TY - JOUR
T1 - Genome-Wide DNA Methylation Patterns in Persistent Attention-Deficit/Hyperactivity Disorder and in Association With Impulsive and Callous Traits
AU - Meijer, Mandy
AU - Klein, Marieke
AU - Hannon, Eilis
AU - van der Meer, Dennis
AU - Hartman, Catharina
AU - Oosterlaan, Jaap
AU - Heslenfeld, Dirk
AU - Hoekstra, Pieter J.
AU - Buitelaar, Jan
AU - Mill, Jonathan
AU - Franke, Barbara
N1 - Funding Information:
This research was supported by an internal grant from the Donders Centre for Medical Neuroscience of Radboudumc. Support was also received from the Dutch National Science Agenda for the NWA NeurolabNL project (grant 400 17 602), and from the European Community's Horizon 2020 Programme (H2020/2014–2020) under grant agreement n° 728018 (Eat2beNICE). BF was also supported by a personal grant from the Netherlands Organization for Scientific Research (NWO) Vici Innovation Program (grant 016-130-669). The NeuroIMAGE project was supported by NIH Grant R01MH62873, NWO Large Investment Grant 1750102007010, and grants from Radboud University Medical Center, University Medical Center Groningen and Accare, and VU University Amsterdam. This work was also supported by grants from NWO Brain & Cognition (433-09-242 and 056-13-015) and from ZonMW (60-60600-97-193).
Publisher Copyright:
© Copyright © 2020 Meijer, Klein, Hannon, van der Meer, Hartman, Oosterlaan, Heslenfeld, Hoekstra, Buitelaar, Mill and Franke.
PY - 2020/1/31
Y1 - 2020/1/31
N2 - Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that often persists into adulthood. ADHD and related personality traits, such as impulsivity and callousness, are caused by genetic and environmental factors and their interplay. Epigenetic modifications of DNA, including methylation, are thought to mediate between such factors and behavior and may behave as biomarkers for disorders. Here, we set out to study DNA methylation in persistent ADHD and related traits. We performed epigenome-wide association studies (EWASs) on peripheral whole blood from participants in the NeuroIMAGE study (age range 12-23 years). We compared participants with persistent ADHD (n = 35) with healthy controls (n = 19) and with participants with remittent ADHD (n = 19). Additionally, we performed EWASs of impulsive and callous traits derived from the Conners Parent Rating Scale and the Callous-Unemotional Inventory, respectively, across all participants. For every EWAS, the linear regression model analyzed included covariates for age, sex, smoking scores, and surrogate variables reflecting blood cell type composition and genetic background. We observed no epigenome-wide significant differences in single CpG site methylation between participants with persistent ADHD and healthy controls or participants with remittent ADHD. However, epigenome-wide analysis of differentially methylated regions provided significant findings showing that hypermethylated regions in the APOB and LPAR5 genes were associated with ADHD persistence compared to ADHD remittance (p = 1.68 * 10(-24) and p = 9.06 * 10(-7), respectively); both genes are involved in cholesterol signaling. Both findings appeared to be linked to genetic variation in cis. We found neither significant epigenome-wide single CpG sites nor regions associated with impulsive and callous traits; the top-hits from these analyses were annotated to genes involved in neurotransmitter release and the regulation of the biological clock. No link to genetic variation was observed for these findings, which thus might reflect environmental influences. In conclusion, in this pilot study with a small sample size, we observed several DNA-methylation-disorder/trait associations of potential significance for ADHD and the related behavioral traits. Although we do not wish to draw conclusions before replication in larger, independent samples, cholesterol signaling and metabolism may be of relevance for the onset and/or persistence of ADHD.
AB - Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that often persists into adulthood. ADHD and related personality traits, such as impulsivity and callousness, are caused by genetic and environmental factors and their interplay. Epigenetic modifications of DNA, including methylation, are thought to mediate between such factors and behavior and may behave as biomarkers for disorders. Here, we set out to study DNA methylation in persistent ADHD and related traits. We performed epigenome-wide association studies (EWASs) on peripheral whole blood from participants in the NeuroIMAGE study (age range 12-23 years). We compared participants with persistent ADHD (n = 35) with healthy controls (n = 19) and with participants with remittent ADHD (n = 19). Additionally, we performed EWASs of impulsive and callous traits derived from the Conners Parent Rating Scale and the Callous-Unemotional Inventory, respectively, across all participants. For every EWAS, the linear regression model analyzed included covariates for age, sex, smoking scores, and surrogate variables reflecting blood cell type composition and genetic background. We observed no epigenome-wide significant differences in single CpG site methylation between participants with persistent ADHD and healthy controls or participants with remittent ADHD. However, epigenome-wide analysis of differentially methylated regions provided significant findings showing that hypermethylated regions in the APOB and LPAR5 genes were associated with ADHD persistence compared to ADHD remittance (p = 1.68 * 10(-24) and p = 9.06 * 10(-7), respectively); both genes are involved in cholesterol signaling. Both findings appeared to be linked to genetic variation in cis. We found neither significant epigenome-wide single CpG sites nor regions associated with impulsive and callous traits; the top-hits from these analyses were annotated to genes involved in neurotransmitter release and the regulation of the biological clock. No link to genetic variation was observed for these findings, which thus might reflect environmental influences. In conclusion, in this pilot study with a small sample size, we observed several DNA-methylation-disorder/trait associations of potential significance for ADHD and the related behavioral traits. Although we do not wish to draw conclusions before replication in larger, independent samples, cholesterol signaling and metabolism may be of relevance for the onset and/or persistence of ADHD.
KW - persistent attention-deficit
KW - hyperactivity disorder
KW - remittent attention-deficit
KW - callous traits
KW - impulsivity
KW - DNA methylation
KW - epigenome-wide association study
KW - DEFICIT HYPERACTIVITY DISORDER
KW - UNEMOTIONAL TRAITS
KW - RELIABILITY
KW - ADHD
KW - SCALE
KW - ADOLESCENTS
KW - AGGRESSION
KW - SYMPTOMS
KW - CHILDREN
KW - VALIDITY
U2 - 10.3389/fgene.2020.00016
DO - 10.3389/fgene.2020.00016
M3 - Article
C2 - 32082368
SN - 1664-8021
VL - 11
JO - Frontiers in Genetics
JF - Frontiers in Genetics
M1 - 16
ER -