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

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

doi:10.1016/j.biopsych.2019.02.016

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

Biol Psychiatry. 2019 Oct 15;86(8):599-607. doi: 10.1016/j.biopsych.2019.02.016. Epub 2019 Mar 1.

Authors

Collaborators

BIOS Consortium:
Bastiaan T Heijmans⁴, Peter A C 't Hoen⁵, Joyce van Meurs⁶, Aaron Isaacs⁷, Rick Jansen⁸, Lude Franke⁹, Dorret I Boomsma¹⁰, René Pool¹⁰, Jenny van Dongen¹⁰, Jouke J Hottenga¹⁰, Marleen M J van Greevenbroek¹¹, Coen D A Stehouwer¹¹, Carla J H van der Kallen¹¹, Casper G Schalkwijk¹¹, Cisca Wijmenga⁹, Lude Franke⁹, Sasha Zhernakova⁹, Ettje F Tigchelaar⁹, P Eline Slagboom⁴, Marian Beekman⁴, Joris Deelen⁴, Diana van Heemst¹², Jan H Veldink¹³, Leonard H van den Berg¹³, Cornelia M van Duijn⁷, Bert A Hofman¹⁴, Aaron Isaacs⁷, André G Uitterlinden⁶, Joyce van Meurs⁶, P Mila Jhamai⁶, Michael Verbiest⁶, H Eka D Suchiman⁴, Marijn Verkerk⁶, Ruud van der Breggen⁴, Jeroen van Rooij⁶, Nico Lakenberg⁴, Hailiang Mei¹⁵, Maarten van Iterson⁴, Michiel van Galen⁵, Jan Bot¹⁶, Dasha V Zhernakova⁹, Rick Jansen⁸, Peter van 't Hof¹⁵, Patrick Deelen⁹, Irene Nooren¹⁶, Peter A C 't Hoen⁵, Bastiaan T Heijmans⁴, Matthijs Moed⁴, Lude Franke⁹, Martijn Vermaat⁵, Dasha V Zhernakova⁹, René Luijk⁴, Marc Jan Bonder⁹, Maarten van Iterson⁴, Patrick Deelen⁹, Freerk van Dijk¹⁷, Michiel van Galen⁵, Wibowo Arindrarto¹⁵, Szymon M Kielbasa¹⁸, Morris A Swertz¹⁷, Erik W van Zwet¹⁸, Rick Jansen⁸, Peter-Bram 't Hoen⁵, Bastiaan T Heijmans⁴

Affiliations

¹ Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam. Electronic address: j.van.dongen@vu.nl.
² Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam.
³ Department of Psychology and Neuroscience, Duke University, Durham, North Carolina; Center for Genomic and Computational Biology, Duke University, Durham, North Carolina.
⁴ Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁶ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁷ Department of Genetic Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁸ Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
⁹ Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
¹⁰ Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
¹¹ Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
¹² Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
¹³ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁴ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹⁵ Sequence Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands.
¹⁶ SURFsara, Amsterdam, The Netherlands.
¹⁷ Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁸ Medical Statistics Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁹ University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
²⁰ Department of Psychology and Neuroscience, Duke University, Durham, North Carolina; Center for Genomic and Computational Biology, Duke University, Durham, North Carolina; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
²¹ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
²² Center for Genomic and Computational Biology, Duke University, Durham, North Carolina.
²³ Dunedin Multidisciplinary Health and Development Research Unit, Department of Psychology, University of Otago, Dunedin, New Zealand.
²⁴ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

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.

Keywords: ADHD; CAARS; DNA methylation; EWAS; Epigenetic; Meta-analysis.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Twin Study

MeSH terms

Adolescent
Adult
Attention Deficit Disorder with Hyperactivity / genetics*
DNA Methylation
Epigenesis, Genetic*
Epigenomics
Genome-Wide Association Study
Humans
Netherlands
Quantitative Trait Loci
Registries
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding