RESUMEN

BACKGROUND: Chronotype is associated with circadian rhythmicity, a core etiological factor underlying bipolar disorder (BD). Given converging evidence linking late chronotype with poor mental health, the goal of the present study was to examine chronotype (in)stability and its relation to mood symptoms over time. METHODS: Participants with BD I (n = 271), BD II (n = 88), and healthy controls (n = 217) were included (follow-upM=10 years, Range=5-15) from the Prechter Longitudinal Study. Chronotype category and midpoint of sleep, corrected for weekend sleep-debt (MSFsc), were measured with the Munich Chronotype Questionnaire administered every 12 months alongside clinician-rated mood and medication usage. Self-reported mood was measured bi-monthly. Mixed effects models tested whether mood was associated with (in)stability of chronotype category and MSFsc covarying for age, sex, age, and medication. RESULTS: Compared to HC, individuals with BD self-reported having a later chronotype that significantly fluctuated over time. Individuals with BDI showed significantly less stability in MSFsc than HC. Anticonvulsant use was associated with more stability in MSFsc whereas antidepressant use was associated with less stability in MSFsc. CONCLUSIONS: In a large longitudinal cohort, individuals with BD displayed significant instability in circadian typology. Psychopharmacology in BD may have differential impacts on circadian timing that is important to monitor.

Asunto(s)

Afecto , Trastorno Bipolar , Ritmo Circadiano , Humanos , Trastorno Bipolar/fisiopatología , Trastorno Bipolar/tratamiento farmacológico , Femenino , Masculino , Adulto , Estudios Longitudinales , Ritmo Circadiano/fisiología , Afecto/fisiología , Afecto/efectos de los fármacos , Persona de Mediana Edad , Sueño/fisiología , Sueño/efectos de los fármacos , Adulto Joven , Cronotipo

RESUMEN

It has been postulated that mitochondrial dysfunction has a significant role in the underlying pathophysiology of bipolar disorder (BD). Mitochondrial functioning plays an important role in regulating synaptic transmission, brain function, and cognition. Neuronal activity is energy dependent and neurons are particularly sensitive to changes in bioenergetic fluctuations, suggesting that mitochondria regulate fundamental aspects of brain function. Vigorous evidence supports the role of mitochondrial dysfunction in the etiology of BD, including dysregulated oxidative phosphorylation, general decrease of energy, altered brain bioenergetics, co-morbidity with mitochondrial disorders, and association with genetic variants in mitochondrial DNA (mtDNA) or nuclear-encoded mitochondrial genes. Despite these advances, the underlying etiology of mitochondrial dysfunction in BD is unclear. A plausible evolutionary explanation is that mitochondrial-nuclear (mitonuclear) incompatibility leads to a desynchronization of machinery required for efficient electron transport and cellular energy production. Approximately 1,200 genes, encoded from both nuclear and mitochondrial genomes, are essential for mitochondrial function. Studies suggest that mitochondrial and nuclear genomes co-evolve, and the coordinated expression of these interacting gene products are essential for optimal organism function. Incompatibilities between mtDNA and nuclear-encoded mitochondrial genes results in inefficiency in electron flow down the respiratory chain, differential oxidative phosphorylation efficiency, increased release of free radicals, altered intracellular Ca2+ signaling, and reduction of catalytic sites and ATP production. This review explores the role of mitonuclear incompatibility in BD susceptibility and resilience against environmental stressors.

RESUMEN

Bipolar disorder (BD) is a neuropsychiatric mood disorder characterized by recurrent episodes of mania and depression in addition to disruptions in sleep, energy, appetite, and cognitive functions-rhythmic behaviors that typically change on daily cycles. BD symptoms can also be provoked by seasonal changes, sleep, and/or circadian disruption, indicating that chronobiological factors linked to the circadian clock may be a common feature in the disorder. Research indicates that BD exists on a clinical spectrum, with distinct subtypes often intersecting with other psychiatric disorders. This heterogeneity has been a major challenge to BD research and contributes to problems in diagnostic stability and treatment outcomes. To address this heterogeneity, we propose that chronobiologically related biomarkers could be useful in classifying BD into objectively measurable phenotypes to establish better diagnoses, inform treatments, and perhaps lead to better clinical outcomes. Presently, we review the biological basis of circadian time keeping in humans, discuss the links of BD to the circadian clock, and pre-sent recent studies that evaluated chronobiological measures as a basis for establishing BD phenotypes. We conclude that chronobiology may inform future research using other novel techniques such as genomics, cell biology, and advanced behavioral analyses to establish new and more biologically based BD phenotypes.

RESUMEN

We previously identified bipolar disorder (BD) susceptibility loci on 8q24, 14q32, and 2q12-14 in a genome-wide nonparametric linkage screen in a Latino cohort. We now perform a fine mapping analysis using a dense map of additional SNPs to identify BD susceptibility genes within these regions. One thousand nine hundred and thirty-eight individuals with Latino ancestry (880 individuals with BD Type I or Schizoaffective, Bipolar Type) from 416 Latino pedigrees from the United States, Mexico, Costa Rica, and Guatemala were genotyped with 3,074 SNPs to provide dense coverage of the 8q24 (11.5 cM), 14q32 (7.5 cM), and 2q12-14 (6.5 cM) chromosomal loci. Single-marker association tests in the presence of linkage were performed using the LAMP software. The top linkage peak (rs7834818; LOD = 5.08, p = 3.30E - 5) and associated single marker (rs2280915, p = 2.70E - 12) were located within FBXO32 on 8q24. On chromosome 2, the top linkage peak (rs6750326; LOD = 5.06, p = 3.50E - 5) and associated single marker (rs11887088, p = 2.90E - 6) were located in intragenic regions near ACTR3 and DPP10. None of the additional markers in the region around chromosome 14q32 met significance levels for linkage or association. We identified six SNPs on 2q12-q14 and one SNP in FBXO32 on 8q24 that were significantly associated with BD in this Latino cohort.

Asunto(s)

Trastorno Bipolar/genética , Cromosomas Humanos Par 2/genética , Trastornos Psicóticos/genética , Proteína 3 Relacionada con la Actina/genética , Proteína 3 Relacionada con la Actina/metabolismo , Adulto , Trastorno Bipolar/psicología , Mapeo Cromosómico/métodos , Costa Rica , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Femenino , Ligamiento Genético/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Guatemala , Hispánicos o Latinos/genética , Humanos , Escala de Lod , Masculino , México , Persona de Mediana Edad , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Polimorfismo de Nucleótido Simple/genética , Trastornos Psicóticos/psicología , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Estados Unidos

RESUMEN

Personality traits have been suggested as potential endophenotypes for Bipolar Disorder (BP), as they can be quantitatively measured and show correlations with BP. The present study utilized data from 2,745 individuals from 686 extended pedigrees originally ascertained for having multiplex cases of BP (963 cases of BPI or schizoaffective BP). Subjects were assessed with the NEO Personality Inventory, Revised (NEO PI-R) and genotyped using the Illumina HumanLinkage-24 Bead Chip, with an average genetic coverage of 0.67 cM. Two point linkage scores were calculated for each trait as a quantitative variable using SOLAR (Sequential Oligogenic Linkage Analysis Routines). Suggestive evidence for linkage was found for neuroticism at 1q32.1 (LOD = 2.52), 6q23.3 (2.32), 16p12 (2.79), extraversion at 4p15.3 (2.33), agreeableness at 4q31.1 (2.37), 5q34 (2.80), 7q31.1 (2.56), 16q22 (2.52), and conscientiousness at 4q31.1 (2.50). Each of the above traits have been shown to be correlated with the broad BP phenotype in this same sample. In addition, for the trait of openness, we found significant evidence of linkage to chromosome 3p24.3 (rs336610, LOD = 4.75) and suggestive evidence at 1q43 (2.74), 5q35.1 (3.03), 11q14.3 (2.61), 11q21 (2.30), and 19q13.1 (2.52). These findings support previous linkage findings of the openness trait to chromosome 19q13 and the agreeableness trait to 4q31 and identify a number of new loci for personality endophenotypes related to bipolar disorder.

Asunto(s)

Trastorno Bipolar/genética , Cromosomas Humanos/genética , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos/genética , Inventario de Personalidad , Sitios de Carácter Cuantitativo , Genotipo , Humanos , Fenotipo

RESUMEN

OBJECTIVES: Recent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD. METHODS: A total of 2254 Latino individuals were genotyped for 91 SNPs identified in previous BD and/or SC GWASs, along with selected SNPs in strong linkage disequilibrium with these markers. Family-based single marker and haplotype association testing was performed using the PBAT software package. Empirical P-values were derived from 10 000 permutations. RESULTS: Associations of eight a priori GWAS SNPs with BD were replicated with nominal (P≤.05) levels of significance. These included SNPs within nuclear factor I A (NFIA), serologically defined colon cancer antigen 8 (SDCCAG8), lysosomal associated membrane protein 3 (LAMP3), nuclear factor kappa B subunit 1 (NFKB1), major histocompatibility complex, class I, B (HLA-B) and 5'-nucleotidase, cytosolic II (NT5C2) and SNPs within intragenic regions microRNA 6828 (MIR6828)-solute carrier family 7 member 14 (SLC7A14) and sonic hedgehog (SHH)-long intergenic non-protein coding RNA 1006 (LINC01006). Of the 76 ancestral haploblocks that were tested for associations with BD, our top associated haploblock was located in LAMP3; however, the association did not meet statistical thresholds of significance following Bonferroni correction. CONCLUSIONS: These results indicate that some of the gene variants found to be associated with BD or SC in other populations are also associated with BD risk in Latinos. Variants in six genes and two intragenic regions were associated with BD in our Latino sample and provide additional evidence for overlap in genetic risk between SC and BD.

Asunto(s)

Trastorno Bipolar , Factores de Transcripción de Tipo Kruppel/genética , Proteínas de Membrana de los Lisosomas/genética , Subunidad p50 de NF-kappa B/genética , Proteínas de Neoplasias/genética , Esquizofrenia , Adulto , Trastorno Bipolar/etnología , Trastorno Bipolar/genética , Costa Rica/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Estudio de Asociación del Genoma Completo , Guatemala/epidemiología , Haplotipos , Hispánicos o Latinos/genética , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Desequilibrio de Ligamiento , Masculino , México/epidemiología , Polimorfismo de Nucleótido Simple , Esquizofrenia/etnología , Esquizofrenia/genética , Estados Unidos/epidemiología

RESUMEN

BACKGROUND: Variations in circadian genes can impact biological rhythms. Given the rhythm disturbances that characterize bipolar disorder (BD), genes encoding components of molecular clocks are good candidate genes for the illness. METHODS: A family based association analysis of circadian gene single nucleotide polymorphisms (SNPs) and BD was conducted in Latino pedigrees. 884 individuals from 207 pedigrees (473BP phenotype and 411 unaffected family members) were genotyped. Family based single marker association testing was performed. Ancestral haplotypes (SNPs found to be in strong LD defined using confidence intervals) were also tested for association with BD. RESULTS: Multiple suggestive associations between circadian gene SNPs and BD were noted. These included CSNK1E (rs1534891, p=0.00689), ARNTL (rs3789327, p=0.021172), CSNK1D (rs4510078, p=0.022801), CLOCK (rs17777927, p=0.031664). Individually, none of the SNPs were significantly associated with BD after correction for multiple testing. However, a 4-locus CSNK1E haplotype encompassing the rs1534891 SNP (Z-score=2.685, permuted p=0.0076) and a 3-locus haplotype in ARNTL (Z-score=3.269, permuted p=0.0011) showed a significant association with BD. LIMITATIONS: Larger samples are required to confirm these findings and assess the relationship between circadian gene SNPs and BD in Latinos. CONCLUSIONS: The results suggest that ARNTL and CSKN1E variants may be associated with BD. Further studies are warranted to assess the relationships between these genes and BD in Latino populations.

Asunto(s)

Factores de Transcripción ARNTL/genética , Trastorno Bipolar/genética , Proteínas CLOCK/genética , Caseína Cinasa 1 épsilon/genética , Ritmo Circadiano/genética , Hispánicos o Latinos/genética , Femenino , Genotipo , Humanos , Masculino , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple

RESUMEN

A genome-wide nonparametric linkage screen was performed to localize Bipolar Disorder (BP) susceptibility loci in a sample of 3757 individuals of Latino ancestry. The sample included 963 individuals with BP phenotype (704 relative pairs) from 686 families recruited from the US, Mexico, Costa Rica, and Guatemala. Non-parametric analyses were performed over a 5 cM grid with an average genetic coverage of 0.67 cM. Multipoint analyses were conducted across the genome using non-parametric Kong & Cox LOD scores along with Sall statistics for all relative pairs. Suggestive and significant genome-wide thresholds were calculated based on 1000 simulations. Single-marker association tests in the presence of linkage were performed assuming a multiplicative model with a population prevalence of 2%. We identified two genome-wide significant susceptibly loci for BP at 8q24 and 14q32, and a third suggestive locus at 2q13-q14. Within these three linkage regions, the top associated single marker (rs1847694, P = 2.40 × 10(-5)) is located 195 Kb upstream of DPP10 in Chromosome 2. DPP10 is prominently expressed in brain neuronal populations, where it has been shown to bind and regulate Kv4-mediated A-type potassium channels. Taken together, these results provide additional evidence that 8q24, 14q32, and 2q13-q14 are susceptibly loci for BP and these regions may be involved in the pathogenesis of BP in the Latino population.

Asunto(s)

Trastorno Bipolar/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 8/genética , Ligamiento Genético , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos/genética , Familia , Humanos , Modelos Genéticos , Fenotipo , Análisis de Secuencia de ADN , Estadísticas no Paramétricas

RESUMEN

OBJECTIVES: Through recent genome-wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage-dependent, L-type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European-American cohorts. We performed a family-based association study to determine whether CACNA1C is associated with BP in the Latino population. METHODS: This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single-nucleotide polymorphisms (SNPs) that spanned a 602.9-kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family-Based Association Test (version 2.0.3) and Haploview (version 4.2) software. RESULTS: An eight-locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). CONCLUSIONS: Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population.

Asunto(s)

Trastorno Bipolar/genética , Canales de Calcio/genética , Salud de la Familia , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Costa Rica , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Guatemala , Haplotipos , Hispánicos o Latinos/genética , Humanos , Masculino , México , Estados Unidos

RESUMEN

The XXth World Congress of Psychiatric Genetics (WCPG), sponsored by The International Society of Psychiatric Genetics (ISPG) took place in Hamburg, Germany on October 14-18, 2012. Approximately 600 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned sessions as rapporteurs. This manuscript represents topics covered in most, but not all, oral presentations during the conference, and some of the major notable new findings reported at this 2012 WCPG.

Asunto(s)

Trastornos Mentales/genética , Animales , Encéfalo/patología , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Endofenotipos , Epigénesis Genética , Pruebas Genéticas , Variación Genética , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Alemania , Humanos , Patrón de Herencia/genética , Imagen por Resonancia Magnética , Ratones , Análisis de Secuencia de ADN

RESUMEN

The mdx mouse is an animal model for Duchenne muscular dystrophy (DMD). In order to evaluate possible treatments and to carry out genetic studies, it is essential to distinguish between mice that carry the dystrophic (mutant) or wild-type (wt) allele(s). The current amplification-resistant mutation system (ARMS) assay is labor intensive and yields false negatives, which reduces its efficiency as a screening tool. An alternate assay based on single-nucleotide polymorphism (SNP) primer extension technology (i.e., SNaPshot) is described. The SNaPshot assay has been optimized to identify both wild-type and mutant alleles, providing a robust, potentially automatable assay for high-throughput analysis.

Asunto(s)

Amplificación de Genes , Distrofia Muscular de Duchenne/genética , Análisis de Secuencia de ADN/métodos , Alelos , Secuencia de Aminoácidos , Animales , ADN/biosíntesis , ADN/genética , Análisis Mutacional de ADN , Cartilla de ADN , ADN Polimerasa Dirigida por ADN/biosíntesis , ADN Polimerasa Dirigida por ADN/genética , Didesoxinucleótidos , Electroforesis Capilar , Colorantes Fluorescentes , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Datos de Secuencia Molecular , Mutación , Polimorfismo de Nucleótido Simple , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa