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1.
Psychoneuroendocrinology ; 114: 104600, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32062372

RESUMO

INTRODUCTION: Previous studies showed significant increases in DNA base damage markers and significant alterations in base excision repair enzymes in patients with unipolar and bipolar depression. We aimed to investigate changes in urine 8-Oxo-2'-deoxyguanosine (8-oxo-dG) and gene expression levels of 8-Oxoguanine DNA glycosylase 1 (OGG1) during a current depressive episode and after remission in bipolar and unipolar disorders. METHODS: Twenty-four acutely depressed bipolar (BD), 33 unipolar depression (UD) patients and 61 healthy controls were included in the study. Clinical evaluations, blood and urine sampling were completed at baseline and at remission after eight weeks. The urine 8-oxo-dG levels were assessed by liquid chromatography tandem mass spectrometry and adjusted for urine creatinine levels. The gene expression levels of OGG1 were determined from cDNA extracted from blood samples, using real time-polymerase chain reaction. RESULTS: At baseline, patients presented significantly higher levels of 8-oxo-dG (p = 0.008), and lower gene expression of OGG1 (p = 0.024) compared to controls. Levels of either 8-oxo-dG or OGG1 expression did not differ between BD and UD. In patients who remitted by the 8th week (n = 30), 8-oxo-dG decreased significantly (p = 0.001), and gene expression levels of OGG1 increased by 2.95 times compared to baseline levels (p = 0.001). All comparisons were adjusted for age, sex, smoking status and body mass index. CONCLUSION: Our results suggest that patients with bipolar and unipolar mood disorders present increased 8-oxo-dG and decreased gene expression levels of OGG1 in current depressive episodes, and that these changes might be reversed by the resolution of depressive symptoms. The causal relationship between DNA damage and repair requires further exploration.

2.
Int J Mol Sci ; 21(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012861

RESUMO

Major depressive disorder (MDD) is the leading cause of disability worldwide and is associated with high rates of suicide and medical comorbidities. Current antidepressant medications are suboptimal, as most MDD patients fail to achieve complete remission from symptoms. At present, clinicians are unable to predict which antidepressant is most effective for a particular patient, exposing patients to multiple medication trials and side effects. Since MDD's etiology includes interactions between genes and environment, the epigenome is of interest for predictive utility and treatment monitoring. Epigenetic mechanisms of antidepressant medications are incompletely understood. Differences in epigenetic profiles may impact treatment response. A systematic literature search yielded 24 studies reporting the interaction between antidepressants and eight genes (BDNF, MAOA, SLC6A2, SLC6A4, HTR1A, HTR1B, IL6, IL11) and whole genome methylation. Methylation of certain sites within BDNF, SLC6A4, HTR1A, HTR1B, IL11, and the whole genome was predictive of antidepressant response. Comparing DNA methylation in patients during depressive episodes, during treatment, in remission, and after antidepressant cessation would help clarify the influence of antidepressant medications on DNA methylation. Individuals' unique methylation profiles may be used clinically for personalization of antidepressant choice in the future.

3.
J Affect Disord ; 267: 96-102, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32063579

RESUMO

BACKGROUND: The brain-derived neurotrophic factor (BDNF) rs6265 (Val66Met) Met allele is associated with early onset (≤ 19 years old) bipolar disorder (BD). Val66Met (G196A) creates a CpG site when the Val/G allele is present. We sought to study the methylation of the BDNF promoter and its interaction with Val66Met genotype in BD. METHODS: Sex/age-matched previously genotyped DNA samples from BD-Type 1 cases [N = 166: early onset (≤ 19 years old) n = 79, late onset (> 20 years old) n = 87] and controls (N = 162) were studied. Pyrosequencing of four CpGs in Promoter-I, four CpGs in promoter-IV, and two CpGs in Promoter-IX (CpG2 includes G= Val allele) was performed. Logistic regression adjusting for batch effect was used to compare cases vs. controls. Analyses also included stratification by disease onset and adjustment for Val66Met genotype. Secondary exploratory analyses for the association of life stressors, comorbid substance abuse, and psychotropic use with methylation patterns were performed. RESULTS: Comparing all BD cases vs. controls and adjusting for Val66Met genotype, BD cases had significantly higher methylation in promoter -IX/CPG-2 (p = 0.0074). This was driven by early onset cases vs. controls (p = 0.00039) and not late onset cases vs. controls (p = 0.2). LIMITATION: Relatively small sample size. CONCLUSION: Early onset BD is associated with increased methylation of CpG site created by Val=G allele of the Val66Met variance. Further studies could include larger sample size and postmortem brain samples in an attempt to replicate these findings.

4.
Bipolar Disord ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31643130

RESUMO

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of the dopaminergic-enhancing agent modafinil/armodafinil (MoArm) as adjunctive treatment for bipolar depression. METHODS: A comprehensive search of major electronic databases was conducted to identify randomized controlled trials (RCTs) of adjunctive MoArm that included patients with bipolar I (BP-I) or bipolar II (BP-II) depression. Data for response/remission and all-cause discontinuation were analyzed. Effect size was summarized by relative risk (RR) using a random effect model. RESULTS: Of 58 studies, five RCTs (N = 795 drug, N = 792 placebo) met inclusion criteria. Four armodafinil studies included only BP-I patients and one modafinil study included both bipolar subtypes with limited heterogeneity (I2  = 34%, P = .19; I2  = 18%, P = .30). Compared to placebo, augmentation with MoArm was associated with significantly greater rates of treatment response (RR, 1.18; 95% CI, 1.01-1.37; P = .03) and remission (RR, 1.38; 95% CI, 1.10-1.73; P = .005). All-cause discontinuation was not different than placebo (RR, 1.08; 95% CI, 0.89-1.30; P = .45) with no evidence of increased risk of mood switch or suicide attempts with MoArm (RR, 0.99; 95% CI, 0.39-2.5; P = .98; RR, 1.02; 95% CI, 0.37-2.85; P = .97). CONCLUSION: This narrower scope meta-analysis of one drug for one disease suggests that adjunctive MoArm may represent a novel therapeutic intervention. Further studies delineating the subtypes of bipolar depression responsive to these novel dopaminergic-enhancing agents are encouraged.

5.
JAMA Psychiatry ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31532468

RESUMO

Importance: Infection-associated immune activation and inflammation are increasingly recognized in the pathophysiology of bipolar disorder. Objective: To determine whether antibodies to common infectious agents, including cytomegalovirus (CMV), Toxoplasma gondii, and measles, as well as the inflammatory marker C-reactive protein, in serum samples differ between patients with bipolar disorder and control individuals without bipolar disorder. Design, Setting, and Participants: In this case-control study, antibody titers were measured in serum samples from 1207 patients with bipolar disorder and 745 controls that were obtained from biobanks with participating sites in Rochester and Minneapolis, Minnesota (n = 1537), and Cincinnati, Ohio (n = 415), from January 5, 2009, through May 12, 2014. A subset of case patients and controls from Minnesota were matched by age, sex, and educational level. Bipolar type, age at onset, and history of psychosis were assessed for case patients as well as current drug treatment at the time of blood sample obtainment from the biobank. Data were analyzed from February 5, 2018, to January 4, 2019. Exposures: The CMV and T gondii antibodies with IgM titers were expressed as z scores and IgG titers dichotomized into seropositive and seronegative based on expected prevalence in the US population and further classified based on the joint CMV-positive/T gondii-negative IgG status, C-reactive protein z score, and drug treatments with antitoxoplasma activity. Main Outcomes and Measures: Patients were stratified by bipolar disorder type I or type II, nonearly (>19 years of age) and early (≤19 years of age) onset, and history of psychosis during mania or no psychosis. Results: Of 1207 patients with bipolar disorder (mean [SD] age, 43.2 [15.1] years; 742 [61.5%] female), the CMV-positive/T gondii-negative IgG status was significantly higher (odds ratio [OR], 1.33; 95% CI, 1.09-1.62; P = .004) compared with that in the 745 controls (mean [SD] age, 44.5 [15.5] years; 444 [59.6%] female). The CMV-positive/T gondii-negative IgG status was associated with bipolar cases type I (OR, 1.41; 95% CI, 1.14-1.75; P = .001), nonearly age at onset (OR, 1.41; 95% CI, 1.16-1.72; P = .001), and history of manic psychosis (OR, 1.46; 95% CI, 1.13-1.88; P = .004). Patients with bipolar disorder who received drug treatment with antitoxoplasma activity (n = 272) had significantly lower T gondii IgM titers (median, 1.59; interquartile range, 1.30-2.07) compared with those (n = 900) who did not receive this treatment (median, 1.69; interquartile range, 1.35-2.25) (P = .03). Conclusions and Relevance: In this sample, increased long-term antibody response to CMV and decreased long-term antibody response to T gondii were associated with bipolar disorder and the subphenotypes of bipolar type I, nonearly disease onset, and manic psychosis. Further work appears to be needed to better understand genetic vs environmental disease risk and infection or immune activation contribution to overall disease pathogenesis with particular reference to disease onset.

7.
J Psychiatr Res ; 117: 45-54, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279243

RESUMO

Dorsolateral prefrontal cortex (DLPFC) and temporal pole (TP) are brain regions that display abnormalities in bipolar disorder (BD) patients. DNA methylation - an epigenetic mechanism both heritable and sensitive to the environment - may be involved in the pathophysiology of BD. To study BD-associated DNA methylomic differences in these brain regions, we extracted genomic DNA from the postmortem tissues of Brodmann Area (BA) 9 (DLPFC) and BA38 (TP) gray matter from 20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850 K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups. The genes of DMPs common to both BD and MDD (hypothetically associated with their common features such as depression) and those distinct to BD (hypothetically associated with BD-specific features such as mania) were enriched in pathways involved in neurodevelopment including axon guidance. Pathways enriched only in the BD-MDD shared list pointed to GABAergic dysregulation, while those enriched in the BD-only list suggested glutamatergic dysregulation and greater impact on synaptogenesis and synaptic plasticity. We further detected group-specific between-brain-region gene expression differences in ODC1, CALY, GALNT2, and GABRD, which contained significant between-brain-region DMPs. In each brain region, no significant DMPs or differentially methylated regions (DMRs) were found between diagnostic groups. In summary, the methylation differences between DLPFC and TP may provide molecular targets for further investigations of genetic and environmental vulnerabilities associated with both unique and common features of various mood disorders and suggest directions of future development of individualized treatment strategies.

8.
Addict Biol ; : e12801, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31267611

RESUMO

Disruptions in circadian rhythms are risk factors for excessive alcohol drinking. The ethanol-sensitive adenosine equilibrative nucleoside transporter type 1 (ENT1, slc29a1) regulates ethanol-related behaviors, sleep, and entrainment of circadian rhythms. However, the mechanism underlying the increased ethanol consumption in ENT1 knockout (KO) mice in constant light (LL) and whether there are sex differences in ethanol consumption in ENT1 mice are less studied. Here, we investigated the effects of loss of ENT1, LL, and sex on ethanol drinking using two-bottle choice. In addition, we monitored the locomotor activity rhythms. We found that LL increased ethanol drinking and reduced accumbal ENT1 expression and adenosine levels in male but not female mice, compared with control mice. Interestingly, only LL-exposed male, not female, ENT1 KO mice exhibited higher ethanol drinking and a longer circadian period with a higher amplitude compared with wild-type (WT) mice. Furthermore, viral-mediated rescue of ENT1 expression in the NAc of ENT1 KO mice reduced ethanol drinking, demonstrating a possible causal link between ENT1 expression and ethanol drinking in males. Together, our findings indicate that deficiency of ENT1 expression contributes to excessive ethanol drinking in a sex-dependent manner.

9.
Transl Psychiatry ; 9(1): 149, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123248

RESUMO

Glutamatergic dysregulation is implicated in the neurobiology of mood disorders. This study investigated the relationship between the anterior cingulate cortex (AC) glutamate, as measured by proton magnetic resonance spectroscopy (1H-MRS), and single-nucleotide polymorphisms (SNPs) from four genes (GLUL, SLC1A3, SLC1A2, and SLC1A7) that regulate the extracellular glutamate in 26 depressed patients with major depressive disorder (MDD; n = 15) and bipolar disorder (BD; n = 11). Two SNPs (rs3812778 and rs3829280), in perfect linkage disequilibrium, in the 3' untranslated region of the EAAT2 gene SLC1A2, were associated with AC glutamate, with minor allele carriers having significantly higher glutamate levels (p < 0.001) in comparison with common allele homozygotes. In silico analysis revealed an association of minor allele carriers of rs3812778/rs382920 with an upregulation of the astrocytic marker CD44 localized downstream of SLC1A2 on chromosome 11. Finally, we tested the disease relevance of these SNPs in a large group of depressed patients [MDD (n = 458); BD (n = 1473)] and found that minor allele carriers had a significantly higher risk for rapid cycling (p = 0.006). Further work is encouraged to delineate the functional impact of excitatory amino acid transporter genetic variation on CD44 associated physiology and glutamatergic neurotransmission, specifically glutamate-glutamine cycling, and its contribution to subphenotypes of mood disorders.

10.
Behav Brain Res ; 370: 111943, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31095992

RESUMO

Adolescent's consumption of caffeine and caffeinated beverage is increasing, yet little is known about the consequences of chronic caffeine exposure during the critical development period of adolescence. In the present study, we investigated the effect of beginning chronic caffeine consumption in adolescence on locomotor, mood, sensorimotor gating, and reward seeking behaviors through adolescence and in adulthood. During the light cycle, caffeine exposed mice exhibited hypoactivity in a novel open-field box and increased anxiety-like and depressive-like behaviors, while maintaining normal home cage locomotor activity. In contrast, during the dark cycle caffeine exposed mice displayed normal locomotor activity in a novel open-field box with hyperactive home cage activity. Interestingly, we found that caffeine exposed mice also showed enhanced prepulse inhibition during the light cycle whereas they displayed a deficit of prepulse inhibition during the dark cycle. Reward seeking for sucrose was higher in caffeine exposed than control mice during the light cycle. Additionally, when granted 24 -h access to ethanol as adults, caffeine exposed mice consumed more ethanol in the absence of acute caffeine use. Altogether, mice that consumed chronic caffeine beginning in adolescence had increased reward seeking and exhibited a circadian-dependent pattern of mood fluctuations in adulthood.

11.
Front Pharmacol ; 10: 83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30837869

RESUMO

Background: Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance. Methods: Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003-2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD24), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups. Results: Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01). Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence.

12.
Genes (Basel) ; 10(2)2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30781888

RESUMO

Post-traumatic stress disorder (PTSD) is an acquired psychiatric disorder with functionally impairing physiological and psychological symptoms following a traumatic exposure. Genetic, epigenetic, and environmental factors act together to determine both an individual's susceptibility to PTSD and its clinical phenotype. In this literature review, we briefly review the candidate genes that have been implicated in the development and severity of the PTSD phenotype. We discuss the importance of the epigenetic regulation of these candidate genes. We review the general epigenetic mechanisms that are currently understood, with examples of each in the PTSD phenotype. Our focus then turns to studies that have examined PTSD in the context of comorbid psychiatric disorders or associated social and behavioral stressors. We examine the epigenetic variation in cases or models of PTSD with comorbid depressive disorders, anxiety disorders, psychotic disorders, and substance use disorders. We reviewed the literature that has explored epigenetic regulation in PTSD in adverse childhood experiences and suicide phenotypes. Finally, we review some of the information available from studies of the transgenerational transmission of epigenetic variation in maternal cases of PTSD. We discuss areas pertinent for future study to further elucidate the complex interactions between epigenetic modifications and this complex psychiatric disorder.


Assuntos
Epigênese Genética , Transtornos Psicóticos/genética , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/fisiopatologia , Comorbidade , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/fisiopatologia , Humanos , Transtornos Psicóticos/fisiopatologia , Índice de Gravidade de Doença , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Suicídio
13.
J Affect Disord ; 246: 62-68, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578947

RESUMO

BACKGROUND: The purpose of this study was to identify specific pharmacokinetic (PK) and pharmacodynamics (PD) factors that affect the likelihood of treatment remission with a serotonin norepinephrine reuptake inhibitor (SNRI) in depressed patients whose initial selective serotonin reuptake inhibitor (SSRI) failed. METHODS: Multiple logistic regression modeling of PK and PD variation hypothesized to contribute to SNRI (i.e. duloxetine or venlafaxine) treatment remission in prior SSRI (i.e. citalopram or escitalopram) failure was conducted on 139 subjects from the Pharmacogenomics Research Network (PGRN) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies. Depressive symptoms were assessed with the Quick Inventory of Depressive Symptomatology Clinician-rated (QIDS-C16). RESULTS: Venlafaxine-XR remission was associated with a significant interaction between CYP2D6 ultra-rapid metabolizer (URM) phenotype and SLC6A4 5-HTTLPR L/L genotype. A similar significant interaction effect was observed between CYP2D6 URM and SLC6A2 G1287A GA genotype. Stratifying by transporter genotypes, venlafaxine-XR remission was associated with CYP2D6 URM in patients with SLC6A4 L/L (p = 0.001) and SLC6A2 G1287A GA genotypes. LIMITATIONS: The primary limitation of this post hoc study was small sample size. CONCLUSION: Our results suggest that CYP2D6 ultra-rapid metabolizer status contributes to venlafaxine-XR treatment remission in MDD patients; in particular, there is a PK-PD interaction with treatment remission associated with CYP2D6 URM phenotype and SLC6A4 5-HTTLPR L/L or SLC6A2 G1287A G/A genotype, respectively. These preliminary data are encouraging and support larger pharmacogenomics studies differentiating treatment response to mechanistically different antidepressants in addition to further PK-PD interactive analyses.


Assuntos
Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Adulto , Antidepressivos/farmacocinética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Fenótipo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/farmacocinética , Falha de Tratamento , Cloridrato de Venlafaxina/farmacocinética
14.
Transl Psychiatry ; 8(1): 188, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30201969

RESUMO

Bipolar disorder (BD) is highly heterogeneous in symptomatology. Narrowing the clinical phenotype may increase the power to identify risk genes that contribute to particular BD subtypes. This study was designed to test the hypothesis that genetic overlap between schizophrenia (SZ) and BD is higher for BD with a history of manic psychosis. Analyses were conducted using a Mayo Clinic Bipolar Biobank cohort of 957 bipolar cases (including 333 with history of psychosis during mania, 64 with history of psychosis only during depression, 547 with no history of psychosis, and 13 with unknown history of psychosis) and 778 controls. Polygenic risk score (PRS) analysis was performed by calculating a SZ-PRS for the BD cases and controls, and comparing the calculated SZ risk between different psychosis subgroups and bipolar types. The SZ-PRS was significantly higher for BD-I cases with manic psychosis than BD-I cases with depressive psychosis (Nagelkerke's R2 = 0.021; p = 0.045), BD-I cases without psychosis (R2 = 0.015; p = 0.007), BD-II cases without psychosis (R2 = 0.014; p = 0.017), and controls (R2 = 0.065; p = 2 × 10-13). No other significant differences were found. Our results show that BD-I with manic psychosis is genetically more similar to SZ than any other tested BD subgroup. Further investigations on genetics of distinct clinical phenotypes composing major psychoses may help refine the current diagnostic classification system.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/genética , Predisposição Genética para Doença , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Adulto , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Fenótipo , Medição de Risco , Psicologia do Esquizofrênico
15.
J Psychiatr Res ; 95: 208-212, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28886448

RESUMO

In a prior discovery study, increased levels of serum Growth Differentiation Factor 15 (GDF15), Hepsin (HPN), and Matrix Metalloproteinase-7 (MMP7) were observed in bipolar depressed patients vs controls. This exploratory post-hoc analysis applied a proteomic-informed genomic research strategy to study the potential functional role of these proteins in bipolar disorder (BP). Utilizing the Genotype-Tissue Expression (GTEx) database to identify cis-acting blood expression quantitative trait loci (cis-eQTLs), five eQTL variants from the HPN gene were analyzed for association with BP cases using genotype data of cases from the discovery study (n = 58) versus healthy controls (n = 777). After adjusting for relevant covariates, we analyzed the relationship between these 5 cis-eQTLs and HPN serum level in the BP cases. All 5 cis-eQTL minor alleles were significantly more frequent in BP cases vs controls [(rs62122114, OR = 1.6, p = 0.02), (rs67003112, OR = 1.6, p = 0.02), (rs4997929, OR = 1.7, p = 0.01), (rs12610663, OR = 1.7, p = 0.01), (rs62122148, OR = 1.7, P = 0.01)]. The minor allele (A) in rs62122114 was significantly associated with increased serum HPN level in BP cases (Beta = 0.12, P = 0.049). However, this same minor allele was associated with reduced gene expression in GTEx controls. These exploratory analyses suggest that genetic variation in/near the gene encoding for hepsin protein may influence risk of bipolar disorder. This genetic variation, at least for the rs62122114-A allele, may have functional impact (i.e. differential expression) as evidenced by serum HPN protein expression. Although limited by small sample size, this study highlights the merits of proteomic informed functional genomic studies as a tool to investigate with greater precision the genetic risk of bipolar disorder and secondary relationships to protein expression recognizing, and encouraging in subsequent studies, high likelihood of epigenetic modification of genetic disease risk.


Assuntos
Transtorno Bipolar/sangue , Transtorno Bipolar/genética , Proteômica/métodos , Locos de Características Quantitativas/genética , Serina Endopeptidases/sangue , Serina Endopeptidases/genética , Bases de Dados Genéticas , Humanos
16.
Front Cell Neurosci ; 11: 217, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28785205

RESUMO

While downregulation of excitatory amino acid transporter 2 (EAAT2), the main transporter removing glutamate from the synapse, has been recognized in bipolar disorder (BD), the underlying mechanisms of downregulation have not been elucidated. BD is influenced by environmental factors, which may, via epigenetic modulation of gene expression, differentially affect illness presentation. This study thus focused on epigenetic DNA methylation regulation of SLC1A2, encoding for EAAT2, in BD with variable environmental influences of addiction. High resolution melting PCR (HRM-PCR) and thymine-adenine (TA) cloning with sequence analysis were conducted to examine methylation of the promoter region of the SLC1A2. DNA was isolated from blood samples drawn from BD patients (N = 150) with or without addiction to alcohol, nicotine, or food, defined as binge eating, and matched controls (N = 32). In comparison to controls, the SLC1A2 promoter region was hypermethylated in BD without addiction but was hypomethylated in BD with addiction. After adjusting for age and sex, the association of methylation levels with nicotine addiction (p = 0.0009) and binge eating (p = 0.0002) remained significant. Consistent with HRM-PCR, direct sequencing revealed increased methylation in CpG site 6 in BD, but decreased methylation in three CpG sites (6, 48, 156) in BD with alcohol and nicotine addictions. These results suggest that individual point methylation within the SLC1A2 promoter region may be modified by exogenous addiction and may have a potential for developing clinically valuable epigenetic biomarkers for BD diagnosis and monitoring.

17.
Psychiatry Res ; 257: 327-337, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28800512

RESUMO

Glutamatergic dysregulation is implicated in the neuropathology of bipolar disorder (BD). There is increasing interest in investigating the role of metabotropic glutamate receptors (mGluRs) in BD and as a target for treatment intervention. Bipolar mGluR studies (published January 1992-April 2016) were identified via PubMed, Embase, Web of Science, and Scopus. Full-text screening, data extraction, and quality appraisal were conducted in duplicate, with strict inclusion and exclusion criteria. The initial literature search for mGluRs in BD, including non-bipolar mood disorders and primary psychotic disorders, identified 1544 articles. 61 abstracts were selected for relevance, 16 articles met full inclusion criteria, and three additional articles were found via citations. Despite limited literature, studies demonstrated: single nucleotide polymorphisms (SNPs) associated with BD, including a GRM3 SNP associated with greater likelihood of psychosis (rs6465084), mRNA binding protein Fragile X Mental Retardation Protein associated with altered mGluR1/5 activity in BD populations, and lithium decreasing mGluR5 expression and mGluR-mediated intracellular calcium signaling. Limited research has been performed on the role of mGluRs in BD, but results highlight the importance of ongoing study. Future directions for research of mGluRs in BD include GRM polymorphisms, epigenetic regulation, intracellular proteins, and pharmacologic interactions.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Humanos
18.
J Clin Psychiatry ; 78(9): 1337-1343, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28199072

RESUMO

OBJECTIVE: In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD). METHODS: Treatment of Early Age Mania (TEAM) study enrollment and sample collection took place from 2003 to 2008. Mayo Clinic Bipolar Biobank samples were collected from 2009 to 2013. Genotyping and analyses for the present study took place from 2013 to 2014. The diagnosis of BD was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Eight single-nucleotide polymorphisms (SNPs), previously reported in genome-wide association studies to be associated with BD, were chosen for GRS analysis in early-onset bipolar disease. These SNPs map to 3 genes: CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit), ANK3 (ankyrin-3, node of Ranvier [ankyrin G]), and ODZ4 (teneurin transmembrane protein 4 [formerly "odz, odd Oz/10-m homolog 4 {Drosophila}, ODZ4"]). The 8 candidate SNPs were genotyped in patients from the TEAM study (n = 69); adult patients with BD (n = 732), including a subset with early-onset illness (n = 192); and healthy controls (n = 776). GRS analyses were performed to compare early-onset cases with controls. In addition, associations of early-onset BD with individual SNPs and haplotypes were explored. RESULTS: GRS analysis revealed associations of the risk score with early-onset BD (P = .01). Gene-level haplotype analysis comparing TEAM patients with controls suggested association of early-onset BD with a CACNA1C haplotype (global test, P = .01). At the level of individual SNPs, comparison of TEAM cases with healthy controls provided nominally significant evidence for association of SNP rs10848632 in CACNA1C with early-onset BD (P = .017), which did not remain significant after correction for multiple comparisons. CONCLUSIONS: These preliminary analyses suggest that previously identified BD risk loci, especially CACNA1C, have a role in early-onset BD, possibly with stronger effects than for late-onset BD.


Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença/genética , Adolescente , Adulto , Idade de Início , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Técnicas de Genotipagem , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto Jovem
19.
J Affect Disord ; 208: 120-129, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27769005

RESUMO

BACKGROUND: Although multiple genes have been implicated in bipolar disorder (BD), they explain only a small proportion of its heritability. Identifying additional BD risk variants may be impaired by phenotypic heterogeneity, which is usually not taken into account in genome-wide association studies (GWAS). BD with early age at onset is a more homogeneous familial form of the disorder associated with greater symptom severity. METHODS: We conducted a GWAS of early-onset BD (onset of mania/hypomania ≤19 years old) in a discovery sample of 419 cases and 1034 controls and a replication sample of 181 cases and 777 controls. These two samples were meta-analyzed, followed by replication of one signal in a third independent sample of 141 cases and 746 controls. RESULTS: No single nucleotide polymorphism (SNP) associations were genome-wide significant in the discovery sample. Of the top 15 SNPs in the discovery analysis, rs114034759 in the muskelin (MKLN1) gene was nominally significant in the replication analysis, and was among the top associations in the meta-analysis (p=2.63E-06, OR=1.9). In the third sample, this SNP was again associated with early-onset BD (p=0.036, OR=1.6). Gene expression analysis showed that the rs114034759 risk allele is associated with decreased hippocampal MKLN1 expression. LIMITATIONS: The sample sizes of the early-onset BD subgroups were relatively small. CONCLUSIONS: Our results suggest MKLN1 is associated with early-onset BD. MKLN1 regulates cellular trafficking of GABA-A receptors, which is involved in synaptic transmission and plasticity, and is implicated in the mechanism of action of a group of antiepileptic mood stabilizers. These results therefore indicate that GABAergic neurotransmission may be implicated in early-onset BD. We propose that an increase in GABA-A receptors in the hippocampus in BD patients due to lower MKLN1 expression might increase the excitability during the GABA-excited early phase of young neurons, leading to an increased risk of developing a manic/hypomanic episode. Further studies are needed to test this model.


Assuntos
Transtorno Bipolar/genética , Moléculas de Adesão Celular/genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Idade de Início , Transtorno Bipolar/metabolismo , Estudos de Casos e Controles , Moléculas de Adesão Celular/metabolismo , Criança , Pré-Escolar , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Genéticos , Neurogênese/genética , Fenótipo , Receptores de GABA-A/metabolismo , Adulto Jovem
20.
J Affect Disord ; 201: 95-8, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27195513

RESUMO

OBJECTIVE: To determine whether bipolar spectrum disorder with binge eating behavior (BE) is an important clinical sub-phenotype. METHODS: Prevalence rates and correlates of different levels of BE were assessed in 1114 bipolar spectrum patients participating in a genetic biobank. BE and eating disorders (EDs) were assessed with the Eating Disorder Diagnostic Scale (EDDS). Psychiatric illness burden was evaluated with measures of suicidality, psychosis, mood instability, anxiety disorder comorbidity, and substance abuse comorbidity. Medical illness burden was evaluated with body mass index (BMI) and the Cumulative Index Rating Scale (CIRS). RESULTS: Thirty percent of patients had any BE and 27% had BE plus an ED diagnosis. Compared with bipolar spectrum patients without BE, bipolar spectrum patients with BE were younger and more likely to be female; had significantly higher levels of eating psychopathology, suicidality, mood instability, and anxiety disorder comorbidity; had a significantly higher mean BMI and a significantly higher rate of obesity; and had a significantly higher medical illness burden. Bipolar spectrum patients with BE but no ED diagnosis were more similar to bipolar spectrum patients without BE than to those with an ED. Nonetheless, the positive predictive value and specificity of BE predicting an ED was 0.90 and 0.96, respectively. LIMITATIONS: As only two patients had co-occurring anorexia nervosa, these results may not generalize to bipolar spectrum patients with restricting EDs. CONCLUSION: Bipolar spectrum disorder with broadly-defined BE may not be as clinically relevant a sub-phenotype as bipolar spectrum disorder with an ED but may be an adequate proxy for the latter when phenotyping large samples of individuals.


Assuntos
Transtorno da Compulsão Alimentar/diagnóstico , Transtorno Bipolar/diagnóstico , Adulto , Transtornos de Ansiedade/epidemiologia , Transtorno da Compulsão Alimentar/epidemiologia , Transtorno da Compulsão Alimentar/psicologia , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/psicologia , Índice de Massa Corporal , Comorbidade , Efeitos Psicossociais da Doença , Comportamento Alimentar/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/psicologia , Prevalência , Inquéritos e Questionários
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