Epigenetic profiling of ADHD symptoms trajectories: A prospective, methylome-wide study

abstract: ...Attention-deficit/hyperactivity disorder (ADHD) is a prevalent developmental disorder, associated with a range of long-term impairments. Variation in DNA methylation, an epigenetic mechanism, is implicated in both neurobiological functioning and psychiatric health. However, the potential role of DNA methylation in ADHD symptoms is currently unclear. In this study, we examined data from the Avon Longitudinal Study of Parents and Children (ALSPAC) specifically the subsample forming the Accessible Resource for Integrated Epigenomics Studies (ARIES) which includes (i) peripheral measures of DNA methylation (Illumina 450k) at birth (n=817, 49% male) and age 7 (n=892, 50% male) and (ii) trajectories of ADHD symptoms (7-15 yrs). We first employed a genome-wide analysis to test whether DNA methylation at birth associates with later ADHD trajectories; and then followed up at age 7 to investigate the stability of associations across early childhood. We found that DNA methylation at birth differentiated ADHD trajectories across multiple genomic locations, including probes annotated to SKI (involved in neural tube development), ZNF544 (previously implicated in ADHD), ST3GAL3 (linked to intellectual disability) and PEX2 (related to perixosomal processes). None of these probes maintained an association with ADHD trajectories at age 7. Findings lend novel insights into the epigenetic landscape of ADHD symptoms, highlighting the potential importance of DNA methylation variation in genes related to neurodevelopmental and peroxisomal processes, which play a key role in the maturation and stability of cortical circuits.

... to SKI (involved in neural tube development), ZNF544 (previously implicated in ADHD), ST3GAL3 (linked to intellectual disability) and PEX2 (related to perixosomal processes). None of these probes maintained an association with ADHD trajectories at age 7. Findings lend novel insights into the epigenetic landscape of ADHD symptoms, highlighting the potential importance of DNA methylation variation in genes related to neurodevelopmental and peroxisomal processes, which play a key role in the

...) ST3GAL3 (cg09989037; stdn = -0.172; p = 9.46*10-7; q = 0.048), a gene linked to mental retardation; 37 (iii) FBXW5 (cg13714586; stdn = 0.170; p = 1.30*10-6; q = 0.048), associated with interleukin-1B signalling; (iv) ELF3 (cg05653018; stdn = 0.169; p = 1.43*10-6; q = 0.048), involved in preimplantation development; and (v) ZNF544 (cg26263766; stdn = 0.173; p = 8.72*10-7; q = 0.048; Figure 2D ), implicated in transcriptional regulation and previously shown to associate with ADHD. 38 Absolute mean

... intellectual disability using linkage analysis, chromosome sorting and next-generation sequencing. 37 , 49 , 50 Furthermore, we identified two probes that are linked to ZNF544 and ZNF454 , respectively. Both genes belong to the same zinc finger family (C2H2-type) and are involved in gene transcription. Strikingly, ZNF544 - along with several other ZNF genes - was previously flagged up in GWAS analysis of ADHD. 38 Using data from 376 family trios and a composite quantitative phenotype of ADHD symptoms based on DSM-IV criteria, the authors of that study identified, among others, a SNP linked to ZNF544 . This marker is around 30,000 basepairs away from the CpG site identified in this study, which is associated with the same gene. Among the 13 probes identified at birth, none were still associated at age 7 years with ADHD trajectories after FDR-correction. A number of non-exclusive factors may drive this non-replication. First, a number of the 13 probes detected at birth may have been false positives

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Gene: ZNF544 - zinc finger protein 544 - (NCBI)

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