333 research outputs found
Dopaminergic hypersensitivity in migraine: clinical and genetic evidence
No full textMigraine is a common disorder characterized by recurrent pain attacks of mild-severe intensity associated with autonomic and occasionally neurological symptoms. The migraine attack is a complex process that involves both central and peripheral structures. Various pathogenetic hypotheses have been proposed but the pathophysiology of the disease is still unknown. The study of the pathophysiology of migraine includes the investigation of neurotransmitter systems and their potential role in the development of the attack. Several studies performed since the '60s have demonstrated the key role of serotonin. The theory whereby hypersensitivity of the dopaminergic system may be involved in the pathogenesis of migraine has been supported by various authors on the basis of clinical, pharmacological and recent genic evidence. Recent neurophysiological studies performed using new techniques have led to a correlation of migraine with central nervous system disorders characterized by an altered neuronal excitability. Migraine seems to be characterized by a low threshold of neuronal excitability which is in turn regulated by genetic factors involving the dopaminergic system. A genetically determined hypersensitivity of the dopaminergic system may be involved in the onset of the migraine attack
Adverse drug reactions: role of pharmacogenomics
No full textAdverse drug reactions (ADRs) are a significant cause of morbidity and mortality. The majority of ADRs can be considered common disorders with considerable clinical variability (clinical phenotype) in which many different genes are involved together with environmental variables. Pharmacogenomics is the study of how genes affect the individual response to drugs. There is some evidence that in the future the use of pharmacogenomics could help to reduce ADRs, as it aims to predict which patients are likely to respond to a particular drug and which patients are likely to have significant ADRs. In this article some examples of genetic polymorphisms affecting drug kinetics, drug toxicity and hypersensitivity related to ADRs are illustrated
Pharmacogenomics of mood stabilizers in the treatment of bipolar disorder
No full textBipolar disorder (BD) is a chronic and often severe psychiatric illness characterized by manic and depressive episodes. Among the most effective treatments, mood stabilizers represent the keystone in acute mania, depression, and maintenance treatment of BD. However, treatment response is a highly heterogeneous trait, thus emphasizing the need for a structured informational framework of phenotypic and genetic predictors. In this paper, we present the current state of pharmacogenomic research on long-term treatment in BD, specifically focusing on mood stabilizers. While the results provided so far support the key role of genetic factors in modulating the response phenotype, strong evidence for genetic predictors is still lacking. In order to facilitate implementation of pharmacogenomics into clinical settings (i.e., the creation of personalized therapy), further research efforts are needed
Investigation of genetic loci shared between bipolar disorder and risk-taking propensity: potential implications for pharmacological interventions
No full textPublished online: 25 May 2021Patients with bipolar disorder (BD) often show increased risk-taking propensity, which may contribute to poor clinical outcome. While these two phenotypes are genetically correlated, there is scarce knowledge on the shared genetic determinants. Using GWAS datasets on BD (41,917 BD cases and 371,549 controls) and risk-taking (n = 466,571), we dissected shared genetic determinants using conjunctional false discovery rate (conjFDR) and local genetic covariance analysis. We investigated specificity of identified targets using GWAS datasets on schizophrenia (SCZ) and attention-deficit hyperactivity disorder (ADHD). The putative functional role of identified targets was evaluated using different tools and GTEx v. 8. Target druggability was evaluated using DGIdb and enrichment for drug targets with genome for REPositioning drugs (GREP). Among 102 loci shared between BD and risk-taking, 87% showed the same direction of effect. Sixty-two were specifically shared between risk-taking propensity and BD, while the others were also shared between risk-taking propensity and either SCZ or ADHD. By leveraging pleiotropic enrichment, we reported 15 novel and specific loci associated with BD and 22 with risk-taking. Among cross-disorder genes, CACNA1C (a known target of calcium channel blockers) was significantly associated with risk-taking propensity and both BD and SCZ using conjFDR (p = 0.001 for both) as well as local genetic covariance analysis, and predicted to be differentially expressed in the cerebellar hemisphere in an eQTL-informed gene-based analysis (BD, Z = 7.48, p = 3.8E-14; risk-taking: Z = 4.66, p = 1.6E-06). We reported for the first time shared genetic determinants between BD and risk-taking propensity. Further investigation into calcium channel blockers or development of innovative ligands of calcium channels might form the basis for innovative pharmacotherapy in patients with BD with increased risk-taking propensity.Claudia Pisanu, Donatella Congiu, Giovanni Severino, Raffaella Ardau, Caterina Chillotti, Maria Del Zompo ... et al
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