund);
                Award ID: 81801773
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100003399, Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission);
                Award ID: 18PJ1400900
                Award ID: No.2018SHZDZX01
                Award ID: No.16JC1420402
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                Funded by: FundRef https://doi.org/10.13039/501100001862, Svenska Forskningsrådet Formas (Swedish Research Council Formas);
                Award ID: 259-2012-23
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: R56 AG058854
                Award ID: U54 EB020403
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | National Institutes of Health (NIH)
                Funded by: FundRef https://doi.org/10.13039/100011103, EC | Sixth Framework Programme (EC Sixth Framework Programme);
                Award ID: LSHM-CT- 2007-037286
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100010661, EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020);
                Award ID: 695313
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100011272, EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health);
                Award ID: 603016
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100011261, EC | EC Seventh Framework Programm | FP7 Joint Technology Initiatives (FP7-JTI - Specific Programme "Cooperation": Joint Technology Initiatives);
                Award ID: 115300-2
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                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: NO.B18015
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                © The Author(s), under exclusive licence to Springer Nature Limited 2021

                Molecular medicine
                genetics,molecular biology,neuroscience
                Molecular medicine
                genetics, molecular biology, neuroscience

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