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Genomics and pharmacogenomics of schizophrenia.

ABSTRACT: Schizophrenia (SCZ) is among the most disabling of mental disorders. Several neurobiological hypotheses have been postulated as responsible for SCZ pathogenesis: polygenic/multifactorial genomic defects, intrauterine and perinatal environment-genome interactions, neurodevelopmental defects, dopaminergic, cholinergic, serotonergic, gamma-aminobutiric acid (GABAergic), neuropeptidergic and glutamatergic/N-Methyl-D-Aspartate (NMDA) dysfunctions, seasonal infection, neuroimmune dysfunction, and epigenetic dysregulation. SCZ has a heritability estimated at 60-90%. Genetic studies in SCZ have revealed the presence of chromosome anomalies, copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single nucleotide polymorphisms (SNPs) in microRNA genes, mitochondrial DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the positive and adverse effects of drug treatment. 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. About 10-20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6+CYP2C19+CYP2C9 genes. The pharmacogenomic response of SCZ patients to conventional psychotropic drugs also depends on genetic variants associated with SCZ-related genes. Consequently, the incorporation of pharmacogenomic procedures both to drugs in development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system (CNS) disorders.

SUBMITTER: Cacabelos R

PROVIDER: S-EPMC6493868 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Genomics and pharmacogenomics of schizophrenia.

Cacabelos Ramón R Martínez-Bouza Rocío R

CNS neuroscience & therapeutics 20100816 5

Schizophrenia (SCZ) is among the most disabling of mental disorders. Several neurobiological hypotheses have been postulated as responsible for SCZ pathogenesis: polygenic/multifactorial genomic defects, intrauterine and perinatal environment-genome interactions, neurodevelopmental defects, dopaminergic, cholinergic, serotonergic, gamma-aminobutiric acid (GABAergic), neuropeptidergic and glutamatergic/N-Methyl-D-Aspartate (NMDA) dysfunctions, seasonal infection, neuroimmune dysfunction, and epig ...[more]

PMID: 20718829

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Project description:Dementia is a major problem of health in developed countries, and a prototypical paradigm of chronic disability, high cost, and social-family burden. Approximately, 10-20% of direct costs in this kind of neuropathology are related to pharmacological treatment, with a moderate responder rate below 30% and questionable cost-effectiveness. Over 200 different genes have been associated with the pathogenesis of dementia. Studies on structural and functional genomics, transcriptomics, proteomics and metabolomics have revealed the paramount importance of these novel technologies for the understanding of pathogenic cascades and the prediction of therapeutic outcomes in dementia. About 10-30% of Western populations are defective in genes of the CYP superfamily. The most frequent CYP2D6 variants in the Iberian peninsula are the *1/*1 (57.84%), *1/*4 (22.78%), *1×N/*1 (6.10%), *4/*4 (2.56%), and *1/*3 (2.01%) genotypes, accounting for more than 80% of the population. The frequency of extensive (EMs), intermediate (IMs), poor (PMs), and ultra-rapid metabolizers (UMs) is about 59.51%, 29,78%, 4.46%, and 6.23%, respectively, in the general population, and 57.76, 31.05%, 5.27%, and 5.90%, respectively, in AD cases. The construction of a genetic map integrating the most prevalent CYP2D6+CYP2C19+CYP2C9 polymorphic variants in a trigenic cluster yields 82 different haplotype-like profiles, with *1*1-*1*1-*1*1 (25.70%), *1*1-*1*2-*1*2 (10.66%), *1*1-*1*1-*1*1 (10.45%), *1*4-*1*1-*1*1 (8.09%), *1*4-*1*2-*1*1 (4.91%), *1*4-*1*1-*1*2 (4.65%), and *1*1-*1*3-*1*3 (4.33%), as the most frequent genotypes. Only 26.51% of AD patients show a pure 3EM phenotype, 15.29% are 2EM1IM, 2.04% are pure 3IM, 0% are pure 3PM, and 0% are 1UM2PM. EMs and IMs are the best responders, and PMs and UMs are the worst responders to a combination therapy with cholinesterase inhibitors, neuroprotectants, and vasoactive substances. The pharmacogenetic response in AD appears to be dependent upon the networking activity of genes involved in drug metabolism and genes involved in AD pathogenesis (e.g., APOE). AD patients harboring the APOE-4/4 genotypes are the worst responders to conventional antidementia drugs. To achieve a mature discipline of pharmacogenomics in CNS disorders and dementia it would be convenient to accelerate the following processes: (i) to educate physicians and the public on the use of genetic/genomic screening in daily clinical practice; (ii) to standardize genetic testing for major categories of drugs; (iii) to validate pharmacogenomic information according to drug category and pathology; (iv) to regulate ethical, social, and economic issues; and (v) to incorporate pharmacogenomic procedures both to drugs in development and drugs on the market in order to optimize therapeutics.

Project description:The authors sought to examine the impact of multiple risk alleles for cognitive dysfunction and cardiovascular disease risk on cognitive function and to determine if these relationships varied by cognitive reserve (CR) or concomitant medication use in patients with schizophrenia. They conducted a cross-sectional study in ambulatory mental health centers. A total of 122 adults with a schizophrenia spectrum diagnosis who were maintained on a stable antipsychotic regimen for at least 6 months before study enrollment were included. Patients were divided into three CR groups based on years of formal education: no high school completion or equivalent (low-education group [18 patients]), completion of high school or equivalent (moderate-education group [36 patients], or any degree of post-high school education (high-education group [68 patients]). The following pharmacogenomic variants were genotyped for each patient: AGT M268T (rs699), ACE insertion/deletion (or ACE I/D, rs1799752), and APOE ε2, ε3, and ε4 (rs429358 and rs7412). Risk allele carrier status (identified per gene as AGT M268 T carriers, ACE D carriers, and APOE ε4 carriers) was not significantly different among CR groups. The Brief Assessment of Cognition in Schizophrenia (BACS) scale was used to assess cognitive function. The mean ± SD patient age was 43.9 ± 11.6 years. Cardiovascular risk factors such as hypertension and hyperlipidemia diagnoses, and use of antihypertensive and lipid-lowering agents, did not significantly differ among CR groups. Mixed modeling revealed that risk allele carrier status was significantly associated with lower verbal memory scores for ACE D and APOE ε4 carriers, but AGT T carrier status was significantly associated with higher verbal memory scores (p=0.0188, p=0.0055, and p=0.0058, respectively). These results were only significant in the low-education group. In addition, medication-gene interactions were not significant predictors of BACS scores. ACE D and APOE ε4 carrier status, independent of medication use, was associated with lower verbal memory scores in patients with schizophrenia who had relatively lower CR, as identified by formal education. These results suggest that increasing CR may be protective against cognitive impairment that may be worsened by select cardiovascular risk alleles in patients with schizophrenia.

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Genomics and pharmacogenomics of schizophrenia.

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Genomics and pharmacogenomics of schizophrenia.

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