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Project description:Bipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI), which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in the BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells that highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas that are involved in metabolism. In astrocytes, knockdown of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knockdown with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.
| S-EPMC8872993 | biostudies-literature
Project description:Bipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI) which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells which highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas which are involved in metabolism. In astrocytes, knock-down of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knock-down with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD-risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.
2021-07-21 | GSE179921 | GEO
Project description:Bipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI) which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells which highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas which are involved in metabolism. In astrocytes, knock-down of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knock-down with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD-risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.
2021-07-21 | GSE179762 | GEO
Project description:TCF7L2 lncRNA: A Link between Bipolar Disorder and Body Mass Index through Glucocorticoid Signaling
| PRJNA745590 | ENA
Project description:TCF7L2 lncRNA: A Link between Bipolar Disorder and Body Mass Index through Glucocorticoid Signaling [ChIP-Seq]
| PRJNA744913 | ENA
Project description:TCF7L2 lncRNA: A Link between Bipolar Disorder and Body Mass Index through Glucocorticoid Signaling [RNA-Seq]
| PRJNA745682 | ENA
Project description:We previously reported that higher body mass index (BMI) was associated with greater hippocampal glutamate+glutamine in people with bipolar disorder (BD), but not in non-BD healthy comparator subjects (HSs). In the current report, we extend these findings by examining the impact of BD diagnosis and BMI on hippocampal volumes and the concentrations of several additional neurochemicals in 57 early-stage BD patients and 31 HSs. Using 3-T magnetic resonance imaging and magnetic resonance spectroscopy, we measured bilateral hippocampal volumes and the hippocampal concentrations of four neurochemicals relevant to BD: N-acetylaspartate+N-acteylaspartylglutamate (tNAA), creatine+phosphocreatine (Cre), myoinositol (Ins) and glycerophosphocholine+phosphatidylcholine (Cho). We used multivariate factorial analysis of covariance to investigate the impact of diagnosis (patient vs HS) and BMI category (normal weight vs overweight/obese) on these variables. We found a main effect of diagnosis on hippocampal volumes, with patients having smaller hippocampi than HSs. There was no association between BMI and hippocampal volumes. We found diagnosis and BMI effects on hippocampal neurochemistry, with patients having lower Cre, Ins and Cho, and overweight/obese subjects having higher levels of these chemicals. In patient-only models that controlled for clinical and treatment variables, we detected an additional association between higher BMI and lower tNAA that was absent in HSs. To our knowledge, this was the first study to investigate the relative contributions of BD diagnosis and BMI to hippocampal volumes, and only the second to investigate their contributions to hippocampal chemistry. It provides further evidence that diagnosis and elevated BMI both impact limbic brain areas relevant to BD.
| S-EPMC5404613 | biostudies-literature
Project description:BACKGROUND:While restrictive and compensatory eating disorders (e.g. anorexia and bulimia) are associated with elevated risk of suicide, less is known about binge eating disorder (BED). There is suggestive evidence of a U-shaped relationship between body mass index (BMI) and completed suicide, but fewer studies on suicidal ideation or attempts. This study examined the association between BED, BMI, and suicidality, and assessed whether these relationships varied by gender. METHODS:Data come from the Collaborative Psychiatric Epidemiologic Surveys (N =?14,497). Binge episodes and BED were assessed using the Composite International Diagnostic Inventory (CIDI). BMI was calculated from self-reported height and weight. Suicidal ideation/attempts were assessed using the CIDI. Weighted logistic regression was used to assess the association between binging/BED, BMI and suicidality. Interaction terms were used to assess whether the relationship between BMI and suicidality was moderated by binging/BED, and whether the relationships between binging/BED and BMI differed by gender. RESULTS:One-third of adults with BED had a history of suicidality, compared to 19% of those without. Both binging (OR: 1.95, 95% CI: 1.50-2.53) and BED (OR: 2.01, 95% CI: 1.41-2.86) were associated with suicidality in fully-adjusted models. BMI was associated with suicidality in a curvilinear manner, and this relationship was exacerbated by binging/BED (ORBinge eating x BMI: 1.04, 95% CI: 1.01-1.09, p <?0.05). The relationship between BMI and suicidality did not differ by gender (ORgender x BMI: 1.00, p <?0.770). However, the relationship between binge eating and suicidality was stronger for women relative to men (ORgender X binge: 1.87, p <?0.012). CONCLUSIONS:Binge eating, even below the threshold for BED, is associated with suicidality. BMI is associated with suicidality in a curvilinear manner, and the BMI-suicidality relationship is potentiated by binge eating/BED. Findings support the thoughtful integration of psychiatric care into weight loss programs for adults with a history of binging behavior.
| S-EPMC6003111 | biostudies-literature
Project description:Inflammation is hypothesized to be a key component of bipolar disorder (BP) development and progression. However, findings linking BP prevalence and symptomology to immune functioning have been mixed, with some work suggesting that obesity may play an important role in BP-relevant inflammation. Here we investigate differences in biomarkers of inflammation [C-reactive protein (CRP), interleukin (IL)-1β, IL-6, IL-8, IL-10] between healthy controls (HC) and individuals with BP or other mental illness (MI). Adults with BP, MI, or HC (n = 545, 70% BP, 21% HC, 9% MI) self-reported depressive and manic symptoms close to a blood draw and physical exam that included measurement of height and weight. A composite score was calculated from the four cytokines measured in plasma; follow-up analyses explored a pro-inflammatory composite and IL-10, individually. BP individuals had elevated cytokine concentrations compared to HC (B = 0.197, [0.062, 0.333], t (542) = 2.855, p = .004); this difference was also evident for the pro-inflammatory composite and for IL-10. Cytokine concentrations were not associated with BP mood states. Body mass index (BMI), an indicator of obesity, was significantly higher in BP compared to HC (B = 3.780, [2.118, 5.443], t (479) = 4.457, p < .001) and differences in cytokines between the two groups was no longer significant after controlling for BMI. No differences in CRP were evident between BP and HC. These results suggest that cytokine concentrations are elevated in BP and this difference from HC is associated with obesity. Interventions targeting immune modulators in BP must carefully consider the complex relationships within the BP-inflammation-obesity triangle.
| S-EPMC10070374 | biostudies-literature
Project description:Patients with bipolar disorder are at increased risk of weight gain, which in turn increases the risk for somatic disease and nonadherence to maintenance therapy. Therefore, interventions addressing weight gain are expedient for the management of this disorder. We set out to evaluate the effects of a lifestyle intervention on body mass index (BMI) and cardiovascular and metabolic parameters in patients with bipolar disorder undergoing mood-stabilizing pharmacologic treatment.Fifty outpatients with bipolar disorder undergoing mood-stabilizing treatment participated in a randomized controlled trial (waiting control group: n = 24 and multimodal lifestyle intervention group: n = 26). Groups consisted of 2 cohorts (cohort 1: March 2005-February 2006; cohort 2: September 2005-August 2006). The intervention lasted 5 months and consisted of 11 group sessions and weekly fitness training. BMI and body weight as well as cardiovascular and metabolic parameters were determined at 3 assessment points: at pretreatment baseline, at 5 months (end of treatment), and at 11 months (6-month follow-up).Intention-to-treat analyses showed that the intervention significantly reduced BMI over time (P = .03), with significant and stable mean differences in BMI change between groups of 0.7 kg/m² (95% CI, 0.2-1.3) at 5 months and 0.8 kg/m² (95% CI, 0.1-1.6) at 11 months' follow-up assessment. The lifestyle intervention had no significant effect on cardiovascular and metabolic parameters (all nonsignificant). The BMI reduction was only seen in female patients (P = .003).BMI in patients with bipolar disorder can be reduced with a long-lasting effect by a multimodal lifestyle intervention. However, this effect was only seen in female participants, indicating the need for gender-specific interventions.clinicaltrials.gov Identifier: NCT00980863.
| S-EPMC3025996 | biostudies-other