TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders

Abstract

TCF4 is involved in neurodevelopment, and intergenic and intronic variants in or close to the TCF4 gene have been associated with susceptibility to schizophrenia. However, the functional role of TCF4 at the level of gene expression and relationship to severity of core psychotic phenotypes are not known. TCF4 mRNA expression level in peripheral blood was determined in a large sample of patients with psychosis spectrum disorders (n=596) and healthy controls (n=385). The previously identified TCF4 risk variants (rs12966547 (G), rs9960767 (C), rs4309482 (A), rs2958182 (T) and rs17512836 (C)) were tested for association with characteristic psychosis phenotypes, including neurocognitive traits, psychotic symptoms and structural magnetic resonance imaging brain morphometric measures, using a linear regression model. Further, we explored the association of additional 59 single nucleotide polymorphisms (SNPs) covering the TCF4 gene to these phenotypes. The rs12966547 and rs4309482 risk variants were associated with poorer verbal fluency in the total sample. There were significant associations of other TCF4 SNPs with negative symptoms, verbal learning, executive functioning and age at onset in psychotic patients and brain abnormalities in total sample. The TCF4 mRNA expression level was significantly increased in psychosis patients compared with controls and positively correlated with positive- and negative-symptom levels. The increase in TCF4 mRNA expression level in psychosis patients and the association of TCF4 SNPs with core psychotic phenotypes across clinical, cognitive and brain morphological domains support that common TCF4 variants are involved in psychosis pathology, probably related to abnormal neurodevelopment.

Association of Transcription Factor 4 (TCF4) variants with schizophrenia and intellectual disability

“…Importantly, this study also found that TCF4 expression in blood was increased in patients with psychoses (schizophrenia, bipolar disorder and other psychoses) compared to controls [82]. Whilst this is a potentially interesting finding, the authors of this study acknowledged that they could not exclude the effects of anti-psychotic medication on TCF4 expression in patients compared to controls [82].…”

“…Paradoxically, schizophrenia patients carrying the risk allele of rs9960767, the original TCF4 SNP to exceed genome-wide significance [7], were less impaired in verbal declarative memory tests compared to patients homozygous for the nonrisk allele [81]. However, using a different study design, Wirgenes and colleagues found that the risk alleles of several TCF4 SNPs influenced verbal learning and a range of other endophenotypes in schizophrenia patients compared to controls [82]. Importantly, this study also found that TCF4 expression in blood was increased in patients with psychoses (schizophrenia, bipolar disorder and other psychoses) compared to controls [82].…”

“…However, using a different study design, Wirgenes and colleagues found that the risk alleles of several TCF4 SNPs influenced verbal learning and a range of other endophenotypes in schizophrenia patients compared to controls [82]. Importantly, this study also found that TCF4 expression in blood was increased in patients with psychoses (schizophrenia, bipolar disorder and other psychoses) compared to controls [82]. Whilst this is a potentially interesting finding, the authors of this study acknowledged that they could not exclude the effects of anti-psychotic medication on TCF4 expression in patients compared to controls [82].…”

Schizophrenia: neuroinflammation, neurodegeneration or neurodevelopment? A genetic overview

“…Moreover, SNPs in genes important for neurodevelopment have been correlated with neuroimaging variances [26][27][28][29][30][31][32] and cognitive impairment 24,25,33 . Specific genes had effects in both healthy control and schizophrenia subjects; other had effects only in schizophrenia individuals or the effects on schizophrenia and control were contrary.…”

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

“…GEO2R analysis of GSE29691 also revealed the upregulation of TCF4 (log 2 FC = 0.55079923) (Figure 8c) and downregulation of PTPN11 (log 2 FC = -0.53875346) (Figure 8d). Even though low levels of TCF4 has resulted in Pitt-Hopkins Syndrome (PHS) [104,111], a disease related to autism with common symptoms, high levels of TCF4 has been observed in patients afflicted with SCZ [112,113]. Since SCZ and autism are closely related, it may be deduced that high levels of TCF4 may lead to development of autism or related disorders.…”