Thursday, May 15, 2008

No genes for schizophrenia--What gives?

Ten years ago, most of us paying attention were exhilarated about the prospects for psychiatric genetics. Heritability is high for many disorders--80% of the variation in vulnerability to bipolar disorder and schizophrenia can be attributed to genetic variations. We thought we would soon find the responsible abnormal genes, and this would quickly reveal the biochemical defects that cause these disorders, and this would quickly lead to ways to cure, or at least dramatically alleviate, these terrible scourges.

Candidate genes were examined by the best researchers using larger and larger samples and sophisticated statistics; a few were identified as prime suspects. Most results could not be replicated, but a few loci were very suspicious based on multiple studies.

Now, in an article by in this month's American Journal of Psychiatry, Saunderset al. report on 433 SNPs associated with 14 candidate genes that were prime suspects for schizophrenia in about 1900 cases and 2000 controls of European ancestry. The results? Not one of the genes was significantly associated with schizophrenia prevalence.
Even a 25% increase would have been detected with high probability.

An editorial by Steven Hamilton doi: http://dx.doi.org/10.1176/appi.ajp.2008.08020218 tries to put the best possible face on the results by noting that studies of tens of thousands of subjects were required to find genes that contribute to real but small (<25%) increases in risk for Type II diabetes. But that is not the point. Sanders, et al. deserve commendation for stating their conclusion clearly:
Our results suggest that, taken together, common DNA variants in these 14 genes are unlikely to explain a large proportion of the genetic risk for schizophrenia in populations of European ancestry. More robust findings are likely to be discovered using genome-wide association methods and, as our knowledge of the biology of mental illness continues to improve, focused studies of genes based on more precise mechanistic hypotheses. Nevertheless, although larger samples could possibly detect small genetic effects that were missed in this experiment, our findings suggest it is unlikely that true associations exist at the population level for the alleles that have formed the basis for the large candidate gene literature for these 14 postulated schizophrenia candidate genes.

Now what? Should we just do larger and larger studies with fancier and fancier bioinformatics? We have been looking for abnormal genes--mutations that cause diseases. But what if that is not the right model? That presumes that there is a normal genome and if all is in order all works fine, but when a part breaks, disease results.

A clue comes from Craig Ventner's genome. The human genome project provided sequences for haploid genomes. But the chromosomes from both Ventner's father and mother have now been sequenced. The results are a big surprise. Variation between human individuals is five times higher than we thought: 0.5% instead of 0.1%. Much of the difference is in the number of copies of a gene, and their locations. DOI: 10.1126/science.317.5843.1311

Copy number variations look likely to explain a lot. They are invisible to genetic testing that just looks for the presence of certain sequences. But they are important. Especially for mental disorders.

In this week's Science,Walsh, et al. report big differences in CNVs in people with schizophrenia: "Novel deletionsand duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases" DOI: 10.1126/science.1155174 In previous work they have found similar differences in autism.

This may well explain why we have not been able to find the genes for schizophrenia--schizophrenics don't have different genes from other people, just different numbers of certain genes. This also fits with paternal age effects on schizophrenia -- the risk of schizophrenia increases as the father's --but not the mother's--age increases. (Male gamtes keep dividing throughout out life, increasing the risk of errors, while the eggs of females are all formed by birth)

So, myriads of different genetic variations may contribute to schizophrenia, many involving micro insertions and deletions. This tells us where to look.

A big piece of the puzzle remains missing, however. Why can so many different genetic variations all cause schizophrenia? Part of the answer is heterogeneity of the phenotypes--we should talk about the schizophrenias, in the plural. Nonetheless, it is remarkably that the brain fails so often in the same general ways. Why are bipolar disorder and schizophrenia so common compared to any number of other disorders, and the myriads of disorders that could exist but don't? The answer will come, I think, when we quit thinking of the body as a machine designed by engineers in which problems are caused by broken single parts. Bodies are fundamentally different from machines. Genes that make traits that on average tend to Darwinian fitness become more common. They form networks and modules, but in ways that often do not correspond to anything a sensible engineer would do. They create robust networks that are resistant to damage, until, that is, some slight variation wrecks the whole system. This may be why certain cognitive system are so vulnerable.

My best guess is that a cliff-edge effect is involved. Some trait has given such a large advantage that it has been pushed rapidly by selection to a value that is close to a cliff-edge, where the system is prone to fail catastrophically. Levels of uric acid in humans are a good example. Uric acid levels have increased in humans relative to other primates, probably because the antioxidant effects of uric acid are selected for in a a species with a long life span, despite the risk of gout. The strong correlation between uric acid levels and life span in primates is supportive evidence. For schizophrenia, Crespi summarize relevant evidence for signals of positive selection on candidate genes.

There are many other ideas out there. Bernie Crespi's work on the possibility that autism and schizophrenia are flip sides of conditions resulting from imprinted genes that advance maternal and paternal genetic interests is particularly intriguing.

We are getting there. But it is increasingly clear that it is a serious mitake to think of the brain as a machine with parts that break. The brain is, instead, an organ in an evolved soma whose information code is nothing like anything a any human programmer would write. It is not irreducibly complex, but it may well be incomprehensibly complex at the molecular level. Deeper evolutionary thinking about genomics may prove essential to understanding schizophrenia and autism.


4 comments:

jill wrenbeck said...

My son & I are in the PRechter longitudinal study @ UofM for bipolar research. I've given up ok getting good help for myself but I'm hoping studying our genetics now will help my children with BP in the future. Am I wasting my time? What should my focus be ? How can I learn more about what you are doing since I believe that is the way for me to go? Please help (you've already helped me immensely)but now I don't know how to look forward using your methods.

Eric Brown said...

While this whole post is interesting to me (I am a psychiatrist also), the last paragraph is conceptually rich. The idea that the body is not to be understood as having all the entailments of the "machine" metaphor is very important. Metaphors both facilitate and constrict productive thinking (an idea brilliantly examined by Lakoff and Johnson in Philosophy in the Flesh), and one of the entailments of the machine metaphor (another useful and flawed concept from Descartes) is that causation in the body can be understood linearly. Ken Kendler (another psychiatrist and, appropriately, a geneticist) has criticized this idea as well, and advocates an understanding of causality in the body as being nonlinear and containing multiple feedback loops, for example. The second concept that strikes me hard is the notion that the body "is not irreducibly complex, but it may well be incomprehensibly complex at the molecular level." This is another point I like to emphasize to my residents, that there are different levels of analysis, some of which may be more epistemologically sound and helpful in understanding mental illness than others. This is an anti-reductionism argument, but not because materialism isn't in some way true, because we are made of molecules after all. Rather it says that a molecular approach may be too inefficient to build our understanding on, especially a clinical understanding of our patients. This is one of the appeals for me of evolutionary psychiatry, is that it provides a more relevant and satisfying conceptual understanding of behavior, and one that I try to convince psyciatrists-in-training can be at least just as helpful as the molecular neuroscience that is so strongly emphasized in their training right now.

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Well I think technology is developing so fast, that in the very near future we will be able to decipher and predict new generation's possible diseases. Thank God.

Joseph B said...

Great post. I'm a fan of your work and was quite happy to come across this blog. The heterogeneity of schizophrenia seems particularly crucial here. Bleuler seemed to understand this exceedingly well. This is evident not only in the title of his great work, but also in the text when he refers to dementia praecox "not as species of disease but as a genus" (p. 279, Bleuler, 1950). On the following page Bleuler goes on to say that, "the subdivision of the group of schizophrenias is a task for the future," and I cannot help but feel an acute sadness that 100 years of research has brought us no closer to the fulfillment of that task. The genetic studies of schizophrenia are perhaps the most salient (but by no means the only) example of just how important it is to examine our own preconceptions and misconceptions before stepping into the lab.

Personally, I feel that there might be advantage to the genetics studies taking a more transdiagnostic approach, operationalizing psychosis as the dysfunction of a specific set of characteristic homo sapiens social, cognitive, and affective traits, and then focusing on that dysfunctional set as the object of study. From that point we might be able to better elucidate the putative biological pathways that converge on a "psychosis syndrome."

Regardless, I definitely agree that CNVs might represent the largest effect size for schizophrenia vulnerability. However, I think the effect is still probably going to be quite small and I doubt that CNVs above the frequency of non-psychotic individuals will prove to be either necessary or sufficient for the presence of schizophrenia. The cliff-edged fitness function is quite intriguing, however. It reminds me of the inverted-U function that seems to dominate so much of the brain's biology, and seems intuitive considering the rapid pace of the neuro-adaptations that exist in our genus.

Anyway, good luck to you and your research!