7 Advances in Schizophrenia
7 Advances in Schizophrenia
That schizophrenia has a considerable heritable component is well established. Offspring of one parent with schizophrenia have a 10% risk of developing the same illness, whereas identical twins have approximately a 50% concordance rate. Although this leaves room for environmental effects and gene/environment interactions, these epidemiologic data clearly suggest a strong heritable component to schizophrenia.
With rapidly evolving advances in genetic methodology and technology, it was hoped that the genetic architecture of many psychiatric disorders would be relatively quickly unraveled, which was expected to lead to new, etiology-based interventions. However, the more we have learned in psychogenomics, the more it has become clear that the complexity of psychiatric disorders does not lend them to quick and simple breakthroughs in this area.
Although yet to have much of an impact in the clinic, 2013 saw several advances in further understanding the genetic underpinnings of psychosis. A study published in February in the Lancet reported genetic overlap among 5 psychiatric disorders: autism spectrum disorder, ADHD, bipolar disorder, major depressive disorder, and schizophrenia. The work was conducted by investigators from the Cross-Disorder Group of the Psychiatric Genomics Consortium and is the largest genetic study of mental illness to date. Results of this genome-wide association study found that single-nucleotide polymorphisms in 2 genes involved in neuronal calcium balance -- CACNA1C and CACNB2 -- are involved in all 5 disorders. The findings suggest that voltage-gated calcium-channel signaling could be a potential therapeutic target in psychiatric illness.
The same group published a follow-up study in August in Nature Genetics, comparing genome-wide genotype data for thousands of people with 1 of the same 5 conditions vs data from control individuals, and calculating the extent of genetic overlap. As Medscape Medical News reported, researchers found that "the overlap in heritability attributable to common genetic variation is about 15% between schizophrenia and bipolar disorder, about 10% between bipolar disorder and depression, about 9% between schizophrenia and depression, and about 3% between schizophrenia and autism."
Finally, multiple genome-wide association studies identified risk loci for schizophrenia, supporting the need for larger studies of this type.
Although severe psychiatric disorders are probably polygenetic and heterogeneous in the sense that multiple different genetic defects can converge on the same psychopathologic expression, future progress will depend on identifying circuits and functions that these disparate genetic defect converge on. A recent study in Cell indicated that of 54 de novo genetic polymorphisms identified in patients with schizophrenia, 50 genes converged on frontal lobe circuits involved in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport.
Moreover, the authors validated a novel and promising method in that they mapped the responsible genes of the de novo mutations in schizophrenia patients onto transcriptome profiles of normal human brain tissues from age 13 weeks' gestation to adulthood. Results from this study raise the question, however, as to whether the hypothesized disruptions of fetal prefrontal cortical neurogenesis that seem to be critical to the pathophysiology of schizophrenia will be amenable to interventions.
Genomic Psychiatry
That schizophrenia has a considerable heritable component is well established. Offspring of one parent with schizophrenia have a 10% risk of developing the same illness, whereas identical twins have approximately a 50% concordance rate. Although this leaves room for environmental effects and gene/environment interactions, these epidemiologic data clearly suggest a strong heritable component to schizophrenia.
With rapidly evolving advances in genetic methodology and technology, it was hoped that the genetic architecture of many psychiatric disorders would be relatively quickly unraveled, which was expected to lead to new, etiology-based interventions. However, the more we have learned in psychogenomics, the more it has become clear that the complexity of psychiatric disorders does not lend them to quick and simple breakthroughs in this area.
Although yet to have much of an impact in the clinic, 2013 saw several advances in further understanding the genetic underpinnings of psychosis. A study published in February in the Lancet reported genetic overlap among 5 psychiatric disorders: autism spectrum disorder, ADHD, bipolar disorder, major depressive disorder, and schizophrenia. The work was conducted by investigators from the Cross-Disorder Group of the Psychiatric Genomics Consortium and is the largest genetic study of mental illness to date. Results of this genome-wide association study found that single-nucleotide polymorphisms in 2 genes involved in neuronal calcium balance -- CACNA1C and CACNB2 -- are involved in all 5 disorders. The findings suggest that voltage-gated calcium-channel signaling could be a potential therapeutic target in psychiatric illness.
The same group published a follow-up study in August in Nature Genetics, comparing genome-wide genotype data for thousands of people with 1 of the same 5 conditions vs data from control individuals, and calculating the extent of genetic overlap. As Medscape Medical News reported, researchers found that "the overlap in heritability attributable to common genetic variation is about 15% between schizophrenia and bipolar disorder, about 10% between bipolar disorder and depression, about 9% between schizophrenia and depression, and about 3% between schizophrenia and autism."
Finally, multiple genome-wide association studies identified risk loci for schizophrenia, supporting the need for larger studies of this type.
Although severe psychiatric disorders are probably polygenetic and heterogeneous in the sense that multiple different genetic defects can converge on the same psychopathologic expression, future progress will depend on identifying circuits and functions that these disparate genetic defect converge on. A recent study in Cell indicated that of 54 de novo genetic polymorphisms identified in patients with schizophrenia, 50 genes converged on frontal lobe circuits involved in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport.
Moreover, the authors validated a novel and promising method in that they mapped the responsible genes of the de novo mutations in schizophrenia patients onto transcriptome profiles of normal human brain tissues from age 13 weeks' gestation to adulthood. Results from this study raise the question, however, as to whether the hypothesized disruptions of fetal prefrontal cortical neurogenesis that seem to be critical to the pathophysiology of schizophrenia will be amenable to interventions.
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