Abstract
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with only symptomatic care available. Genome-wide association (GWA) studies can provide a starting point in the search for novel drug targets and possibilities of drug repurposing. Here, we explored the druggable genome in ADHD by utilising GWA studies on ADHD and its co-morbid conditions. First, we explored whether the genes targeted by current ADHD drugs show association with the disorder and/or its co-morbidities. Second, we aimed to identify genes and pathways involved in the biological processes underlying ADHD that can be targeted by pharmacological agents. These ADHD-associated druggable genes and pathways were also examined in co-morbidities of ADHD, as commonalities in their aetiology and management may lead to novel pharmacological insights. Strikingly, none of the genes encoding targets of first-line pharmacotherapeutics for ADHD were significantly associated with the disorder, suggesting that FDA-approved ADHD drugs may act through different mechanisms than those underlying ADHD. In the examined druggable genome, three loci on chromosomes 1, 4 and 12 revealed significant association with ADHD and contained nine druggable genes, five of which encode established drug targets for malignancies, autoimmune and neurodevelopmental disorders. To conclude, we present a framework to assess the druggable genome in a disorder, exemplified by ADHD. We highlight signal transduction and cell adhesion as potential novel avenues for ADHD treatment. Our findings add to knowledge on known ADHD drugs and present the exploration of druggable genome associated with ADHD, which may offer interventions at the aetiological level of the disorder.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorised users.1 K.G
We explored the druggable genome in Attention-Deficit/Hyperactivity Disorder (ADHD) by utilising the summary statistics from Genome-wide association (GWA) studies on ADHD and its major co-morbid conditions
In ADHD, we examined 3826 genes and 2759 gene sets in the druggable genome (2560 Gene Ontology (GO), 198 Kyoto encyclopaedia of genes and genomes (KEGG) and one set of genes targeted by Food and Drug Administration (FDA)-approved ADHD drugs), bringing the Bonferroni-corrected significance threshold to p = 7.59E−06
Summary
1 K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway. Attention deficit/hyperactivity disorder (ADHD) is a common and highly heritable childhood-onset neurodevelopmental disorder that often persists into adulthood [1, 2]. The prevalence of the disorder in children is 6.5%, while in adults the estimates vary between 2.5 and 3.4% [3]. No treatments cure ADHD, available therapies offer symptomatic relief. Current management of ADHD is based on either nonpharmacologic or pharmacologic treatments as well as the combination of the two. The non-pharmacologic treatments usually involve psychological and/or behavioural therapies, while the pharmacologic interventions include stimulant and/or non-stimulant drugs [1, 8]. For ADHD treatment, the U.S Food and Drug Administration (FDA) has approved the stimulants methylphenidate (MPH) and amphetamine
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