Integrative genomic and epigenomic analysis of adhd

Attention deficit/hyperactivity disorder (ADHD) is a common and complex neurobehavioural disorder. It affects 5% of children and 2.5% of adults worldwide and its core symptoms are chronic and impairing inattention, impulsivity, and hyperactivity. Risk of ADHD is influenced by a combination of genetic variants (h2 70-80% with h2SNP = 0.14) and environmental risk factors. Both genetic variation and environment alter epigenetic landscape and DNA methylation (DNAm) plays a pivotal role in neurodevelopment and proper brain functioning. Therefore, in this study we investigated DNAm signatures of ADHD at the time of birth and specifically impact of common genetic ADHD risk variants on epigenetic landscape. We profiled DNAm levels at >850,000 loci in the human genome in 2,065 neonatal dried blood spots from the Danish iPSYCH 2012 cohort. Genotyping data from Illumina PsychChip was available for 2022 individuals. We applied 3 different methodologies to study epigenetic contributions to ADHD aetiology: 1) epigenome-wide association study (EWAS) of ADHD (854 cases, 688 controls) in iPSYCH and meta-EWASes with other cohorts to search for loci with differential DNAm; 2) EWAS of ADHD PRS (n = 2022) to identify DNAm changes associated with polygenic burden of ADHD; 3) methylation Quantiative Trait Loci (mQTL) analysis to determine if the credible genetic variants located in the 27 loci identified in the GWAS meta-analysis of ADHD impact epigenetic regulation of the genome. EWAS of ADHD and following analyses identified significant differentially methylated regions (DMRs), with Šidák-adjusted p-value < 0.05, in genes important to neuron development, neuron differentiation, synapse formation, as well as genes linked to hyperactivity and risk-taking behaviors. EWAS of ADHD PRS identified significant differential DNAm and several significant DMRs. The mQTLs analysis demonstrated that the credible genetic variants located in the 27 loci ADHD risk loci impact DNAm in genes important to neuronal development and brain formation. Additionally, genes where mQTL epigenetic changes were observed were significantly enriched in multiple mental disorders gene sets and pathways, with “Synapse organization” and “Axon guidance” identified as the most enriched Gene Ontology pathways. In this epigenetic study we combined epigenomic and genomic data to study molecular aetiology of ADHD at the time of birth. The results from 3 different approaches highlight the importance and advantage of combining genomic and epigenomic approaches in studying psychiatric phenotypes suggest that DNAm differences measured in early postnatal period are associated with ADHD diagnosis and that common genetic risk variants of the disorder impact epigenetic landscape in the genome what could modify risk of this neurodevelopmental disorder. This study highlights the importance and advantage of combining genomic and epigenomic approaches in studying psychiatric phenotypes to provide deeper understanding of their molecular pathophysiology.