RESUMO
Bipolar I Disorder (BP) is a serious, recurrent mood disorder that is characterized by alternating episodes of mania and depression. To begin to identify novel approaches and pathways involved in BP, we have obtained skin samples from BP patients and undiagnosed control (C) individuals, reprogrammed them to form induced pluripotent stem cells (iPSC), and then differentiated the stem cells into astrocytes. RNAs from BP and C astrocytes were extracted and RNAseq analysis carried out. 501 differentially expressed genes were identified, including genes for cytoskeletal elements, extracellular matrix, signaling pathways, neurodegeneration, and notably transcripts that identify exosomes. When we compared highly expressed genes using hierarchial cluster analysis, "Exosome" was the first and most highly significant cluster identified, p < 5 × 10-13, Benjamini correction. Exosomes are membrane-bound vesicles that package and remove toxic proteins from cells and also enable cell to cell communication. They carry genetic material, including DNA, mRNA and microRNAs, proteins, and lipids to target cells throughout the body. Exosomes are released by cortical neurons and astrocytes in culture and are present in BP vs C postmortem brain tissue. Little is known about what transcripts and proteins are targeted to neurons, how they regulate biological functions of the acceptor cell, or how that may be altered in mood disorders. Since astrocyte-derived exosomes have been suggested to promote neuronal plasticity, as well as to remove toxic proteins in the brain, alterations in their function or content may be involved in neurodevelopmental, neuropathological, and neuropsychiatric conditions. To examine exosome cargos and interactions with neural precursor cells, astrocytes were differentiated from four bipolar disorder (BP) and four control (C) iPSC lines. Culture supernatants from these astrocytes were collected, and exosomes isolated by ultra-centrifugation. Western blot analysis demonstrated the presence of the exosome markers CD9, CD81, and Hsp70. Nanosight technology was used to characterize exosomes from each astrocyte cell line, suggesting that exosomes were slightly more concentrated in culture supernatants derived from BP compared with C astrocytes but there was no difference in the mean sizes of the exosomes. Analysis of their function in neuronal differentiation is being carried out by labeling exosomes derived from bipolar patient and control astrocytes and adding them to control neural progenitor cells. Given the current interest in clearing toxic proteins from brains of patients with neurodegenerative disorders, exosomes may present similar opportunities in BP.
Assuntos
Transtorno Bipolar , Exossomos , Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Astrócitos , HumanosRESUMO
GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABAA receptor-associated protein (GABARAP) to stabilize cell surface GABAA receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.
Assuntos
Anquirinas/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Vias Neurais , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Adulto , Idoso , Animais , Anquirinas/genética , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Células Cultivadas , Feminino , Neurônios GABAérgicos/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Sinapses/metabolismo , Adulto JovemRESUMO
In the original version of this article, affiliation 3 was given as: "Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong, University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China". This has now been corrected to: "Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China".Additionally in the 'Data availability' section an incorrect accession code was given. The accession code has now been changed from 'PDB A9X (AnkG:GABARAPL)' to 'PDB 6A9X (AnkG:GABARAP)'.These errors have been corrected in both the PDF and HTML versions of the Article.
RESUMO
The Diagnostic and Statistical Manual of Mental Disorder (DSM) classification of bipolar disorder defines categories to reflect common understanding of mood symptoms rather than scientific evidence. This work aimed to determine whether bipolar I can be objectively classified from longitudinal mood data and whether resulting classes have clinical associations. Bayesian nonparametric hierarchical models with latent classes and patient-specific models of mood are fit to data from Longitudinal Interval Follow-up Evaluations (LIFE) of bipolar I patients (N=209). Classes are tested for clinical associations. No classes are justified using the time course of DSM-IV mood states. Three classes are justified using the course of subsyndromal mood symptoms. Classes differed in attempted suicides (P=0.017), disability status (P=0.012) and chronicity of affective symptoms (P=0.009). Thus, bipolar I disorder can be objectively classified from mood course, and individuals in the resulting classes share clinical features. Data-driven classification from mood course could be used to enrich sample populations for pharmacological and etiological studies.
Assuntos
Afeto , Transtorno Bipolar/classificação , Transtorno Bipolar/psicologia , Adulto , Transtorno Bipolar/diagnóstico , Doença Crônica , Manual Diagnóstico e Estatístico de Transtornos Mentais , Avaliação da Deficiência , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tentativa de Suicídio/psicologiaRESUMO
OBJECTIVE: Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder. METHOD: The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6-month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models. RESULTS: At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome. CONCLUSION: Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment.
RESUMO
The neurobiology of mood states is complicated by exposure to everyday stressors (e.g., psychosocial, ubiquitous environmental infections like CMV), each fluctuating between latency and reactivation. CMV reactivation induces proinflammatory cytokines (e.g., TNF-α) associated with induction of neurotoxic metabolites and the presence of mood states in bipolar disorder (BD). Whether CMV reactivation is associated with bipolar diagnoses (trait) or specific mood states is unclear. We investigated 139 BD type I and 99 healthy controls to determine if concentrations of IgG antibodies to Herpesviridae (e.g., CMV, HSV-1, and HSV-2) were associated with BD-I diagnosis and specific mood states. We found higher CMV antibody concentration in BD-I than in healthy controls (T234 = 3.1, P uncorr = 0.002; P corr = 0.006) but no difference in HSV-1 (P > 0.10) or HSV-2 (P > 0.10). Compared to euthymic BD-I volunteers, CMV IgG was higher in BD-I volunteers with elevated moods (P < 0.03) but not different in depressed moods (P > 0.10). While relationships presented between BD-I diagnosis, mood states, and CMV antibodies are encouraging, they are limited by the study's cross sectional nature. Nevertheless, further testing is warranted to replicate findings and determine whether reactivation of CMV infection exacerbates elevated mood states in BD-I.
Assuntos
Afeto/fisiologia , Transtorno Bipolar/virologia , Infecções por Citomegalovirus/diagnóstico , Adulto , Anticorpos Antivirais/sangue , Transtorno Bipolar/complicações , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , MasculinoRESUMO
BACKGROUND: The first aim was to use confirmatory factor analysis (CFA) to test a hypothesis that two factors (internalizing and externalizing) account for lifetime co-morbid DSM-IV diagnoses among adults with bipolar I (BPI) disorder. The second aim was to use confirmatory latent class analysis (CLCA) to test the hypothesis that four clinical subtypes are detectible: pure BPI; BPI plus internalizing disorders only; BPI plus externalizing disorders only; and BPI plus internalizing and externalizing disorders. METHOD: A cohort of 699 multiplex BPI families was studied, ascertained and assessed (1998-2003) by the National Institute of Mental Health Genetics Initiative Bipolar Consortium: 1156 with BPI disorder (504 adult probands; 594 first-degree relatives; and 58 more distant relatives) and 563 first-degree relatives without BPI. Best-estimate consensus DSM-IV diagnoses were based on structured interviews, family history and medical records. MPLUS software was used for CFA and CLCA. RESULTS: The two-factor CFA model fit the data very well, and could not be improved by adding or removing paths. The four-class CLCA model fit better than exploratory LCA models or post-hoc-modified CLCA models. The two factors and four classes were associated with distinctive clinical course and severity variables, adjusted for proband gender. Co-morbidity, especially more than one internalizing and/or externalizing disorder, was associated with a more severe and complicated course of illness. The four classes demonstrated significant familial aggregation, adjusted for gender and age of relatives. CONCLUSIONS: The BPI two-factor and four-cluster hypotheses demonstrated substantial confirmatory support. These models may be useful for subtyping BPI disorders, predicting course of illness and refining the phenotype in genetic studies.
Assuntos
Transtorno Bipolar/psicologia , Família/psicologia , Predisposição Genética para Doença , Controle Interno-Externo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Comorbidade , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , National Institute of Mental Health (U.S.) , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Depression is characterized by poor executive function, but - counterintuitively - in some studies, it has been associated with highly accurate performance on certain cognitively demanding tasks. The psychological mechanisms responsible for this paradoxical finding are unclear. To address this issue, we applied a drift diffusion model (DDM) to flanker task data from depressed and healthy adults participating in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study. METHOD: One hundred unmedicated, depressed adults and 40 healthy controls completed a flanker task. We investigated the effect of flanker interference on accuracy and response time, and used the DDM to examine group differences in three cognitive processes: prepotent response bias (tendency to respond to the distracting flankers), response inhibition (necessary to resist prepotency), and executive control (required for execution of correct response on incongruent trials). RESULTS: Consistent with prior reports, depressed participants responded more slowly and accurately than controls on incongruent trials. The DDM indicated that although executive control was sluggish in depressed participants, this was more than offset by decreased prepotent response bias. Among the depressed participants, anhedonia was negatively correlated with a parameter indexing the speed of executive control (r = -0.28, p = 0.007). CONCLUSIONS: Executive control was delayed in depression but this was counterbalanced by reduced prepotent response bias, demonstrating how participants with executive function deficits can nevertheless perform accurately in a cognitive control task. Drawing on data from neural network simulations, we speculate that these results may reflect tonically reduced striatal dopamine in depression.
Assuntos
Cognição , Depressão/psicologia , Função Executiva , Tempo de Reação , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Testes Neuropsicológicos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inquéritos e Questionários , Adulto JovemRESUMO
Bipolar disorder (BP) is a chronic psychiatric condition characterized by dynamic, pathological mood fluctuations from mania to depression. To date, a major challenge in studying human neuropsychiatric conditions such as BP has been limited access to viable central nervous system tissue to examine disease progression. Patient-derived induced pluripotent stem cells (iPSCs) now offer an opportunity to analyze the full compliment of neural tissues and the prospect of identifying novel disease mechanisms. We have examined changes in gene expression as iPSC derived from well-characterized patients differentiate into neurons; there was little difference in the transcriptome of iPSC, but BP neurons were significantly different than controls in their transcriptional profile. Expression of transcripts for membrane bound receptors and ion channels was significantly increased in BP-derived neurons compared with controls, and we found that lithium pretreatment of BP neurons significantly altered their calcium transient and wave amplitude. The expression of transcription factors involved in the specification of telencephalic neuronal identity was also altered. Control neurons expressed transcripts that confer dorsal telencephalic fate, whereas BP neurons expressed genes involved in the differentiation of ventral (medial ganglionic eminence) regions. Cells were responsive to dorsal/ventral patterning cues, as addition of the Hedgehog (ventral) pathway activator purmorphamine or a dorsalizing agent (lithium) stimulated expression of NKX2-1 (ventral identity) or EMX2 (dorsal) in both groups. Cell-based models should have a significant impact on our understanding of the genesis and therefore treatment of BP; the iPSC cell lines themselves provide an important resource for comparison with other neurodevelopmental disorders.
Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Sinalização do Cálcio/genética , Células-Tronco Pluripotentes/patologia , Telencéfalo/metabolismo , Telencéfalo/patologia , Transcrição Gênica/genética , Adulto , Transtorno Bipolar/tratamento farmacológico , Padronização Corporal/genética , Sinalização do Cálcio/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Progressão da Doença , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Proteínas de Homeodomínio/genética , Humanos , Carbonato de Lítio/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Células-Tronco Pluripotentes/efeitos dos fármacos , Valores de Referência , Telencéfalo/efeitos dos fármacos , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/genética , Transcrição Gênica/efeitos dos fármacosRESUMO
BACKGROUND: Internet-based educational interventions may be useful for impacting knowledge and behavioral change. However, in AD prevention, little data exists about which educational tools work best in terms of learning and interest in participating in clinical trials. OBJECTIVES: Primary: Assess effectiveness of interactive webinars vs. written blog-posts on AD prevention learning. Secondary: Evaluate the effect of AD prevention education on interest in participating in clinical trials; Assess usability of, and user perceptions about, an online AD education research platform; Classify target populations (demographics, learning needs, interests). DESIGN: Observational. SETTING: Online. PARTICIPANTS: Men/Women, aged 25+, recruited via facebook.com. INTERVENTION: Alzheimer's Universe (www.AlzU.org) education research platform. MEASUREMENTS: Pre/post-test performance, self-reported Likert-scale ratings, completion rates. RESULTS: Over two-weeks, 4268 visits were generated. 503 signed-up for a user account (11.8% join rate), 196 participated in the lessons (39.0%) and 100 completed all beta-testing steps (19.9%). Users randomized to webinar instruction about AD prevention and the stages of AD demonstrated significant increases (p=0.01) in pre vs. post-testing scores compared to blog-post intervention. Upon joining, 42% were interested in participating in a clinical trial in AD prevention. After completing all beta-test activities, interest increased to 86%. Users were primarily women and the largest category was children of AD patients. 66.3% joined to learn more about AD prevention, 65.3% to learn more about AD treatment. CONCLUSIONS: Webinar-based education led to significant improvements in learning about AD prevention and the stages of AD. AlzU.org participation more than doubled interest in AD prevention clinical trial participation. Subjects were quickly and cost-effectively recruited, and highly satisfied with the AD education research platform. Based on these data, we will further refine AlzU.org prior to public launch and aim to study the effectiveness of 25 interactive webinar-based vs. blog-post style lessons on learning and patient outcomes, in a randomized, within-subjects design trial.
RESUMO
Research utilizing visual event-related brain potentials (ERPs) has demonstrated that reduced P300 amplitude and prolonged latency may qualify as a biological marker (biomarker) for schizophrenia (SZ). We examined P300 characteristics in response inhibition among three putatively distinct psychopathology groups including schizophrenia (SZ), bipolar I disorder (BD) and schizoaffective disorder (SA) in comparison with healthy controls (CT) to determine their electrophysiological distinctiveness. In two separate studies, deficits in response inhibition indexed by the P300 component were investigated using a lateralized Go/NoGo task. We hypothesized that deficits in response inhibition would be present and distinctive among the groups. In both studies, SZ showed response inhibition deficits as measured by P300 when stimuli were presented to the right visual field. In Study 2, delayed cognitive stimulus evaluation was observed in BD as indexed by prolonged P300 latency for NoGo trials. Six selected NoGo P300 variables out of thirty six NoGo P300 variables (18 amplitude, 18 latency) correctly classified SZ (79%), SA (64%) in Study 1 and seven variables selected in Study 2 classified CT (80%), and SZ (61%), BD (67%) and CT (68%) with the accuracy higher than chance level (33%). The findings suggest that distinct P300 features in response inhibition may be biomarkers with the capacity to distinguish BD and SZ, although SA was not clearly distinguishable from SZ and CT.
Assuntos
Transtorno Bipolar/diagnóstico , Potenciais Evocados P300/fisiologia , Inibição Psicológica , Transtornos Psicóticos/diagnóstico , Esquizofrenia/diagnóstico , Adulto , Transtorno Bipolar/fisiopatologia , Tomada de Decisões , Eletroencefalografia , Feminino , Lateralidade Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estimulação Luminosa , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/fisiopatologia , Tempo de Reação , Esquizofrenia/fisiopatologiaRESUMO
We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.
Assuntos
Transtorno Bipolar/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Cerebelo/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Metilação , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.
Assuntos
Transtorno Bipolar/genética , Negro ou Afro-Americano/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Transtorno Bipolar/etnologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genoma Humano , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valores de Referência , População Branca , Adulto JovemRESUMO
An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania Assuntos
Transtorno Bipolar/genética
, Predisposição Genética para Doença
, Genoma Humano/genética
, Deleção de Sequência/genética
, Estudos de Casos e Controles
, Feminino
, Dosagem de Genes
, Estudo de Associação Genômica Ampla
, Genótipo
, Humanos
, Masculino
, Razão de Chances
, Análise de Sequência com Séries de Oligonucleotídeos/métodos
, Risco
RESUMO
Despite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the genetic heterogeneity of the disorder. We sought to identify susceptibility loci for BP in a genome-wide linkage scan with and without clinical covariates that might reflect the underlying heterogeneity of the disorder. We genotyped 428 subjects in 98 BP families at the Center for Inherited Disease Research with 402 microsatellite markers. We first carried out a non-parametric linkage analysis with MERLIN, and then reanalyzed the data with LODPAL to incorporate clinical covariates for age at onset (AAO), psychosis and comorbid anxiety. We sought to further examine the top findings in the covariate analysis in an independent sample of 64 previously collected BP families. In the non-parametric linkage analysis, three loci were nominally significant under a narrow diagnostic model and seven other loci were nominally significant under a broader model. The top findings were on chromosomes 2q24 and 3q28. The covariate analyses yielded additional evidence for linkage on 3q28 with AAO in the primary and independent samples. Although none of the linked loci were genome-wide significant, their congruence with prior results and, for the covariate analyses, their identification in two separate samples increases the likelihood that they are true positives and deserve further investigation. These findings further demonstrate the value of considering clinical features that may reflect the underlying heterogeneity of disease in order to facilitate gene mapping.
Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 3/genética , Ligação Genética , Predisposição Genética para Doença/genética , Idade de Início , Transtorno Bipolar/classificação , Mapeamento Cromossômico , Humanos , Transtornos do Humor/classificação , Transtornos do Humor/genética , Linhagem , Estatísticas não ParamétricasAssuntos
Transtorno Bipolar/genética , Proteínas de Ciclo Celular/genética , Cromossomos Humanos Par 12 , Proteínas Serina-Treonina Quinases/genética , Mapeamento Cromossômico , Citoesqueleto/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Deleção de Sequência , Sinapses/fisiologiaRESUMO
Our group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at theta=0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the 'common disease-common variant' hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 (alpha=0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).
Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 8 , Ligação Genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Adenilil Ciclases/genética , Seguimentos , Predisposição Genética para Doença , Humanos , Canal de Potássio KCNQ3 , Repetições de Microssatélites , Canais de Potássio/genética , Tireoglobulina/genéticaRESUMO
Markers near the nested genes G72 and G30 on chromosome 13q33 have been implicated in the etiology of schizophrenia and, recently, bipolar affective disorder (BPAD). Hattori et al (2003) reported that single-nucleotide polymorphisms (SNPs) near the G72/G30 locus were associated with BPAD in a sample of 22 pedigrees, and that SNP haplotypes were associated in a second, larger sample of triads. The present study attempts to replicate this finding in an independent case-control sample. Six SNPs near the G72/G30 locus, including the most strongly associated markers in the previous study, were tested in 139 cases and 113 ethnically matched controls. Significant association was detected between BPAD and two adjacent SNPs (smallest P=0.007; global P=0.024). Haplotype analysis produced additional support for association (smallest P=0.004; global P=0.004). Analysis of 31 unlinked microsatellite markers detected no population stratification in the cases or controls studied. Although the associated alleles and haplotypes differ from those previously reported, these new results provide further evidence, in an independent sample, for an association between BPAD and genetic variation in the vicinity of the genes G72 and G30.
Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 13 , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The possible presence of anticipation in bipolar affective disorder and schizophrenia has led to the hypothesis that repeat expansion mutations could contribute to the genetic etiology of these diseases. Using the repeat expansion detection (RED) assay, we have systematically examined genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. Our results show that 28% of the probands with schizophrenia and 30% of probands with bipolar disorder have a CAG/CTG repeat in the expanded range, but that each expansion could be explained by one of three nonpathogenic repeat expansions known to exist in the general population. We conclude that novel CAG/CTG repeat expansions are not a common genetic risk factor for bipolar disorder or schizophrenia.
Assuntos
Transtorno Bipolar/genética , Mutação , Esquizofrenia/genética , Expansão das Repetições de Trinucleotídeos/genética , Genótipo , Humanos , Fatores de RiscoRESUMO
In a search for novel genes on chromosome 18 (HC18), on which several regions have been linked to bipolar disorder, we applied exon trapping to HC18-specific cosmids. Among the 1138 exons trapped, 1052 of them have been mapped to HC18, and the remaining 86 have not been localized. No exons were localized to genomic regions other than HC18. BLAST database search revealed that 190 exons were identical to 98 Unigenes on HC18; 98 identical to additional 82 clusters of ESTs not present in the HC18 Unigene set; 39 homologous to genes from human and other species (e<10(-3)); and the remaining 811 exons had no significant homology to transcripts in public databases. The mapped exons were compared to the 867 annotated genes on HC18 in the Celera databases; 216 exons were identical to 104 Celera 'genes' and the remaining 836 exons were not found in the Celera databases. On average, there were two exons for a matched transcript (known genes and ESTs). Therefore, the 850 novel exons may represent hundreds of novel genes on chromosome 18.