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Genetic Studies of PTSD and Substance Use Disorders
Published in Anka A. Vujanovic, Sudie E. Back, Posttraumatic Stress and Substance Use Disorders, 2019
Christina M. Sheerin, Leslie A. Brick, Nicole R. Nugent, Ana B. Amstadter
Cannabis. Among developed nations, cannabis is the most commonly used illicit psychoactive substance, and a growing number of GWAS have been conducted using cannabis-related phenotypes (Degenhardt & Hall, 2012). The first GWAS of cannabis dependence (N = 3,054) found no significant SNPs at the genome-wide significance level, though two SNPs in the ANKFN1 gene (linked to tumorigenesis) approached genome-wide significance (Agrawal et al., 2011). More recently, three SNPs reached genome-wide significance and were successfully replicated in three independent cohorts (N = 6,000 African American; N = 8,754 European Americans) with DSM-IV cannabis dependence (Sherva et al., 2016). One SNP was a known antisense transcript located in RP11-206M11.7 and the others were located in SLC35G1 (a possible drug/metabolite transporter) and CSMD1 (may regulate the activation and inflammation of neurons). As with alcohol phenotypes, many studies have also failed to find significant effects and researchers have turned to alternate cannabis-related phenotypes. Studies examining cannabis use or initiation, factor scores of dependence items, and meta-analyses have failed to find individual SNP- or gene-based effects reaching genome-wide significance in samples ranging from ~3,000 to ~10,000 (Agrawal et al., 2014; Minica et al., 2015; Verweij et al., 2013); however, in a gene-based association test, Stringer et al. (2016) identified four genes that were significantly associated with lifetime cannabis use, including NCAM1, CADM2, SCOC, and KCNT2 (meta-analytic N = 32,330; replication N = 5,627).
Detection of altered methylation of MB-COMT promotor and DRD2 gene in cannabinoid or synthetic cannabinoid use disorder regarding gene variants and clinical parameters
Published in Journal of Addictive Diseases, 2021
Yasemin Oyaci, Hasan Mervan Aytac, Ozge Pasin, Pinar Cetinay Aydin, Sacide Pehlivan
Numerous researches have tried to identify specific genetic risk factors connected to CUD/SCUD. Although no individual single-nucleotide polymorphisms reached genome-wide significance, gene-based tests identified four genes significantly associated with lifetime cannabis use: CADM2, KCNT2, NCAM1, and SCOC.40 On the other hand, in research examining the COMT (rs4680), CNR2 (rs2501432), CNR2 (rs2229579), UCP2 (rs659366), and IL-17F (rs763780) gene variants in SCUD patients have been reported that the CNR2 (rs2229579) and UCP2 (rs659366) variants were associated with SCUD.33 Although previous studies on methylation have been performed mostly in the context of AUD, our recently published study reported that the global DNA methylation might be associated with the SCUD.41 Earlier researches have also shown that cannabinoids significantly alter histone methylation and acetylation. Prini et al. demonstrated that Δ9-THC alters histone modifications in the prefrontal cortex, essentially methylation of H3K9, and the expression of a subset of plasticity genes crucial for the improvement of adult cognitive deficits.42
Potassium channels as prominent targets and tools for the treatment of epilepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Multiple antiseizure drugs (ASDs) inhibit epileptic bursting, synchronization and seizure spread via modulation of voltage-gated ion channels (usually blockade of sodium or calcium channels) [147]. Potassium channels represent a promising target for the development of new ASDs, while activation of the K+ channels can be used for restoring control on neuronal excitability in patients with epilepsy. While opening of potassium channels effectively suppresses epileptiform activity in vitro [148–150], only one potassium channel opener, retigabine has been approved as an antiepileptic drug. Retigabine is a potent and selective opener of Kv7 channels approved for therapy of the drug-resistant focal and focal to bilateral tonic-clonic seizures [151]. Experiments on mice with severe and mild forms of genetic epilepsy have shown that the antiepileptic efficacy of retigabine and its side effects are strongly affected by genetic background [152]. Another selective potassium channel opener that acts on voltage-gated Kv7 channels and GIRK channels, flupirtine is effective against neonatal seizures [153]. However, the treatment with both retigabine and flupirtine is now limited due to intolerable side effects: tissue discoloration for retigabine and hepatotoxicity for flupirtine. However, because the adverse effects seem to be unrelated to the drug’s action on potassium channels, other Kv7 activators are currently under investigation, including selective openers of neuronal Kv7 channels: SCR2682, 1OP-2198/XEN1101, and XEN496 [154–156]. XEN496, a pediatric form of retigabine, is advancing into Phase 3 clinical trial in pediatric patients with Kv7.2 developmental and epileptic encephalopathy. XEN1101, a second-generation Kv7 channel opener, is more potent and target selective than retigabine and has good safety results in preclinical and Phase 1 clinical trials [155]. Quinidine, a partial antagonist of sodium-activated potassium KCNT1 channels, has been used to treat KCNT1-related epilepsy but clinical evidence for its efficacy is controversial [157–159], though successful use of quinidine for treatment of KCNT1- and KCNT2-related developmental and epileptic encephalopathies has been reported recently [102,160].