Puzzling over schizophrenia: Schizophrenia, social environment and the brain


maturation13,14, this yields a testable hypothesis about a definable pathway that might mediate some component of risk. Finally, schizophrenia is highly polygenic. We now know that polygenicity is a cardinal feature of many human diseases and anthropometric traits characterized by complex inheritance of dozens to hundreds of loci (for example, Crohn’s disease, type 2 diabetes, height and body mass)15. The genetic variants involved are common with subtle effects, and some of these gene sets may have singular clinical utility. For schizophrenia, there is strong and replicated evidence that the number of loci is in the thousands8. Indeed, this polygenic component (that must include common variation rather than being a reflection of multiple rare variants) accounts for 23–33% of variance in liability to schizophrenia on the order of a third of the heritability8,16. This also suggests that so-called ‘missing heritability’ is merely hidden and imperfectly assessed by current genotyping technologies. A recent paper about nonsyndromic autism provided a tantalizing glimpse of how genetic variation might relate to altered biological pathways17. Typical patterns of gene expression in frontal and temporal cortex were attenuated in autism. An empirically derived gene expression module that was underexpressed in autism was enriched for known autism susceptibility genes and genetic association signals. Although not completely elucidated, these data support the notion that polygenetic variation for autism alters the expression and regulation of a transcriptional network that mediates risk for autism. A similar model could hold for schizophrenia. For schizophrenia, the hypothesis is that polygenetic variation alters a biological pathway. Removal of any single node through protein-killing mutation either may have no effect, owing to the emergent network property of robustness, or, for network hubs, may yield a phenotype other than schizophrenia, such as mental retardation or autism. There are many ways in which such a pathway could mediate liability to schizophrenia—by being insufficiently robust or overly rigid in response to environmental insult, for example, or by coding an inappropriate developmental program. The conceptualization of schizophrenia as a pathway disease has an immediate implication. A priority for the field18 must be to complete genomic screens of a sufficient number of cases to define the pathway components with precision (for instance, 50,000 cases and 50,000 controls would afford power19 similar to the GIANT height meta-analysis20). If this can be accomplished, it should be possible to develop assays to monitor pathway function in living cells. Knowledge derived from this work could lead to the fulfillment of the ultimate promise of genomics—primary prevention of the development of schizophrenia in those at risk and the development of more effective therapeutics in an era where big pharma has turned sharply away from psychiatric drug development. Critically, it is possible that any such pathway is intrinsically modifiable and that people with schizophrenia are not ‘doomed from the womb’ but rather could anticipate return to relatively normal long-term function.

DOI: 10.1038/nm.2671

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@article{Tost2012PuzzlingOS, title={Puzzling over schizophrenia: Schizophrenia, social environment and the brain}, author={Heike Tost and Andreas Meyer-Lindenberg}, journal={Nature Medicine}, year={2012}, volume={18}, pages={211-213} }