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

BIOS Consortium

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
JournalBiological Psychiatry
DOIs
Publication statusPublished - 1 Jan 2019

Cite this

@article{b2ac1f3fbc63458398e783d9c0d61d3e,
title = "Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults",
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, Epigenetic, EWAS, Meta-analysis",
author = "{BIOS Consortium} and {van Dongen}, Jenny and Zilh{\~a}o, {Nuno R.} and Karen Sugden and Heijmans, {Bastiaan T.} and {’t Hoen}, {Peter A.C.} and {van Meurs}, Joyce and Aaron Isaacs and Rick Jansen and Lude Franke and Boomsma, {Dorret I.} and Ren{\'e} Pool and Hottenga, {Jouke J.} and {van Greevenbroek}, {Marleen M.J.} and Stehouwer, {Coen D.A.} and {van der Kallen}, {Carla J.H.} and Schalkwijk, {Casper G.} and Cisca Wijmenga and Sasha Zhernakova and Tigchelaar, {Ettje F.} and Slagboom, {P. Eline} and Marian Beekman and Joris Deelen and {van Heemst}, Diana and Veldink, {Jan H.} and {van den Berg}, {Leonard H.} and {van Duijn}, {Cornelia M.} and Hofman, {Bert A.} and Uitterlinden, {Andr{\'e} G.} and Jhamai, {P. Mila} and Michael Verbiest and Suchiman, {H. Eka D.} and Marijn Verkerk and {van der Breggen}, Ruud and {van Rooij}, Jeroen and Nico Lakenberg and Hailiang Mei and {van Iterson}, Maarten and {van Galen}, Michiel and Jan Bot and Zhernakova, {Dasha V.} and Hof, {Peter van ’t} and Patrick Deelen and Irene Nooren and Moed Matthijs and Martijn Vermaat and Ren{\'e} Luijk and Bonder, {Marc Jan} and {van Dijk}, Freerk and Wibowo Arindrarto and Kielbasa, {Szymon M.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.biopsych.2019.02.016",
language = "English",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",

}

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

In: Biological Psychiatry, 01.01.2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults

AU - BIOS Consortium

AU - van Dongen, Jenny

AU - Zilhão, Nuno R.

AU - Sugden, Karen

AU - Heijmans, Bastiaan T.

AU - ’t Hoen, Peter A.C.

AU - van Meurs, Joyce

AU - Isaacs, Aaron

AU - Jansen, Rick

AU - Franke, Lude

AU - Boomsma, Dorret I.

AU - Pool, René

AU - Hottenga, Jouke J.

AU - van Greevenbroek, Marleen M.J.

AU - Stehouwer, Coen D.A.

AU - van der Kallen, Carla J.H.

AU - Schalkwijk, Casper G.

AU - Wijmenga, Cisca

AU - Zhernakova, Sasha

AU - Tigchelaar, Ettje F.

AU - Slagboom, P. Eline

AU - Beekman, Marian

AU - Deelen, Joris

AU - van Heemst, Diana

AU - Veldink, Jan H.

AU - van den Berg, Leonard H.

AU - van Duijn, Cornelia M.

AU - Hofman, Bert A.

AU - Uitterlinden, André G.

AU - Jhamai, P. Mila

AU - Verbiest, Michael

AU - Suchiman, H. Eka D.

AU - Verkerk, Marijn

AU - van der Breggen, Ruud

AU - van Rooij, Jeroen

AU - Lakenberg, Nico

AU - Mei, Hailiang

AU - van Iterson, Maarten

AU - van Galen, Michiel

AU - Bot, Jan

AU - Zhernakova, Dasha V.

AU - Hof, Peter van ’t

AU - Deelen, Patrick

AU - Nooren, Irene

AU - Matthijs, Moed

AU - Vermaat, Martijn

AU - Luijk, René

AU - Bonder, Marc Jan

AU - van Dijk, Freerk

AU - Arindrarto, Wibowo

AU - Kielbasa, Szymon M.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - ADHD

KW - CAARS

KW - DNA methylation

KW - Epigenetic

KW - EWAS

KW - Meta-analysis

UR - http://www.scopus.com/inward/record.url?scp=85064245734&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2019.02.016

DO - 10.1016/j.biopsych.2019.02.016

M3 - Article

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

ER -