Abstract
BackgroundA variety of DNA-based methods have been applied to identify genetic markers of attention deficit hyperactivity disorder (ADHD), but the connection to RNA-based gene expression has not been fully exploited.MethodsUsing well defined cohorts of discordant, monozygotic twins from the Michigan State University Twin Registry, and case-controlled ADHD cases in adolescents, the present studies utilized advanced single molecule RNA sequencing to identify expressed changes in whole blood RNA in ADHD. Multiple analytical strategies were employed to narrow differentially expressed RNA targets to a small set of potential biomarkers of ADHD.ResultsRNA markers common to both the discordant twin study and case-controlled subjects further narrowed the putative targets, some of which had been previously associated with ADHD at the DNA level. The potential role of several differentially expressed genes, including ABCB5, RGS2, GAK, GIT1 and 3 members of the galactose metabolism pathway (GALE, GALT, GALK1) are substantiated by prior associations to ADHD and by established mechanistic connections to molecular pathways relevant to ADHD and behavioral control.ConclusionsThe convergence of DNA, RNA, and metabolic data suggests these may be promising targets for diagnostics and therapeutics in ADHD.
Highlights
A variety of DNA-based methods have been applied to identify genetic markers of attention deficit hyperactivity disorder (ADHD), but the connection to RNA-based gene expression has not been fully exploited
Several lines of evidence, including the utility of drugs such as methyphenidate, amphetamines, and atomoxetine has suggested that deficits in the dopaminergic and adrenergic systems could underlie the neurochemical basis of ADHD [6]
The results provide a deep and broad map of RNA changes potentially related to ADHD, and can be combined with other ‘omic data, such as genome-wide association studies (GWAS), DNA methylation, and proteomic analysis to help identify new biomarkers, and secondarily, new clues to biological processes related to ADHD
Summary
A variety of DNA-based methods have been applied to identify genetic markers of attention deficit hyperactivity disorder (ADHD), but the connection to RNA-based gene expression has not been fully exploited. Attention deficit hyperactivity disorder (ADHD) is the most common psychiatric disorder in childhood and adolescence, affecting roughly 5% of youth worldwide [1]. One theory holds that ADHD involves changes in the glutaminergic neurotransmitter systems, a major excitatory pathway in the brain, McCaffrey et al BMC Med Genomics (2020) 13:160 genome-wide SNP analysis has so far failed to identify glutamate receptor DNA variants as a significant association with ADHD [5]. While a major focus has been on neurodevelopmental pathways, there are reasons to be cognizant of potentially important changes in non-neural endocrine systems. The strong linkage of ADHD with male gender has raised potential connections to steroid hormones, but it is difficult to exclude sex-linked genetic elements, and/or cultural perceptions related to the diagnosis of ADHD [7]
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