30 March 2012. Schizophrenia risk alleles for transcription factor 4 (TCF4) are associated with decreased sensory gating in healthy subjects, and this effect is modulated by smoking behavior, according to a new study published online March 26 in the Proceedings of the National Academy of Sciences.
TCF4 was first identified as a schizophrenia risk gene by a 2009 genomewide association study (GWAS) (see SRF related news story), and is one of only a handful of genes to withstand replication (see SRF related news story; SRF news story; Li et al., 2010). TCF4 is a transcription factor containing a basic helix-turn-helix DNA-binding motif that plays a crucial role in neurodevelopment. In fact, underexpression of TCF4 results in a neurodevelopmental disorder characterized by mental retardation known as Pitt-Hopkins syndrome.
TCF4 and sensory gating
Mice with an overexpression of TCF4 exhibit reduced sensorimotor gating, as shown using prepulse inhibition (PPI) of the acoustic startle response (Brzózka et al., 2010), in which the presentation of a weaker pre-stimulus diminishes the startle response to a subsequent, stronger stimulus. PPI is similarly impaired in schizophrenia (Braff et al., 2001), and has been proposed to be an endophenotype of the illness (Gottesman and Gould, 2003). In fact, a schizophrenia risk allele in TCF4 has recently been associated with diminished PPI in both schizophrenia subjects and controls (Quednow et al., 2011).
In the current study, led by Georg Winterer of Helmholtz Research Center in Jülich, Germany, researchers hypothesized that TCF4 risk polymorphisms would also be associated with impairments in another sensory gating paradigm, P50 suppression of the auditory evoked potential. When two identical stimuli are presented with an inter-stimulus interval of at least 500 ms, healthy subjects exhibit a suppressed P50 response (occurring 50 ms after the second stimulus) as measured using electroencephalography (EEG). Schizophrenia subjects exhibit attenuated P50 suppression (Bramon et al., 2004), another proposed endophenotype of the illness Although PPI and P50 suppression measures are not correlated (Braff et al., 2007) and are potentially regulated by separate neural mechanisms (Oranje et al., 2006), recent studies suggest the two may share common genetic regulation (Greenwood et al., 2012).
Schizophrenia risk SNPs in TCF4 are common in the general population, and, in the current study, Winterer’s group examined healthy individuals, allowing for larger sample sizes and the elimination of confounding effects of illness and treatment. First authors Boris Quednow and Jürgen Brinkmeyer genotyped 1,821 German subjects for the 20 TCF4 SNPs that were most significant in recent schizophrenia GWAS. Subjects also underwent testing on an auditory P50 paradigm. In four of the 20 SNPs, the percent of P50 suppression was significantly lower in schizophrenia risk allele carriers versus non-carriers.
Interestingly, the TCF4 effect on P50 suppression was most prominent at the frontal electrode, consistent with recent evidence implicating the prefrontal cortex in sensory gating (Bak et al., 2011; Williams et al., 2011). In fact, a schizophrenia risk allele in TCF4 influences prefrontal cortex-dependent verbal learning and memory in patients, though surprisingly, in a positive manner (Lennertz et al., 2011).
Modulation by smoking status
The percent of P50 suppression was also affected by smoking status, with heavy smokers displaying lower levels of P50 suppression than light or non-smokers, consistent with a previous report from the same group (Brinkmeyer et al., 2011). There was also significant genotype-smoking interaction at each SNP. Heavy smokers displayed stronger gene effects of TCF4 on P50 suppression than light smokers or those who had never smoked. However, there was no association between the four significant TCF4 SNPs and smoking status alone.
The smoking-genotype interaction on P50 suppression observed in the current study was not seen in an earlier study examining the effect of TCF4 genotype on PPI (Quednow et al., 2011), perhaps due to a smaller sample size in the latter, or because of a selective effect of smoking on P50 suppression. So, what mechanisms may account for the observed interaction? The authors provide two possible models: a “hidden” gene-gene interaction and a gene-environment interaction. In the first scenario, one or more additional risk genes combine with TCF4 SNPs to produce the interaction between smoking behavior and P50 suppression, since TCF4 SNPs alone were not associated with smoking behavior. The clandestine gene(s) may encode for nicotinic acetylcholine receptor subtypes (e.g., CHRNA7), since they are associated with both sensory gating and smoking (Freedman et al., 2003; Saccone et al., 2010). An alternative hypothesis suggested by the authors is that smoking is an environmental factor that exerts an ongoing effect. This idea is consistent with recent data demonstrating that a TCF4 schizophrenia risk SNP is nonfunctional and does not affect adult mRNA levels, suggestive of a developmental role in illness pathogenesis (Freedman et al., 2003; Williams et al., 2011).
Whatever the mechanism mediating the smoking-TCF4 interaction may be, the presence of such an interaction raises the question of whether smoking itself can elevate the risk for schizophrenia, consistent with prospective studies implicating smoking in illness pathophysiology (Rössler et al., 2011; Weiser et al. 2004). Additionally, the authors suggest that an “extended” endophenotype that combines measures of sensory gating, smoking status, and risk genes may be useful to predict later psychosis.—Allison A. Curley.
Quednow BB, Brinkmeyer J, Mobascher A, Nothnagel M, Musso F, Gründer G, Savary N, Petrovsky N, Frommann I, Lennertz L, Spreckelmeyer KN, Wienker TF, Dahmen N, Thuerauf N, Clepce M, Kiefer F, Majic T, Mössner R, Maier W, Gallinat J, Diaz-Lacava A, Toliat MR, Thiele H, Nürnberg P, Wagner M, Winterer G. Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating. Proc Natl Acad Sci U S A. 2012 Mar 26. Abstract