Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating

Abstract

Several polymorphisms of the transcription factor 4 (TCF4) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition-an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerström Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 (P < 0.0002-0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score ≥4) showed stronger gene effects on P50 suppression than light smokers and neversmokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia.R ecent large genomewide association studies (GWAS) identified and consistently confirmed that common variants of the transcription factor 4 (TCF4) gene contribute to the risk of schizophrenia (1-3). In these analyses, two single nucleotide polymorphisms (SNPs) located in the intron of the TCF4 gene on chromosome 18q21.1 (rs9960767, rs17512836) and an intragenic SNP near the TCF4 gene (rs4309482) have shown the strongest association with the disease (1-3). TCF4 is a class I basic helixloop-helix (bHLH) protein involved in the control of neuronal and glial progenitor cells, which are important for the development of the mammalian central nervous system (CNS) (4, 5).The exact role of TCF4 in the brain and the functional activity of these nonsynonymous TCF4 variants on the level of gene expression are not yet fully understood (4, 6). A recent postmortem study suggested that the rs9960767 SNP is neither functional nor affects mRNA expression in the adult human brain, indicating that TCF4 mutations may exert their effects on expression through posttranscriptional effects or exclusively in a developmental context (e.g., by gene-environment interactions) (7).In a translational animal study, it was initially shown that tra...

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

“…However, this genotype effect was strongly modulated by smoking behaviour given that only smokers showed reliable TCF4-sensory gating associations, while the gene effect was not present in never-smokers. Moreover, the genotype*smoking interaction was dose-related as the TCF4 genotype effect grows with increasing smoking severity [114]. However, the moderating influence of smoking on the TCF4 genotype effect was not present in the previous investigation on TCF4 gene effects on sensorimotor gating measured by PPI [113].…”

“…The potentially moderating effect of smoking on TCF4 gene effects on PPI (and other schizophrenia endophenotypes) should therefore be investigated in larger samples. Finally, the TCF4 genotype effect on PPI displayed a much stronger effect size (Cohen's d=0.90) than the mean effect on P50 suppression (mean d=0.23, ranging from 0.03 in neversmokers to 0.69 in heavy smokers), which could partially be explained by a superior reliability of PPI compared to P50 suppression [114].…”

“…By combining electrophysiological measurements with genetics it has been shown that TCF4 risk alleles correlate with particular schizophrenia endophenotypes -namely sensory and sensorimotor gating [112][113][114]. Specifically sensory gating revealed an interesting and unexpected gene*environment interaction: The schizophrenia risk allele C of the TCF4 rs9960767 SNP was robustly associated with reduced P50 suppression of the AEP.…”

“…Moreover, it should be further explored if nicotine use itself might enhance the risk for schizophrenia as indicated by longitudinal studies showing that beyond cannabis and alcohol use also early consumption of tobacco increases the risk for psychosis [120,121]. Finally, an extended endophenotype including electrophysiological gating measures such as PPI or P50 suppression, smoking behaviour, and risk genes such as TCF4 may be suitable as an early indicator for a developing psychosis [114]. Moreover, dedicated gene*environment studies could be performed in mouse models providing additional evidence for TCF4*smoking interactions and allowing the investigation of underlying molecular mechanisms.…”

“…Subsequently, we also investigated the influence of 21 TCF4 polymorphisms -which were most strongly associated with schizophrenia in a recent meta-analysis [19] -on sensory gating as assessed by P50 suppression of the AEP [114]. We used a multi-centre study done including six academic institutions throughout Germany with 1821 subjects (1023 never-smokers, 798 smokers) randomly selected from the general population ( Table 1).…”