15 May 2012

542 Genes Collectively Predict Schizophrenia

A new, wide-ranging effort has uncovered a set of DNA signatures that are shared by people with the disease consistently enough that the set can be used to reliably predict whether someone has the disease. . . . By analyzing a battery of 542 genetic variants, researchers could predict who had schizophrenia in a group of European Americans and African Americans. The confirmation of the result in people of varying ancestry suggests that the set of genes truly does detect the core features of the disorder, scientists report online May 15 in Molecular Psychiatry.
From here, citing M. Ayalew et al. Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Molecular Psychiatry. doi: 10.1038/mp.2012.37.

This battery of genetic variants was compiled based on meta-analysis of a nearly comprehensive set of human and animal studies already in existence.

The list is surely not complete, and it probably has some false positives, since anytime you add that many degrees of freedom to a model, you will pick up some chance associations between otherwise unclassified cases.  The study also doesn't squarely address models that assign a significant share of genetic causation in schizophrenia to non-specific accumulated volumes of mutations in relevant parts of the genome and to first generation mutations.


But, simply providing an order of magnitude estimate of how many genes go into this polygenetic trait has value, and this kind of objective genetic predictor of psychosis could be particular useful in contexts such as insanity defenses where the biases of the psychiatric experts and the defendant cloud the usefulness of more subjective measurements.  This tool also opens the door to genotype based cluster analysis to subtype cases, which could be used to refine non-genetic diagnostic criteria and to personalize the process of prescribing medicines to treat schizophrenia which otherwise have a very large trial and error component.

Also, while biomarker tests are starting to emerge to confirm a schizophrenia diagnosis shortly before clinically definitive symptoms appear, a genotype test could be administered much earlier in individuals with a family history of psychosis - alleviating fears about the future for children in high risk families, while allowing for early treatment for children at high risk.  An ability to know whether or not you are likely to develop a psychosis in your late teens or early twenties would have a practical value to  

Another opportunity that genotyping on this model presents is the opportunity to identify individuals who have a schizophrenia genotype but are non-symptomatic, with an eye towards determining which, if any, environmental factors are part of a gene x environment interaction that gives rise to the syndrome (i.e. cluster of similar symptoms) that we called schizophrenia.

Finally, there is an emerging consensus that a significant share of the hereditary risk associated with developing schizophrenia is really a shared genetic risk of developing schizophrenia and/or bipolar disorder.  One suspects, therefore, that the battery of genes necessary to develop a genotype test for bipolar may have a similar number of genes and that the genese in the two genotype diagnostic batteries may significantly overlap.  For example, there might be about 270 schizophrenia specific genes, about 270 schizophrenia and bipolar genes, and 260 bipolar genes, for a total of perhaps 800 genes for psychosis generally. 

Examining the functional differences between the shared risk factors and the condition specific risk factors might help researchers to better understand the neuroscientific basis of both conditions and how the brain works more generally even in normal as opposed to abnormal psychology.  It is entirely likely that we will discover entire new systems that are out of whack in these conditions that we previously hadn't been aware existed in the brain.  And, every new system within the larger organ of the brain that we discover provides a new potential target for new classes of drugs.  This has recently happened in the efforts to find genotypes for anxiety disorders.

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