The Schizophrenia Risk Allele C of the<i>TCF4</i>rs9960767 Polymorphism Disrupts Sensorimotor Gating in Schizophrenia Spectrum and Healthy Volunteers

Quednow, Boris B.; Ettinger, Ulrich; Mößner, Rainald; Rujescu, Dan; Giegling, Ina; Collier, David; Schmechtig, Anne; Kühn, Kai‐Uwe; Möller, Hans‐Jürgen; Maier, Wolfgang; Wagner, Michael; Kumari, Veena

doi:10.1523/jneurosci.0526-11.2011

Cited by 84 publications

(70 citation statements)

References 59 publications

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“…Consistent with this explanation, none of the studies cited above for higher symptoms used cognitive tasks. In contrast, other genetic studies that used cognitive measures as intermediate phenotypes (eg, Hashimoto et al, 2010;Quednow et al, 2011;Opgen-Rhein et al, 2008;Ehlis et al, 2007) had similar PANSS scores as the current study. In any case, however, it should be cautioned that results from studies that used cognitive tasks might not be generalized to low-functioning patients.…”

Section: Discussioncontrasting

confidence: 54%

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Chen

Zhai

et al. 2012

Neuropsychopharmacol

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ZNF804A gene polymorphism rs1344706 has been suggested as the most compelling case of a candidate gene for schizophrenia by a genome-wide association study and several replication studies. The current study of 570 schizophrenia patients and 448 controls again found significantly different genotype frequencies of rs1344706 between patients and controls. More important, we found that this association was modulated by IQ, with a stronger association among individuals with relatively high IQ, which replicated results of Walters et al, 2010. We further examined whether this IQ-modulated association also existed between the SNP and the intermediate phenotypes (working memory and executive functions) of schizophrenia. Data were available from an N-back task (366 patients and 414 controls) and the attention network task (361 patients and 416 controls). We found that the SNP and IQ had significant interaction effects on the intermediate phenotypes for patients, but not for controls. The disease risk allele was associated with poorer cognitive function in patients with high IQ, but better cognitive function in patients with low IQ. Together, these results indicated that IQ may modulate the role of rs1344706 in the etiology of both schizophrenia and its cognitive impairments, and pointed to the necessity of considering general cognitive function as indexed by IQ in the future studies of genetic bases of schizophrenia.

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Section: Discussioncontrasting

confidence: 54%

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Chen

Zhai

et al. 2012

Neuropsychopharmacol

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“…In two independent samples, we recently demonstrated that the schizophrenia risk allele C of the TCF4 rs9960767 SNP is strongly associated with reduced sensorimotor gating [27]. In accordance with recent animal data, showing that transgenic mice overexpressing the TCF4 gene in the brain display decreased sensorimotor gating [5], this finding suggests that TCF4 plays an important role in the development of early information deficits in schizophrenia at least in a subgroup of patients who display diminished PPI.…”

Section: Tcf4 and Sensorimotor Gatingsupporting

confidence: 85%

“…This pattern suggests that TCF4 genotype probably influences PPI at an early level of information processing. Finally, given that TCF4 genotype was significantly associated with PPI reduction, a combination of TCF4 genotype and a PPI deficit syndrome might be a promising marker for the early detection of schizophrenia [27].…”

Section: Tcf4 and Sensorimotor Gatingmentioning

confidence: 99%

Impact of TCF4 on the genetics of schizophrenia

Lennertz

Quednow

Benninghoff

et al. 2011

Eur Arch Psychiatry Clin Neurosci

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Mutations of the transcription factor 4 (TCF4) gene cause mental retardation with or without associated facial dysmorphisms and intermittent hyperventilation. Subsequently, a polymorphism of TCF4 was shown in a genome-wide association study to slightly increase the risk of schizophrenia. We have further analysed the impact of this TCF4 variant rs9960767 on early information processing and cognitive functions in schizophrenia patients. We have shown in a sample of 401 schizophrenia patients that TCF4 influences verbal memory in the Rey Auditory Verbal Learning Test. Contrary to expectations, carriers of the schizophrenia-associated allele showed better recognition, thus indicating that while TCF4 influences verbal memory, the TCF4-mediated schizophrenia risk is not determined by the influence of TCF4 on verbal memory. TCF4 does not impact on various other cognitive functions belonging to the domains of attention and executive functions. Moreover, in a pharmacogenetic approach, TCF4 does not modulate the improvement of positive or negative schizophrenia symptoms during treatment with antipsychotics. Finally, we have assessed a key electrophysiological endophenotype of schizophrenia, sensorimotor gating. As measured by prepulse inhibition, the schizophrenia risk allele C of TCF4 rs9960767 reduces sensorimotor gating. This indicates that TCF4 influences key mechanisms of information processing, which may contribute to the pathogenesis of schizophrenia.

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“…Human haploinsufficiency of TCF4 may result in severe cognitive deficiency (ie, mental retardation) in patients with Pitt-Hopkins syndrome (Pitt and Hopkins, 1978) or Angelman syndrome (Takano et al, 2010). However, the role of the TCF4 gene in cognitive deficiency in SCZ patients has seldom been studied (for exceptions, see Lennertz et al (2011); Quednow et al (2011)). …”

Section: Introductionmentioning

confidence: 99%

“…A study in humans further suggested that the SCZ risk allele (C) of rs9960767 in this gene was significantly associated with reduced PPI in both healthy controls and patients with SCZ spectrum disorder (Quednow et al, 2011). Reduced PPI is an important intermediate phenotype of SCZ and is believed to be modulated by attention as assessed by the continuous performance test (CPT) (Hazlett et al, 2001(Hazlett et al, , 2008, the attention network test (ANT) (Sobin et al, 2005) and the Stroop test (Molina et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Associations between TCF4 Gene Polymorphism and Cognitive Functions in Schizophrenia Patients and Healthy Controls

Zhu

Liu

et al. 2012

Neuropsychopharmacol

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The SNP rs2958182 was reported to be significantly associated with schizophrenia (SCZ) in Han Chinese. This study examined this SNP's associations with cognitive functions in 580 SCZ patients and 498 controls. Cognitive functions were assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-RC), the Attention Network Task (ANT), the Stroop task, the dot pattern expectancy (DPX), task and the N-back working memory task. Results showed significant or marginally significant interaction effects between genotype and diagnosis status on IQ (P ¼ 0.011) and attention-related tasks (ie, the forward digit span of WAIS-RC, P ¼ 0.005; the ANT conflict effect; P ¼ 0.020, and its ratios over mean reaction time (RT), P ¼ 0.036; the Stroop conflict effect, P ¼ 0.032, and its ratios over mean RT, P ¼ 0.062; and the DPX task's error rate under the BX condition, Po0.001, and the error rate of BX minus the error rate of AY (BX À AY), P ¼ 0.002). There were no such interaction effects on the measures of working memory (all P-values 40.05). Further analysis of the significant genotype-by-diagnosis interactions showed that the risk (T) allele was associated with better performance on cognitive tasks in patients but with worse performance in controls. These results seem to indicate that the association between this SNP and selected cognitive functions may be of an inverted U-shaped pattern. Future research is needed to replicate these results and to explore the biochemical mechanisms behind this association.

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The Schizophrenia Risk Allele C of theTCF4rs9960767 Polymorphism Disrupts Sensorimotor Gating in Schizophrenia Spectrum and Healthy Volunteers

Cited by 84 publications

References 59 publications

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Impact of TCF4 on the genetics of schizophrenia

Associations between TCF4 Gene Polymorphism and Cognitive Functions in Schizophrenia Patients and Healthy Controls

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