Genomics and Pharmacogenomics of Brain Disorders

Abstract

CNS disorders are the third major problem of health in developed countries, with approximately 10% of direct costs associated with a pharmacological treatment of doubtful cost-effectiveness. There is an alarming abuse of psychotropic drugs worldwide and only 20-30% of patients with CNS disorders appropriately respond to conventional drugs. The pathogenesis of most CNS disorders is the result of the interplay of genetic and epigenetic factors with environmental factors leading to post-transcriptional changes and proteomic and metabolomic dysfunctions. It is estimated that genetics accounts for 20% to 95% of variability in drug disposition and pharmacodynamics, and about 25-60% of the Western population is defective in genes responsible for drug metabolism. In the European population only 25% of subjects are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6, CYP2C19 and CYP2C9 genes. About 50% of adverse drug events in CNS disorders might be attributed to pharmacogenomic factors. The rationale for practical pharmacogenomics and personalized therapeutics based on individual genomic profiles implies the management of different types of genes and their products including (i) genes associated with the mechanism of action of psychotropic drugs (neurotransmitters, receptors, transporters), (ii) genes encoding enzymes responsible for drug metabolism (phase I, phase II reactions), (iii) disease-specific genes associated with a particular pathogenic cascade, and (iv) pleiotropic genes with multilocative effects in metabolomic networks. The incorporation of genomic medicine procedures and pharmacogenomics into clinical practice, together with educational programs for the correct use of medication, must help to optimize therapeutics in CNS disorders.

Epigenetics of Brain Disorders: The Paradigm of Alzheimer ’s Disease

“…As a complex polygenic/multifactorial disorder, in which hundreds of polymorphic variants of risk might be involved, AD fulfills the "golden rule" of complex disorders, according to which the larger the number of genetic defects distributed in the human genome, the earlier the onset of the disease and the poorer its therapeutic response to conventional treatments; and the smaller the number of pathogenic SNPs, the later the onset of the disease, and the better the therapeutic response to different pharmacological interventions [1,3,48,50,53]; however, conventional genomics do not explain in full AD pathogenesis in which epigenetics may help to understand some enigmatic events. DNA methylation, histone modifications and chromatin remodeling and non-coding RNA dysregulation may contribute to AD pathology, although evidence is still very limited [9,15,16,[54][55][56].…”

“…Among these susceptibility genes, the apolipoprotein E (APOE) gene (19q13.2)(AD2) is the most prevalent as a risk factor for AD, especially in those subjects harboring the APOE-4 allele, whereas carriers of the APOE-2 allele might be protected against dementia [1,3] APOE-related pathogenic mechanisms are also associated with brain aging and with the neuro pathological hallmarks of AD [1][2][3]34,35,[40][41][42][43][48][49][50]. mtDNA damage may also contribute to increase brain vulnerability and neuro degeneration [51,52]. …”

Pharmacogenomics of Antidepressants

“…The principal enzymes with polymorphic variants involved in phase I reactions are the Cytochrome P450 monooxygenases (CYP3A4/5/7, CYP2E1, CYP2D6, CYP2C19, CYP2C9, CYP2C8, CYP2B6, CYP2A6, CYP1B1, CYP1A1/2), and other enzymes such as epoxide hydrolase, esterases, NQO1 (NADPH-Quinone Oxidoreductase), DPD (Dihydropyrimidine Dehydrogenase), ADH (Alcohol Dehydrogenase), and ALDH (Aldehyde Dehydrogenase); and major enzymes involved in phase II reactions include UGTs (Uridine 5'-Triphosphate Glucuronosyl Transferases), TPMT (Thiopurine Methyltransferase), COMT (Catechol-O-Methyltransferase), HMT (Histamine Methyl-Transferase), STs (Sulfotransferases), GST-A (Glutathione S-Transferase A), GST-P, GST-T, GST-M, NAT1 (N-Acetyl Transferase 1), NAT2, and others. Among these enzymes, CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 are the most relevant in the pharmacogenetics of Central Nervous System (CNS) drugs in general, and antidepressants in particular [1,4,17,18]. Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4.…”

Pharmacogenetics of Neurodegenerative Disorders

“…A growing body of fresh knowledge on the pathogenesis of NDDs, together with data on neurogenomics and pharmacogenomics, is emerging in recent times. The incorporation of this new armamentarium of molecular pathology and genomic medicine to daily medical practice, together with educational programmes for the correct use of drugs, must help to: understand brain pathogenesis, establish an early diagnosis, and optimize therapeutics either as a preventive strategy or as a formal symptomatic treatment [12][13][14][15][16]. Table 1 (continued) Most NDDs share some common features: they are polygenic disorders in which genetic, epigenetic and environmental factors are involved; some of them follow a golden rule: the higher the number of genes affected, the earlier the onset of the disease, with a faster progression, and a poorer therapeutic response to conventional drugs; and the smaller the number of genes disturbed, the later the onset, with a slower progression and a more favourable therapeutic response to current treatments; multifactorial dysfunctions in several metabolomic networks lead to functional damage to specific brain circuits; accumulation of toxic proteins (i.e., conformational changes) in the nervous tissue is involved in many cases of NDDs; all of them are costly for society, deteriorating the quality of life of sufferers and increasing disability; and although NDDs do not have a curative treatment, in practice available therapeutics is susceptible to pharmacogenomic intervention [17][18][19].…”