Association between DNA methylation and ADHD symptoms from birth to school age: A prospective meta-analysis

Abstract

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is not known. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school-age. We examined associations of DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age range 4-15 years) in 2477 children from five cohorts and DNA methylation at school-age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from ten cohorts. The regression estimates at nominal significance of the two EWAS (birth and school-age methylation) correlated (ρ=0.30) between both time points. At birth, we identified nine probes that were associated with later ADHD symptoms at genome-wide significance, including ERC2 and CREB5. Peripheral blood DNA methylation at one of these probes (cg01271805 located in the promotor region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another genome-wide significant probe (cg25520701) lies within the gene body of CREB5, which was associated with neurite outgrowth and an ADHD diagnosis in previous studies. In contrast, no probes reached genome-wide significance when ADHD was associated with school-age DNA methylation. In conclusion, DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

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

“…In this context, epigenetic processes have emerged as a plausible mechanism by which environmental exposures can lead to long-lasting alterations, such as variation in brain structure or neuronal circuits, found in psychiatric disorders [5][6][7] . There is growing evidence that epigenetic dysregulation is a feature of ADHD 6,[8][9][10][11] , depression 12 , autism [13][14][15][16] , schizophrenia 17,18 and bipolar disorder 19 .…”

“…Studies of DNA methylation profiles in ADHD have been conducted using peripheral blood, cord blood, buccal samples or saliva 6,[9][10][11][20][21][22][23][24][25][26][27][28] . Candidate gene studies have revealed differential methylation patterns in genes involved in the dopaminergic, serotoninergic and neurotrophic systems, including SLC6A4, DRD4, COMT, ANKK1, BDNF, or NGFR, associated with ADHD symptomatology and severity [23][24][25][26][27][28] .…”

“…Candidate gene studies have revealed differential methylation patterns in genes involved in the dopaminergic, serotoninergic and neurotrophic systems, including SLC6A4, DRD4, COMT, ANKK1, BDNF, or NGFR, associated with ADHD symptomatology and severity [23][24][25][26][27][28] . Seven epigenome-wide association studies (EWASs) on ADHD have been run to date, with sample sizes ranging from 54 subjects for clinical samples 21 to 4,689 individuals in a meta-analysis considering ADHD symptomatology in general population 9 , yielding nonoverlapping findings across them 6,[9][10][11][20][21][22] . There is limited research on adults using this approach, given that most of the EWASs have focused on pediatric samples 6,10,11,20,22 .…”

“…Seven epigenome-wide association studies (EWASs) on ADHD have been run to date, with sample sizes ranging from 54 subjects for clinical samples 21 to 4,689 individuals in a meta-analysis considering ADHD symptomatology in general population 9 , yielding nonoverlapping findings across them 6,[9][10][11][20][21][22] . There is limited research on adults using this approach, given that most of the EWASs have focused on pediatric samples 6,10,11,20,22 . To the best of our knowledge, only two studies evaluated methylome-wide patterns on adults 9,21 .…”

“…In a similar aged population cohort, Walton et al investigated ADHD symptom trajectories from birth to adolescence and pointed to epigenetic marks in genes related to neural tube development and peroxisomal mechanisms as candidates to be involved in the different ADHD symptom trajectories across time 6 . In the most recent EWAS evaluating ADHD symptoms in population-based cohorts, aberrant methylation patterns at birth in different regions, lying in the ERC2 and CREB5 genes among others, were associated with later ADHD symptoms in childhood or adolescence 11 . And finally, the latest and largest EWAS conducted in a clinical sample of children with ADHD supported the association between ADHD polygenic risk and DNA methylation patterns at the GART and SON genes 22 .…”