Accumulating evidence for a role of <scp>TCF</scp>7L2 variants in bipolar disorder with elevated body mass index

Cuellar-Barboza, Alfredo B.; Winham, Stacey J.; McElroy, Susan L.; Geske, Jennifer R.; Jenkins, Gregory D.; Colby, Colin; Prieto, Miguel L.; Ryu, Euijung; Cunningham, Julie M.; Frye, Mark A.; Biernacka, Joanna M.

doi:10.1111/bdi.12368

Cited by 33 publications

(27 citation statements)

References 44 publications

(64 reference statements)

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“…4, Table S6). TCF7L2 (T-cell Specific, HMG-Box) is a transcription factor and effector of the Wnt signaling pathway that regulates peptide secretion and is associated with type 2 diabetes, binge eating in bipolar disorder (Cuellar-Barboza et al ., 2016) and binge eating in our preclinical model (Kirkpatrick et al ., 2016). …”

Section: Resultsmentioning

confidence: 99%

Casein kinase 1‐epsilon deletion increases mu opioid receptor‐dependent behaviors and binge eating1

Goldberg

Kirkpatrick

Yazdani

et al. 2017

Genes Brain and Behavior

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Genetic and pharmacological studies indicate that casein kinase-1 epsilon (Csnk1e) contributes to psychostimulant, opioid, and ethanol motivated behaviors. We previously used pharmacological inhibition to demonstrate that Csnk1e negatively regulates the locomotor stimulant properties of opioids and psychostimulants. Here, we tested the hypothesis that Csnk1e negatively regulates opioid and psychostimulant reward using genetic inhibition and the conditioned place preference assay in Csnk1e knockout mice. Similar to pharmacological inhibition, Csnk1e knockout mice showed enhanced opioid-induced locomotor activity with the mu opioid receptor agonist fentanyl (0.2 mg/kg i.p.) as well as enhanced sensitivity to low-dose fentanyl reward (0.05 mg/kg). Interestingly, female knockout mice also showed a markedly greater escalation in consumption of sweetened palatable food – a behavioral pattern consistent with binge eating that also depends on mu opioid receptor activation. No difference was observed in fentanyl analgesia in the 52.5°C hot plate assay (0–0.4 mg/kg), naloxone conditioned place aversion (4 mg/kg), or methamphetamine conditioned place preference (0–4 mg/kg). To identify molecular adaptations associated with increased drug and food behaviors in knockout mice, we completed transcriptome analysis via mRNA sequencing of the striatum. Enrichment analysis identified terms associated with myelination and axon guidance and pathway analysis identified a differentially expressed gene set predicted to be regulated by the Wnt signaling transcription factor, Tcf7l2. To summarize, Csnk1e deletion increased mu opioid receptor-dependent behaviors, supporting previous studies indicating an endogenous negative regulatory role of Csnk1e in opioid behavior.

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Section: Resultsmentioning

confidence: 99%

Casein kinase 1‐epsilon deletion increases mu opioid receptor‐dependent behaviors and binge eating1

Goldberg

Kirkpatrick

Yazdani

et al. 2017

Genes Brain and Behavior

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“…TCF7L2 was the top IPA upstream regulator (p=1.09 × 10 −23 ) with 21 downregulated genes (see the TCF7L2 node in Fig.4D ). TCF7L2 (T-Cell Specific, HMG-Box) is a transcription factor that regulates peptide secretion and is associated with type 2 diabetes, dietary preference, obesity, blood glucose homeostasis, metabolic syndrome, and BE in bipolar disorder(40, 41). The top IPA network for Treatment included 30 downregulated genes enriched for “Cellular Development, Nervous System Development and Function, Tissue Morphology” ( Fig.4D ).…”

Section: Resultsmentioning

confidence: 99%

Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating

Kirkpatrick

Goldberg

Yazdani

et al. 2017

Biological Psychiatry

147

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Background Eating disorders are lethal and heritable; however, the underlying genetic factors are unknown. Binge eating is a highly heritable trait associated with eating disorders that is comorbid with mood and substance use disorders. Therefore, understanding its genetic basis will inform therapeutic development that could improve several comorbid neuropsychiatric conditions. Methods We assessed binge eating in closely related C57BL/6 mouse substrains and in an F2 cross to identify quantitative trait loci (QTL) associated with binge eating. We used gene targeting to validated candidate genetic factors. Finally, we used transcriptome analysis of the striatum via mRNA sequencing (RNA-seq) to identify the premorbid transcriptome and the binge-induced transcriptome to inform molecular mechanisms mediating binge eating susceptibility and establishment. Results C57BL/6NJ but not C57BL/6J mice showed rapid and robust escalation in palatable food consumption. We mapped a single genome-wide significant QTL on chromosome 11 (LOD=7.4) to a missense mutation in cytoplasmic FMR1-interacting protein 2 (Cyfip2). We validated Cyfip2 as a major genetic factor underlying binge eating in heterozygous knockout mice on a C57BL/6N background that showed reduced binge eating toward a wild-type C57BL/6J-like level. Transcriptome analysis of premorbid genetic risk identified the enrichment terms “morphine addiction” and “retrograde endocannabinoid signaling” whereas binge eating resulted in the downregulation of a gene set enriched for decreased myelination, oligodendrocyte differentiation, and expression. Conclusions We identified Cyfip2 as a major significant genetic factor underlying binge eating and provide a behavioral paradigm for future genome-wide association studies in populations with increased genetic complexity.

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“…Genomic analysis of BD, with an estimated heritability of ∼60-85% [286,294,295], has also uncovered disruptions in Wnt/β-catenin pathway loci, including WNT7A and WNT2B [296], DISC1 [297,298,299,300], and TCF7L2 ( TCF4 ) [301,302]. Other genes that help regulate the Wnt/β-catenin signaling have also been identified.…”

Section: Human Genomic Studiesmentioning

confidence: 99%

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Mulligan

Cheyette

2016

Complex Psychiatry

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Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.

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Accumulating evidence for a role of TCF7L2 variants in bipolar disorder with elevated body mass index

Abstract: The current study provides further evidence suggesting that TCF7L2 involvement in BD risk may be regulated by BMI. Detailed, prospective assessment of BMI, comorbidity, and other possible contributing factors is necessary to explain fully the mechanisms underlying this association.

Cited by 33 publications

References 44 publications

Casein kinase 1‐epsilon deletion increases mu opioid receptor‐dependent behaviors and binge eating1

Casein kinase 1‐epsilon deletion increases mu opioid receptor‐dependent behaviors and binge eating1

Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

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