Epigenome-wide association study of attention-deficit/hyperactivity disorder in adults

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that often persists into adulthood. There is growing evidence that epigenetic dysregulation participates in ADHD. Given that only a limited number of epigenome-wide association studies (EWASs) of ADHD have been conducted so far and they have mainly focused on pediatric and population-based samples, we performed an EWAS in a clinical sample of adults with ADHD. We report one CpG site and four regions differentially methylated between patients and controls, which are located in or near genes previously involved in autoimmune diseases, cancer or neuroticism. Our sensitivity analyses indicate that smoking status is not responsible for these results and that polygenic risk burden for ADHD does not greatly impact the signatures identified. Additionally, we show an overlap of our EWAS findings with genetic signatures previously described for ADHD and with epigenetic signatures for smoking behavior and maternal smoking. These findings support a role of DNA methylation in ADHD and emphasize the need for additional efforts in larger samples to clarify the role of epigenetic mechanisms on ADHD across the lifespan.

Association of Epigenetic Differences Screened in a Few Cases of Monozygotic Twins Discordant for Attention-Deficit Hyperactivity Disorder With Brain Structures

“…We suggested that SorCS2 methylation is involved in ADHD through methylation array analysis of MZ twin discordant cases and case-control groups, while previous epigenome-wide studies found no evidence that SorCS2 methylation is involved in either children or adults with ADHD ( van Dongen et al, 2019 ; Neumann et al, 2020 ; Rovira et al, 2020 ). Although SorCS2 is known to play a crucial role in neuronal viability and function ( Glerup et al, 2016 ), human epidemiological studies have reported that single nucleotide polymorphisms in SorCS2 are associated with the risk of developing psychiatric disorders such as ADHD ( Alemany et al, 2015 ), bipolar disorder ( Baum et al, 2008 ; Ollila et al, 2009 ), and schizophrenia ( Christoforou et al, 2011 ).…”

Comprehensive analysis of omics data identifies relevant gene networks for Attention-Deficit/Hyperactivity Disorder (ADHD)

“… Modules of co-expressed genes were identified from peripheral blood mononuclear cells (PBMCs) of processed transcriptomic data from 270 ADHD cases and 279 controls by using Weighted Gene Correlation Network Analysis (WGCNA). Then, we assessed the association of the resulting modules with the ADHD status and investigated their biologically relevance by (i) performing enrichment analyses in brain expression ( ABAenrichment R package), functional pathways, druggable genes and miRNA target genes using WebGestAlt webtool; (ii) integrating ADHD transcriptomic, genetic and epigenetic data from GWAS meta-analysis [ 3 ] and EWAS [ 7 ] on ADHD; and (iii) running a co-expression module eQTL analysis to identify loci regulating the ADHD-associated modules of co-expressed genes. …”

“…histone modifications, DNA methylation and microRNAs) are potential mechanisms by which environmental risk factors lead to changes on gene expression and long-lasting alterations in the neuronal circuits found in psychiatric disorders like ADHD [ 6 ]. Recently, the first epigenome-wide association study (EWAS) in peripheral blood mononuclear cells (PBMCs) from adults with ADHD was published, identifying four regions differentially methylated and located in genes previously related to autoimmune disorders, cancer, or neuroticism [ 7 ]. Additional EWAS in saliva and whole blood have been performed both in adults and children with ADHD diagnosis or ADHD symptoms, however, results among studies are not consistent and further studies with larger sample sizes are needed [ 8 – 12 ].…”

Epigenetics and ADHD: Reflections on Current Knowledge, Research Priorities and Translational Potential

“…In time, the increased availability and decreased cost of methylation arrays has led to a shift towards the use of hypothesis-free approaches (following in the footsteps of genetics), by allowing researchers to interrogate hundreds of thousands of DNAm sites across the genome in relation to ADHD. As shown in Table 1, most of these epigenome-wide association studies (EWASs) have been performed comparing peripheral DNAm patterns between ADHD cases versus controls (in children [54][55][56], adolescents [57], and adults [58]). While only one of these studies detected genome-wide significant differences in DNAm between groups [58] (likely due to limited power in available datasets), some promising targets have been identified, with the most notable example being VIPR2 methylation.…”

“…As shown in Table 1, most of these epigenome-wide association studies (EWASs) have been performed comparing peripheral DNAm patterns between ADHD cases versus controls (in children [54][55][56], adolescents [57], and adults [58]). While only one of these studies detected genome-wide significant differences in DNAm between groups [58] (likely due to limited power in available datasets), some promising targets have been identified, with the most notable example being VIPR2 methylation. VIPR2 encodes a receptor for vasoactive intestinal peptide, a small neuropeptide that is widely expressed in the CNS where it functions as both a neurotransmitter and neuroendocrine hormone, regulating several processes relevant for mood and behavior such as circadian rhythm [54].…”