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

BIOS Consortium, 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, Dorret I Boomsma, N. Rodrigues Zilhao Nogueira

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.

LanguageEnglish
JournalBiological Psychiatry
DOIs
Publication statusE-pub ahead of print - 1 Mar 2019

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Attention Deficit Disorder with Hyperactivity
Methylation
DNA Methylation
Netherlands
Meta-Analysis
Twin Studies
Major Histocompatibility Complex
Longitudinal Studies
Quantitative Trait Loci
Epigenomics
Sample Size
Psychiatry
Comorbidity
Schizophrenia
Gene Expression
Health
Brain
Research
Population

Bibliographical note

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

Cite this

@article{fa0de079965c4167bfb45a752313aa1e,
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.",
author = "{BIOS Consortium} and {van Dongen}, Jenny and Zilh{\~a}o, {Nuno R} and Karen Sugden and Hannon, {Eilis J} and Jonathan Mill and Avshalom Caspi and Jessica Agnew-Blais and Louise Arseneault and Corcoran, {David L} and Moffitt, {Terrie E} and Richie Poulton and Barbara Franke and Boomsma, {Dorret I} and {Rodrigues Zilhao Nogueira}, N.",
note = "Copyright {\circledC} 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = "3",
day = "1",
doi = "10.1016/j.biopsych.2019.02.016",
language = "English",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",

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Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults. / BIOS Consortium; Rodrigues Zilhao Nogueira, N.

In: Biological Psychiatry, 01.03.2019.

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 - Hannon, Eilis J

AU - Mill, Jonathan

AU - Caspi, Avshalom

AU - Agnew-Blais, Jessica

AU - Arseneault, Louise

AU - Corcoran, David L

AU - Moffitt, Terrie E

AU - Poulton, Richie

AU - Franke, Barbara

AU - Boomsma, Dorret I

AU - Rodrigues Zilhao Nogueira, N.

N1 - Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PY - 2019/3/1

Y1 - 2019/3/1

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.

U2 - 10.1016/j.biopsych.2019.02.016

DO - 10.1016/j.biopsych.2019.02.016

M3 - Article

JO - Biological Psychiatry

T2 - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

ER -