Association of the Type 2 Diabetes Mellitus Susceptibility Gene, TCF7L2, with Schizophrenia in an Arab-Israeli Family Sample

Alkelai, Anna; Greenbaum, Lior; Lupoli, Sara; Kohn, Yoav; Sarner-Kanyas, Kyra; Ben-Asher, Edna; Lancet, Doron; Macciardi, Fabìo; Lerer, Bernard

doi:10.1371/journal.pone.0029228

Cited by 59 publications

(49 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Schizophrenia has also been associated with thalamic dysfunction [79-84]. Moreover, some variants of Tcf7l2 have been recently shown to be a risk factor in schizophrenia [23,85], and a group of synaptic genes involved in excitability has been found to be associated with the risk of schizophrenia [86]. Interestingly, Gabra3 -deficient mice display impairments in sensorimotor gating, which is a feature of this disorder [87].…”

Section: Discussionmentioning

confidence: 99%

Novel β-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability

et al. 2012

View full text Add to dashboard Cite

BackgroundLEF1/TCF transcription factors and their activator β-catenin are effectors of the canonical Wnt pathway. Although Wnt/β-catenin signaling has been implicated in neurodegenerative and psychiatric disorders, its possible role in the adult brain remains enigmatic. To address this issue, we sought to identify the genetic program activated by β-catenin in neurons. We recently showed that β-catenin accumulates specifically in thalamic neurons where it activates Cacna1g gene expression. In the present study, we combined bioinformatics and experimental approaches to find new β-catenin targets in the adult thalamus.ResultsWe first selected the genes with at least two conserved LEF/TCF motifs within the regulatory elements. The resulting list of 428 putative LEF1/TCF targets was significantly enriched in known Wnt targets, validating our approach. Functional annotation of the presumed targets also revealed a group of 41 genes, heretofore not associated with Wnt pathway activity, that encode proteins involved in neuronal signal transmission. Using custom polymerase chain reaction arrays, we profiled the expression of these genes in the rat forebrain. We found that nine of the analyzed genes were highly expressed in the thalamus compared with the cortex and hippocampus. Removal of nuclear β-catenin from thalamic neurons in vitro by introducing its negative regulator Axin2 reduced the expression of six of the nine genes. Immunoprecipitation of chromatin from the brain tissues confirmed the interaction between β-catenin and some of the predicted LEF1/TCF motifs. The results of these experiments validated four genes as authentic and direct targets of β-catenin: Gabra3 for the receptor of GABA neurotransmitter, Calb2 for the Ca2+-binding protein calretinin, and the Cacna1g and Kcna6 genes for voltage-gated ion channels. Two other genes from the latter cluster, Cacna2d2 and Kcnh8, appeared to be regulated by β-catenin, although the binding of β-catenin to the regulatory sequences of these genes could not be confirmed.ConclusionsIn the thalamus, β-catenin regulates the expression of a novel group of genes that encode proteins involved in neuronal excitation. This implies that the transcriptional activity of β-catenin is necessary for the proper excitability of thalamic neurons, may influence activity in the thalamocortical circuit, and may contribute to thalamic pathologies.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel β-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability

et al. 2012

View full text Add to dashboard Cite

show abstract

“…106 Association findings further support that TCF7L2, which is responsible for diabetes, increases risk of schizophrenia in two further studies. 107,108 Web-based catalog for published genome-wide association studies (GWAS) to search for overlapped findings for diabetes and schizophrenia 109 provided no evidence for shared etiology (with a significance level of p<10?8). Proposed explanation therefore is that the genetic overlap for schizophrenia and diabetes may depend on combination of rare variants with small effect acting in concert to cause both diseases or to variants other than single nucleotide polymorphisms (SNPs).…”

Section: Genetic Predisposition For Comorbidity Schizophrenia and Typmentioning

confidence: 99%

Schizophrenia and type 2 diabetes mellitus

et al. 2018

View full text Add to dashboard Cite

S chizophrenia is associated with increased risk for type 2 diabetes mellitus, resulting in elevated cardiovascular risk and limited life expectancy, translated into a weighted average of 14.5 years of potential life lost and an overall weighted average life expectancy of 64.7 years. The exact prevalence of type 2 diabetes among people with schizophrenia varies across studies and ranges 2-5fold higher than in the general population, whereas the aetiology is complex and multifactorial. Besides common diabetogenic factors, applied similarly in the general population, such as obesity, hyperlipidemia, smoking, hypertension, poor diet and limited physical activity, the co-occurrence of schizophrenia and diabetes is also attributed to unique conditions. Specifically, excessive sedentary lifestyle, social determinants, adverse effects of antipsychotic drugs and limited access to medical care are considered aggravating factors for diabetes onset and low quality of diabetes management. Schizophrenia itself is further proposed as causal factor for diabetes, given the observed higher prevalence of diabetes in young patients, newly diagnosed with schizophrenia and unexposed to antipsychotics. Furthermore, studies support genetic predisposition to diabetes among people with schizophrenia, suggesting shared genetic risk and disclosing a number of overlapped risk loci. Therefore, special attention should be paid in preventing diabetes in people with schizophrenia, through intervention in all possible modifiable risk factors. Implementation of careful antipsychotic prescription, provision of adequate motivation for balanced diet and physical activity and facilitating access to primary health care, could serve in reducing diabetes prevalence. On the other hand, increasing calls are made for early diagnosis of diabetes, application of the appropriate anti-diabetic therapy and strict inspection of therapy adherence, to limit the excess mortality due to cardiovascular events in people with schizophrenia. Moreover, population health programs could help counseling and preventing diabetes risk, additionally to early screening and diagnosis set, aiming to reduce disparities in populations. Finally, mental health-care providers might greatly promote offered health services to patients with schizophrenia, through a holistic individualized approach, considering additionally the physical health of the patients and working closely, preventively and therapeutically, in collaboration with the physicians and diabetologists.

show abstract

“…The second gene we studied, TCF7L2, is among the most strongly associated and best replicated genetic risk factors for type 2 diabetes (Fuchsberger et al, 2016; Grant et al, 2006; Morris et al, 2012). In addition to its metabolic role, TCF7L2 has also been associated with schizophrenia and bipolar disorder (Alkelai et al, 2012; Hansen et al, 2011; Winham et al, 2013). Mice with a null allele for Tcf7l2 exhibit both physiological and behavioral phenotypes including improved glucose tolerance, altered fear learning, and anxiety (Savic et al, 2011a, 2011b).…”

Section: Introductionmentioning

confidence: 99%

Genetic Background Limits Generalizability of Genotype-Phenotype Relationships

Sittig

Carbonetto

Engel

et al. 2016

Neuron

228

175

View full text Add to dashboard Cite

Summary Genome wide association studies (GWAS) have identified numerous loci that influence risk for psychiatric diseases. Genetically engineered mice are often used to characterize genes implicated by GWAS. These studies are based on the assumption that observed genotype-phenotype relationships will generalize to humans, implying that the results would at least generalize to other inbred mouse strains. Given current concerns about reproducibility we sought to directly test this assumption. We produced F1 crosses between male C57BL/6J mice heterozygous for null alleles of Cacna1c and Tcf7l2 and wild-type females from 30 inbred laboratory strains. We found extremely strong interactions with genetic background that sometimes supported diametrically opposing conclusions. These results do not negate the invaluable contributions of mouse genetics to biomedical science, but they do show that genotype-phenotype relationships cannot be reliably inferred by studying a single genetic background, and thus constitute a major challenge to the status quo.

show abstract

Association of the Type 2 Diabetes Mellitus Susceptibility Gene, TCF7L2, with Schizophrenia in an Arab-Israeli Family Sample

Cited by 59 publications

References 71 publications

Novel β-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability

Novel β-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability

Schizophrenia and type 2 diabetes mellitus

Genetic Background Limits Generalizability of Genotype-Phenotype Relationships

Contact Info

Product

Resources

About