Incomplete concordancewhat does that really mean even

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Unformatted text preview: ference in percentage from that which would be expected in the general population, challenging the Causes: III. Incomplete concordancewhat does that really mean? Even with monozygotic twins concordance rate is a only about 50%.! ! Being a relative does not capture half of the ! ! genetic? ! or environmental? ! or both? ! ! mechanisms at work.! ! Prevalence stable across cultures and continents…! ! Prominent susceptibility genes as indicated by reliable neuronal markers of schizophrenia I. Cortical GABAergic interneurons Chandelier cells and number of GABAergic contacts reliably decreased by 40% in PFC of schizophrenics; Woo et al., PNAS 1998, 95:5341-6) Prominent susceptibility genes as indicated by reliable neuronal markers of schizophrenia II. Calcium channels. III. Metabotropic glutamate receptors Emerging Genetic Evidence on Complex Brain Disorders Converges on Specific Molecular Complexes ! (A) Multiple subunits of voltage-gated calcium channels are among the genome’s strongest associations to schizophrenia and bipolar disorder. ! (B) Genes encoding the postsynaptic components of excitatory synapses are implicated by both rare and common variants in schizophrenia. !18 Susceptibility genes impair synaptic functions and plasticity Harrison and Weinberger, Molecular Psychiatry 2005, 10:40-68 Causes: genetic vs nongenetic? • Concordance rate for identical twins: 48% • Fraternal (dizygotic) twins: 17% • Multiple (even thousands) susceptibility genes. • Incidence rate: stable across continents, cultures, socioeconomic conditions. • Efforts to identify viral and other obvious causes were not or not reliably substantiated by massive longitudinal studies. • BUT: Obstetric complications, maternal infections etc.: early insults that can affect brain development, or interactions with genetic vulnerabilities? • Concordance rate: truly reflecting environmental variables or hitherto unknown genomic mechanisms for bestowing genetic vulnerability? (such as epigenetic, copy number variations, micod...
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