Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults

Jenny van Dongen*, Nuno R Zilhão, Karen Sugden, Eilis J Hannon, Jonathan Mill, Avshalom Caspi, Jessica Agnew-Blais, Louise Arseneault, David L Corcoran, Terrie E Moffitt, Richie Poulton, Barbara Franke, D.I. Boomsma, BIOS Consortium

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

BACKGROUND: Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts.

METHODS: An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed.

RESULTS: One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92% were associated with methylation quantitative trait loci, and 68% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia.

CONCLUSIONS: Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.

Original languageEnglish
Pages (from-to)599-607
Number of pages9
JournalBiological Psychiatry
Volume86
Issue number8
DOIs
Publication statusPublished - 15 Oct 2019

Bibliographical note

Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Funding

NTR: NTR was supported by Biobanking and Biomolecular Research Infrastructure, the Netherlands (BBMRI-NL), Netherlands Organisation for Scientific Research ( NWO) 480-15-001/674 , Netherlands Twin Registry Repository : researching the interplay between genome and environment ( NWO 184.021.007 ), and Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies (ACTION). ACTION receives funding from the European Union Seventh Framework Program ( FP7/2007-2013 ) (Grant No. 602768 ). NTR was also supported by the Royal Netherlands Academy of Science Professor Award (Grant No. PAH/6635 to DIB), Netherlands Organization for Scientific Research (Vici Grant No. 016-130-669 to BF), Dutch National Science Agenda for the NWANeurolabNL project (Grant No. 400 17 602 to BF), European Community FP7 (Grant No. 602805 [Aggressotype] to BF), and European Community Horizon 2020 Program ( H2020/2014–2020 ) (Grant No. 728018 [Eat2beNICE] to BF). Dunedin study: The Dunedin Multidisciplinary Health and Development Research Unit was supported by the New Zealand Health Research Council and New Zealand Ministry of Business, Innovation and Employment, and also by the National Institutes of Health National Institute of Aging (Grant No. R01AG032282 ), Medical Research Council (Grant No. MR/P005918 ), and Jacobs Foundation . This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (“HARDAC+: Reproducible HPC for Next-generation Genomics”) from the North Carolina Biotechnology Center . NTR: NTR was supported by Biobanking and Biomolecular Research Infrastructure, the Netherlands (BBMRI-NL), Netherlands Organisation for Scientific Research (NWO) 480-15-001/674, Netherlands Twin Registry Repository: researching the interplay between genome and environment (NWO 184.021.007), and Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies (ACTION). ACTION receives funding from the European Union Seventh Framework Program (FP7/2007-2013) (Grant No. 602768). NTR was also supported by the Royal Netherlands Academy of Science Professor Award (Grant No. PAH/6635 to DIB), Netherlands Organization for Scientific Research (Vici Grant No. 016-130-669 to BF), Dutch National Science Agenda for the NWANeurolabNL project (Grant No. 400 17 602 to BF), European Community FP7 (Grant No. 602805 [Aggressotype] to BF), and European Community Horizon 2020 Program (H2020/2014–2020) (Grant No. 728018 [Eat2beNICE] to BF). Dunedin study: The Dunedin Multidisciplinary Health and Development Research Unit was supported by the New Zealand Health Research Council and New Zealand Ministry of Business, Innovation and Employment, and also by the National Institutes of Health National Institute of Aging (Grant No. R01AG032282), Medical Research Council (Grant No. MR/P005918), and Jacobs Foundation. This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (“HARDAC+: Reproducible HPC for Next-generation Genomics”) from the North Carolina Biotechnology Center. E-Risk study: The E-Risk study was supported by the Medical Research Council (Grant No. G1002190), National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. HD077482), American Asthma Foundation Distinguished Investigator Award (to JM), Jacobs Foundation, Avielle Foundation, Economic and Social Research Council Mental Health Leadership Fellowship (to LA), and Medical Research Council Skills Development Fellowship (to JA-B). This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (“HARDAC+: Reproducible HPC for Next-generation Genomics”) from the North Carolina Biotechnology Center. NTR: We thank the twins and their family members for their participation. Dunedin study: We thank the Dunedin Study members, unit research staff, and study founder Phil Silva. E-Risk study: We thank the study families for their participation and members of the E-Risk team for their dedication, hard work, and insights. The HumanMethylation450K BeadChip and RNA sequencing data from the BIOS Consortium are available in the European Genome-phenome Archive, under accession code EGAD00010000887. Data from the Dunedin Multidisciplinary Health and Development are available via a managed access system (contact: ac115@duke.edu). The HumanMethylation450K BeadChip DNA methylation data from the E-Risk study are available in Gene Expression Omnibus under accession number GSE105018. BF has received educational speaking fees from Shire and MEDICE. The other authors report no biomedical financial interests or potential conflicts of interest. E-Risk study: The E-Risk study was supported by the Medical Research Council (Grant No. G1002190 ), National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. HD077482 ), American Asthma Foundation Distinguished Investigator Award (to JM), Jacobs Foundation, Avielle Foundation, Economic and Social Research Council Mental Health Leadership Fellowship (to LA), and Medical Research Council Skills Development Fellowship (to JA-B). This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (“HARDAC+: Reproducible HPC for Next-generation Genomics”) from the North Carolina Biotechnology Center . NTR: NTR was supported by Biobanking and Biomolecular Research Infrastructure, the Netherlands (BBMRI-NL), Netherlands Organisation for Scientific Research (NWO) 480-15-001/674, Netherlands Twin Registry Repository: researching the interplay between genome and environment (NWO 184.021.007), and Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies (ACTION). ACTION receives funding from the European Union Seventh Framework Program (FP7/2007-2013) (Grant No. 602768). NTR was also supported by the Royal Netherlands Academy of Science Professor Award (Grant No. PAH/6635 to DIB), Netherlands Organization for Scientific Research (Vici Grant No. 016-130-669 to BF), Dutch National Science Agenda for the NWANeurolabNL project (Grant No. 400 17 602 to BF), European Community FP7 (Grant No. 602805 [Aggressotype] to BF), and European Community Horizon 2020 Program (H2020/2014?2020) (Grant No. 728018 [Eat2beNICE] to BF). Dunedin study: The Dunedin Multidisciplinary Health and Development Research Unit was supported by the New Zealand Health Research Council and New Zealand Ministry of Business, Innovation and Employment, and also by the National Institutes of Health National Institute of Aging (Grant No. R01AG032282), Medical Research Council (Grant No. MR/P005918), and Jacobs Foundation. This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (?HARDAC+: Reproducible HPC for Next-generation Genomics?) from the North Carolina Biotechnology Center. E-Risk study: The E-Risk study was supported by the Medical Research Council (Grant No. G1002190), National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. HD077482), American Asthma Foundation Distinguished Investigator Award (to JM), Jacobs Foundation, Avielle Foundation, Economic and Social Research Council Mental Health Leadership Fellowship (to LA), and Medical Research Council Skills Development Fellowship (to JA-B). This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (?HARDAC+: Reproducible HPC for Next-generation Genomics?) from the North Carolina Biotechnology Center. NTR: We thank the twins and their family members for their participation. Dunedin study: We thank the Dunedin Study members, unit research staff, and study founder Phil Silva. E-Risk study: We thank the study families for their participation and members of the E-Risk team for their dedication, hard work, and insights. The HumanMethylation450K BeadChip and RNA sequencing data from the BIOS Consortium are available in the European Genome-phenome Archive, under accession code EGAD00010000887. Data from the Dunedin Multidisciplinary Health and Development are available via a managed access system (contact: ac115@duke.edu). The HumanMethylation450K BeadChip DNA methylation data from the E-Risk study are available in Gene Expression Omnibus under accession number GSE105018. BF has received educational speaking fees from Shire and MEDICE. The other authors report no biomedical financial interests or potential conflicts of interest.

FundersFunder number
Aggression in Children
Avielle Foundation
BBMRI-NL
Economic and Social Research Council Mental Health LeadershipEGAD00010000887, GSE105018
European Community Horizon 2020 ProgramEat2beNICE, H2020/2014–2020, 728018
European Union Seventh Framework Program602768
MEDICE
National Institutes of Health National Institute of Aging
Netherlands Organization for Scientific Research
Royal Netherlands Academy of SciencePAH/6635
National Institutes of Health
National Institute on AgingR01AG032282
North Carolina Biotechnology Center
Shire
American Asthma Foundation
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentHD077482
Medical Research CouncilMR/P005918, 2016-IDG-1013, G1002190
Health Research Council of New Zealand
Nederlandse Organisatie voor Wetenschappelijk Onderzoek016-130-669, 400 17 602, 184.021.007, 480-15-001/674
Ministry of Business, Innovation and Employment
Jacobs Foundation
Seventh Framework Programme602805

    Cohort Studies

    • Netherlands Twin Register (NTR)

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