| 1 | Schizophr. Res. 2009 Oct 114: 50-6 |
|---|---|
| PMID | 19643578 |
| Title | Genetic risk factors for type 2 diabetes with pharmacologic intervention in African-American patients with schizophrenia or schizoaffective disorder. |
| Abstract | An increased prevalence of type 2 diabetes (T2D) in schizophrenia (SCZ) patients has been observed. Exposure to antipsychotics (APs) has been shown to induce metabolic dysregulation in some patients but not all treated patients. We hypothesized that important candidate genes for T2D may increase risk for T2D in African-American patients with SCZ or schizoaffective disorder. The PAARTNERS study comprises African-American families with at least one proband with SCZ or schizoaffective disorder. The current study of PAARTNERS SCZ and schizoaffective disorder cases (N=820) examined single nucleotide polymorphisms (SNPs) within select T2D candidate genes including transcription factor 7-like 2 (TCF7L2), calpain 10 (CAPN10), and ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENNP1) for association with prevalent T2D. We report the association of TCF7L2 (rs7903146) with T2D under both additive and recessive models for the risk allele T. Specifically, the odds ratio (OR) for having T2D was 1.4 (p=0.03) under an additive model and 2.4 (p=0.004) under a recessive model. We also report a marginally significant TCF7L2 by AP treatment interaction that should be investigated in future studies. CAPN10 (rs3792267) was marginally associated with T2D with OR=1.5 (p=0.08) when considering the model GG vs. AG/AA with risk allele G. ENPP1 (rs1044498) was not associated with T2D. We conclude TCF7L2, a risk factor for T2D in the general population, is also a risk factor for T2D in African-American patients with SCZ or schizoaffective disorder. Research is needed to determine if T2D associated polymorphisms are of interest in the pharmacogenetics and future treatment choices of antipsychotics in African-American patients. |
| SCZ Keywords | schizophrenia |
| 2 | PLoS ONE 2011 -1 6: e26897 |
| PMID | 22046400 |
| Title | Modulation ofTcf7l2 expression alters behavior in mice. |
| Abstract | The comorbidity of type 2 diabetes (T2D) with several psychiatric diseases is well established. While environmental factors may partially account for these co-occurrences, common genetic susceptibilities could also be implicated in the confluence of these diseases. In support of shared genetic burdens, TCF7L2, the strongest genetic determinant for T2D risk in the human population, has been recently implicated in schizophrenia (SCZ) risk, suggesting that this may be one of many loci that pleiotropically influence both diseases. To investigate whether TCF7L2 is involved in behavioral phenotypes in addition to its roles in glucose metabolism, we conducted several behavioral tests in mice with null alleles of TCF7L2 or overexpressing TCF7L2. We identified a role for TCF7L2 in anxiety-like behavior and a dose-dependent effect of TCF7L2 alleles on fear learning. None of the mutant mice showed differences in prepulse inhibition (PPI), which is a well-established endophenotype for SCZ. These results show that TCF7L2 alters behavior in mice. Importantly, these differences are observed prior to the onset of detectable glucose metabolism abnormalities. Whether these differences are related to human anxiety-disorders or schizophrenia remains to be determined. These animal models have the potential to elucidate the molecular basis of psychiatric comorbidities in diabetes and should therefore be studied further. |
| SCZ Keywords | schizophrenia |
| 3 | Biol. Psychiatry 2011 Jul 70: 59-63 |
| PMID | 21414605 |
| Title | At-risk variant in TCF7L2 for type II diabetes increases risk of schizophrenia. |
| Abstract | schizophrenia is associated with increased risk of type II diabetes and metabolic disorders. However, it is unclear whether this comorbidity reflects shared genetic risk factors, at-risk lifestyle, or side effects of antipsychotic medication. Eleven known risk variants of type II diabetes were genotyped in patients with schizophrenia in a sample of 410 Danish patients, each matched with two healthy control subjects on sex, birth year, and month. Replication was carried out in a large multinational European sample of 4089 patients with schizophrenia and 17,597 controls (SGENE+) using Mantel-Haenszel test. One type II diabetes at-risk allele located in TCF7L2, rs7903146 [T], was associated with schizophrenia in the discovery sample (p = .0052) and in the replication with an odds ratio of 1.07 (95% confidence interval 1.01-1.14, p = .033). The association reported here with a well-known diabetes variant suggests that the observed comorbidity is partially caused by genetic risk variants. This study also demonstrates how genetic studies can successfully examine an epidemiologically derived hypothesis of comorbidity. |
| SCZ Keywords | schizophrenia |
| 4 | PLoS ONE 2012 -1 7: e29228 |
| PMID | 22247771 |
| Title | Association of the type 2 diabetes mellitus susceptibility gene, TCF7L2, with schizophrenia in an Arab-Israeli family sample. |
| Abstract | Many reports in different populations have demonstrated linkage of the 10q24-q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24-q26 region to schizophrenia in a unique, homogeneous sample of Arab-Israeli families with multiple schizophrenia-affected individuals, under a dominant model of inheritance. To further explore this candidate region and identify specific susceptibility variants within it, we performed re-analysis of the 10q24-26 genotype data, taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011). We analyzed 2089 SNPs in an extended sample of 57 Arab Israeli families (189 genotyped individuals), under the dominant model of inheritance, which best fits this locus according to previously performed MOD score analysis. We found significant association with schizophrenia of the TCF7L2 gene intronic SNP, rs12573128, (p?=?7.01×10??) and of the nearby intergenic SNP, rs1033772, (p?=?6.59×10??) which is positioned between TCF7L2 and HABP2. TCF7L2 is one of the best confirmed susceptibility genes for type 2 diabetes (T2D) among different ethnic groups, has a role in pancreatic beta cell function and may contribute to the comorbidity of schizophrenia and T2D. These preliminary results independently support previous findings regarding a possible role of TCF7L2 in susceptibility to schizophrenia, and strengthen the importance of integrating linkage analysis models of inheritance while performing association analyses in regions of interest. Further validation studies in additional populations are required. |
| SCZ Keywords | schizophrenia |
| 5 | Microrna 2015 -1 4: 209-16 |
| PMID | 26729022 |
| Title | Generation of Knock down Tools for Transcription Factor 7-like-2 (TCF7L2) and Evaluation of its Expression Pattern in Developing Chicken Optic Tectum. |
| Abstract | Backgroud: TCF7L2 encodes for a transcription factor that plays a significant role in the Wnt signaling pathway and has been implicated in schizophrenia and blood glucose homeostasis. During embryonic development, TCF7L2 is expressed widely in the midbrain and forebrain regions of mouse brain. However, expression data of TCF7L2 and its functional studies are much scarcer for chicken brain. Our study demonstrated interesting expression pattern of TCF7L2 in the optic tectum of developing chicken embryo. Further study was undertaken to develop and test the knock down tools for TCF7L2 in the developing chicken embryo which would help in its functional characterization. An RNAi based strategy was chosen to knock down TCF7L2A. miRNA based construct was designed and developed to target TCF7L2. However these miRNA construct may or may not be effective in knocking down their target gene, therefore the efficiency of the miRNA construct in knocking down TCF7L2 was tested. First the efficiency was measured in vitro using a sensor assay. The efficient pre-miRNA was cloned in an avian retrovirus to achieve in vivo knock down in the developing chicken embryo. RCAS-miRNA construct targeting TCF7L2, was electroporated in the tectum of embryonic day 3.5 chicken embryo. The extent of in vivo knock down of TCF7L2 by the RCAS-miRNA-TCF7L2 was examined using RNA in situ hybridization technique. TCF7L2 showed strong layer specific expression from embryonic day 5 to embryonic day 13 which is also the important time window for tectal development. In addition to the layer specific expression, TCF7L2 is also strongly expressed in the pre-tegmentum area of the tectum. The TCF7L2 transcript showed marked decrease in the region that was electroporated with RCAS-miRNA-TCF7L2. Therefore this study has led to the generation and validation of RCAS-pre miRNA-TCF7L2 which effectively knocks down TCF7L2 in vivo and thus has paved the way for further functional characterization of TCF7L2 in the chicken optic tectum. |
| SCZ Keywords | schizophrenia |