RESEARCH: Druggable genome in attention deficit/hyperactivity disorder and its co-morbid conditions. New avenues for treatment (2019)

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POST SUMMARY
This post shares information from a 2019 scientific article which reports that current ADHD medications do not actually target the genes involved in ADHD, however there are some other medications being used for other (mostly autoimmune or malignant) conditions which do target the some of the genes found in ADHD. These findings will hopefully lead to more potential treatments for ADHD.

Here is an interesting new paper from Molecular Psychiatry on the genetics of ADHD + current medications. As executive dysfunction (EDf) is the defining feature of ADHD, advancements made in the treatment of this condition may hopefully lead to better treatments for people with EDf across diagnosises!

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.

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Tile plot of the association between druggable genes and ADHD (p 
LINK: Druggable genome in attention deficit/hyperactivity disorder and its co-morbid conditions. New avenues for treatment.
(Molecular Psychiatry, 2019)

Article Highlights:

About Specific Genes:

  • “PTPRF…. encodes a tyrosine phosphatase, a signalling molecule involved in a myriad of cellular processes, including cell adhesion, neuronal development and functioning [41, 42]. PTPRF has mainly been studied in the context of cancer. However, its involvement in hyperactivity [42] and axonal growth [43] has also been reported.” (p.9)
  • “Similarly, sarcosine has also been tested as a possible ADHD drug, although the preliminary analyses indicate that its effect may be limited to oppositional symptoms only [46].” (p.9)
  • “…the KCNH3 gene is also interacting with drugs that are FDA-approved or are in clinical trials. This gene encodes a voltage-dependent potassium channel, a selective inhibitor of which was recently described [47]. It is also a non-specific target of blood–brain barrier penetrating drug dalfampridine [48] used to relieve the symptoms of multiple sclerosis and related neurologic disorders [44, 49]. Knocking out KCNH3 in mice has been reported to enhance cognitive skills, including attention, further supporting a potential role of dalfampridine-like drugs in the treatment of ADHD [50].” (p.9)
  • “The aforementioned druggable genes also showed significant association with educational attainment, suggesting that drugs targeting them may have a possible impact on quality of life of ADHD patients.” (p.9)
  • “…LEPRE1 interacts with a number of compounds in clinical trials, such as nutraceutical ascorbate, succinic acid and L-proline. This gene encodes an enzyme needed for collagen synthesis and assembly, which has recently been proposed as a novel therapeutic vista for protection and regeneration of neurons [51].”

CITATION:

Hegvik, T., Waløen, K., Pandey, S.K. et al. Druggable genome in attention deficit/hyperactivity disorder and its co-morbid conditions. New avenues for treatment. Mol Psychiatry (2019) doi:10.1038/s41380-019-0540-z