Comments on News and Primary Papers
Primary Papers: The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers.Comment by: Arpi Minassian
Submitted 19 May 2011
Posted 19 May 2011
Studying the genetic underpinnings of sensorimotor gating, which is a function critical to adaptive everyday living, is an important endeavor. Quednow and colleagues’ work joins several others linking PPI to particular genotypes and will ultimately help us understand which genes, or more likely what interactions among genes, influence cognitive abilities such as inhibition. The findings’ specific implications for schizophrenia may be a more complex issue. First, as with some other genes (e.g., COMT; Roussos et al., 2008), the association between the “risk” genotype and decreased PPI is present in healthy subjects. Other neuropsychiatric populations are known to have PPI deficits, and they may also demonstrate this genotype-phenotype relationship. Furthermore, although PPI impairment in schizophrenia fits most of the criteria for an intermediate or endophenotype (see Goldberg and Weinberger, 2004) in that it is heritable and its underlying neurobiology is consistent with what we know about brain dysfunction in schizophrenia, the enduring nature of impaired PPI is less clear. PPI deficits in schizophrenia have been shown to normalize with treatment (Kumari et al., 2000; Minassian et al., 2007) and seem to improve over a several-year period of time (Hammer et al., 2011). TCF4 certainly shows promise as a potential genetic marker for risk of psychosis, and its relationship to other phenotypes of schizophrenia should be further examined.
Goldberg TE, Weinberger DR (2004). Genes and the parsing of cognitive processes. Trends in Cognitive Sciences 8(7): 325-335. Abstract
Hammer TB, Oranje B, Fagerlund B, Bro H, Glenthoj BY (2011). Stability of prepulse inhibition and habituation of the startle reflex in schizophrenia: a 6-year follow-up study of initially antipsychotic-naïve, first-episode schizophrenia patients. International Journal of Neuropsychopharmacology 4: 1-13. Abstract
Kumari V, Soni W, Mathew VM, Sharma T (2000). Prepulse inhibition of the startle response in men with schizophrenia: effects of age of onset of illness, symptoms, and medication. Archives of General Psychiatry 57: 609-614. Abstract
Minassian A, Feifel D, Perry, W (2007). The relationship between sensorimotor gating and clinical improvement in acutely ill schizophrenia patients. Schizophrenia Research 89(1-3): 225-231. Abstract
Roussos P, Giakoumaki SG, Rogdaki M, Pavlakis S, Frangou S, Bitsios P (2008). Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase Val158Met gene polymorphism. Psychological Medicine 38(11): 1651-1658. Abstract
View all comments by Arpi Minassian
Primary Papers: The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers.
Comment by: Neal R. Swerdlow
Submitted 24 May 2011
Posted 24 May 2011
Genes and phenes: what do they mean?
In this very impressive and important study, the authors report reduced prepulse inhibition of acoustic startle (PPI) among individuals carrying the schizophrenia susceptibility gene, TCF4 (rs9960767), in two cohorts: healthy individuals from London (12 carriers), and schizophrenia-spectrum individuals from Bonn (11 carriers). TCF4 becomes another schizophrenia risk gene (along with COMT, DRD3, NRG1, CHRNA7, CHRNA3, among others) that appears to be associated with, or perhaps influence, PPI levels in healthy or schizophrenia subjects. Thus, PPI, along with a number of other endophenotypes, appears to be regulated by many of the same genes that confer an increased risk for developing schizophrenia (Greenwood et al., 2011).
PPI is a useful measure for translational studies. As has already been demonstrated with many other "risk genes," rodents carrying a mutant TCF4 gene appear to exhibit PPI deficits (Brzózka et al., 2010). With any luck, this convergence of human and animal model findings will provide us with a neurobiological explanation for reduced PPI among individuals carrying risk allele C of the TCF4 gene. Importantly, and implicit in the title of the report by Quednow et al., it is not the polymorphism per se that disrupts PPI, but rather the neurobiological events that occur downstream from that gene.
This report raises important questions about the utility of gene-phene relationships for the development of treatments for neuropsychiatric disorders. At the end of the day, how will this genetic/neurobiological explanation enhance our ability to understand or treat schizophrenia? Schizophrenia is not Huntington's disease, where the disorder and presumably its associated PPI deficits, and those in its transgenic mouse model, reflect the impact of a single gene. The investigators correctly acknowledge, "…since very few schizophrenia patients seem to share identical genomic causation (Need et al., 2009), reduced PPI most likely also arises from several independent genetic variations." Each of many different genes contributes small amounts of the variance to the PPI phenotype. In this report, about one out of 10 schizophrenia-spectrum patients carried the "risk gene," which is actually a huge number—a full 30-fold more than are thought to carry other highly publicized risk genes (Vacic et al., 2011). So, when all is said and done, the vast majority of people with schizophrenia do not carry most of these genes, and the vast majority of people with "low" PPI are perfectly healthy and carry no obvious family loading for any particular brain disorder.
Even more to the point, let’s suppose that a list of PPI-associated genetic markers that are associated with a small increased risk for the development of schizophrenia could be identified in clinically normal children. How would we implement this information within a new treatment or approach to schizophrenia? Let's say that with the help of a mutant mouse, molecular biologists, and neuroscientists, we identify the neurobiological impact of some of these genes. Then, with the help of some astute neurochemists and pharmacologists, let's say we develop some drugs that counteract the effects of these genes early in development, before the etiological process of failed cell migration, failed prefrontal-hippocampal connectivity, failed synaptic formation, whatever it may be, had disrupted normal circuitry and synaptic organization in dozens of brain regions, from the prefrontal cortex to the occipital lobes. Would we then widely administer these drugs to asymptomatic children to try to prevent the development of schizophrenia in a very small percentage of them, on the hope that such drugs would otherwise be innocuous in these mostly healthy children? I don't think so; it's a struggle to convince parents to even vaccinate their children for measles. Would we stratify children or fetuses based on the presence of these genes detected by genetic testing? I don't think so; we could, at best, offer parents risk estimates, and without effective treatments, such genetic testing often goes unused. So, how does this information become "implementable?"
None of these issues detract from the outstanding quality of the science reported by Quednow et al. (Quednow et al., 2011) or others, in the quest to link schizophrenia risk genes and related phenes. But I wonder whether our field is now reaching a critical inflection point where we need to ask not whether we can do this kind of science, but rather, whether we should, and to what end? What will we find, digging deeper and deeper into the smaller and smaller spaces of the neuromolecular world of schizophrenia? Do we really believe that this approach will lead to treatments for a disorder that almost certainly starts early in brain development, with profound, widely distributed, hard-wired neural circuit perturbations being increasingly identified pre-symptomatically in at-risk individuals and asymptomatic relatives? These events are triggered almost certainly by any one of numerous genes, including rare, highly penetrant mutations. After many years of exquisite neuropathological studies, David Lewis and colleagues have provided us with detailed diagrams of the complex synaptic interactions within one small locus of schizophrenia neuropathology: the prefrontal cortex. In a healthy brain, this synaptic machinery is orchestrated with precise spatial, temporal, and neurochemical choreography. The neurodevelopmental miscues in schizophrenia upset this circuitry and its counterparts in dozens of other regions distributed from one end of the brain to the other in complex ways that almost certainly vary widely across any two individuals with this disorder. One can never foresee the future, but I find it implausible that, even with the help of genes and phenes, pharmacology will allow us to reach backwards two decades through a variable web of absent and misguided neural connections, restore the intended physiological design, and thereby disentangle schizophrenia from the circuitry that its risk genes produced.
We may already have at hand effective cognitive and behavioral therapies for schizophrenia, and there may be very important information in the connection of schizophrenia risk genes and endophenotypes, if these "biomarkers" can predict responses to non-pharmacologic therapies for schizophrenia. I believe that at least some of these authors are pursuing precisely this line of inquiry, and I have advocated for this strategy at some length in a recent commentary (Swerdlow, 2011, in press). With complex endophenotypes and even more complex disorders, we can be certain that the list of risk genes will continue to grow, but that most of these genes will account only for a very small fraction of the variance of either. Each report will be greeted with public comments deserving of the rigorous and successful scientific effort that produced it. But in the end, we will still need to turn this long list of genes into implementable interventions that help our patients and their families.
Acknowledgements: Helpful comments were provided by David Braff and Greg Light. NRS's funding sources are NIMH (MH59803, MH42228), NIDA (DA27483), and the VISN 22 MIRECC. Conflicts of interest: none.
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View all comments by Neal R. Swerdlow