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The genomics of schizophrenia: update and implications.

ABSTRACT: Schizophrenia is strongly familial yet rarely (if ever) exhibits classical Mendelian inheritance patterns. The advent of large-scale genotyping and sequencing projects has yielded large data sets with higher statistical power in an effort to uncover new associations with schizophrenia. Here, we review the challenges in dissecting the genetics of schizophrenia and provide an update of the current understanding of the underlying genomics. We discuss the breadth of susceptibility alleles, including those that may occur with low frequency and high disease risk, such as the 22q11.2 hemideletion, as well as alleles that may occur with greater frequency but convey a lower risk of schizophrenia, such as variants in genes encoding subunits of the voltage-gated L-type calcium channel. Finally, we provide an overview of the clinical implications for the diagnosis and treatment of schizophrenia based on progress in understanding the underlying genetic basis.

SUBMITTER: Giusti-Rodriguez P

PROVIDER: S-EPMC3809776 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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The genomics of schizophrenia: update and implications.

Giusti-Rodríguez Paola P Sullivan Patrick F PF

The Journal of clinical investigation 20131101 11

Schizophrenia is strongly familial yet rarely (if ever) exhibits classical Mendelian inheritance patterns. The advent of large-scale genotyping and sequencing projects has yielded large data sets with higher statistical power in an effort to uncover new associations with schizophrenia. Here, we review the challenges in dissecting the genetics of schizophrenia and provide an update of the current understanding of the underlying genomics. We discuss the breadth of susceptibility alleles, including ...[more]

PMID: 24177465

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Project description: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.

Dataset Information

The genomics of schizophrenia: update and implications.

Publications

The genomics of schizophrenia: update and implications.

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