Epigenome-wide association study of Attention-Deficit/Hyperactivity Disorder symptoms in adults

Jenny van Dongen, Nuno R. Zilhão, Karen Sugden, Bastiaan T. Heijmans, Peter A.C. ’t Hoen, Joyce van Meurs, Aaron Isaacs, Rick Jansen, Lude Franke, Dorret I. Boomsma, René Pool, Jouke J. Hottenga, Marleen M.J. van Greevenbroek, Coen D.A. Stehouwer, Carla J.H. van der Kallen, Casper G. Schalkwijk, Cisca Wijmenga, Sasha Zhernakova, Ettje F. Tigchelaar, P. Eline SlagboomMarian Beekman, Joris Deelen, Diana van Heemst, Jan H. Veldink, Leonard H. van den Berg, Cornelia M. van Duijn, Bert A. Hofman, André G. Uitterlinden, P. Mila Jhamai, Michael Verbiest, H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Hailiang Mei, Maarten van Iterson, Michiel van Galen, Jan Bot, Dasha V. Zhernakova, Peter van ’t Hof, Patrick Deelen, Irene Nooren, Moed Matthijs, Martijn Vermaat, René Luijk, Marc Jan Bonder, Freerk van Dijk, Wibowo Arindrarto, Szymon M. Kielbasa, BIOS Consortium, Szymon M. Kielbasa, Morris A. Swertz, Erik W. van Zwet, Peter-Bram ’t Hoen, Eilis Hannon, Jonathan Mill, A Caspi, Louise Arseneault, David L Corcoran, TE Moffitt, Richie Poulton, Barbara Franke, Dorret I. Boomsma

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

Cite this

van Dongen, J., Zilhão, N. R., Sugden, K., Heijmans, B. T., ’t Hoen, P. A. C., van Meurs, J., ... Boomsma, D. I. (2019). Epigenome-wide association study of Attention-Deficit/Hyperactivity Disorder symptoms in adults. Biological Psychiatry, 86(8), 599-607. https://doi.org/10.1016/j.biopsych.2019.02.016