Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

• MeSH
• antimanika farmakologie   terapeutické užití   MeSH
• bipolární porucha * farmakoterapie   genetika   MeSH
• celogenomová asociační studie * metody   MeSH
• farmakogenetika metody   MeSH
• fokální adheze * účinky léků   genetika   MeSH
• genomika metody   MeSH
• genové regulační sítě * účinky léků   genetika   MeSH
• indukované pluripotentní kmenové buňky účinky léků   metabolismus   MeSH
• lidé MeSH
• lithium * farmakologie   terapeutické užití   MeSH
• multiomika MeSH
• neurony metabolismus   účinky léků   MeSH
• sloučeniny lithia farmakologie   terapeutické užití   MeSH
• stanovení celkové genové exprese metody   MeSH
• transkriptom * genetika   účinky léků   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Understanding the underlying architecture of mood regulation in bipolar disorder (BD) is important, as we are starting to conceptualize BD as a more complex disorder than one of recurring manic or depressive episodes. Nonlinear techniques are employed to understand and model the behavior of complex systems. Our aim was to assess the underlying nonlinear properties that account for mood and energy fluctuations in patients with BD; and to compare whether these processes were different in healthy controls (HC) and unaffected first-degree relatives (FDR). We used three different nonlinear techniques: Lyapunov exponent, detrended fluctuation analysis and fractal dimension to assess the underlying behavior of mood and energy fluctuations in all groups; and subsequently to assess whether these arise from different processes in each of these groups. RESULTS: There was a positive, short-term autocorrelation for both mood and energy series in all three groups. In the mood series, the largest Lyapunov exponent was found in HC (1.84), compared to BD (1.63) and FDR (1.71) groups [F (2, 87) = 8.42, p < 0.005]. A post-hoc Tukey test showed that Lyapunov exponent in HC was significantly higher than both the BD (p = 0.003) and FDR groups (p = 0.03). Similarly, in the energy series, the largest Lyapunov exponent was found in HC (1.85), compared to BD (1.76) and FDR (1.67) [F (2, 87) = 11.02; p < 0.005]. There were no significant differences between groups for the detrended fluctuation analysis or fractal dimension. CONCLUSIONS: The underlying nature of mood variability is in keeping with that of a chaotic system, which means that fluctuations are generated by deterministic nonlinear process(es) in HC, BD, and FDR. The value of this complex modeling lies in analyzing the nature of the processes involved in mood regulation. It also suggests that the window for episode prediction in BD will be inevitably short.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. AIMS: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. METHOD: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. RESULTS: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. CONCLUSIONS: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

• MeSH
• bipolární porucha * diagnóza   epidemiologie   genetika   MeSH
• celogenomová asociační studie MeSH
• depresivní porucha unipolární * genetika   MeSH
• lidé MeSH
• multifaktoriální dědičnost MeSH
• poruchy autistického spektra * MeSH
• věk při počátku nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

• MeSH
• bipolární porucha genetika   MeSH
• celogenomová asociační studie * MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• genom lidský MeSH
• hlavní histokompatibilní komplex genetika   MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• lokus kvantitativního znaku genetika   MeSH
• multifaktoriální dědičnost genetika   MeSH
• rizikové faktory MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

• MeSH
• bipolární porucha * diagnóza   farmakoterapie   genetika   MeSH
• farmakogenetika MeSH
• lidé MeSH
• lithium terapeutické užití   MeSH
• prospektivní studie MeSH
• sloučeniny lithia terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

OBJECTIVE: Bipolar disorders increase the risk of dementia and show biological and brain alterations, which resemble accelerated aging. Lithium may counter some of these processes and lower the risk of dementia. However, until now no study has specifically investigated the effects of Li on brain age. METHODS: We acquired structural magnetic resonance imaging scans from 84 participants with bipolar disorders (41 with and 43 without Li treatment) and 45 controls. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants, and calculated BrainAGE by subtracting chronological from the estimated brain age. RESULTS: BrainAGE was significantly greater in non-Li relative to Li or control participants, F(2, 125) = 10.22, p < 0.001, with no differences between the Li treated and control groups. The estimated brain age was significantly higher than the chronological age in the non-Li (4.28 ± 6.33 years, matched t(42) = 4.43, p < 0.001), but not the Li-treated group (0.48 ± 7.60 years, not significant). Even Li-treated participants with partial prophylactic treatment response showed lower BrainAGE than the non-Li group, F(1, 64) = 4.80, p = 0.03. CONCLUSIONS: Bipolar disorders were associated with greater, whereas Li treatment with lower discrepancy between brain and chronological age. These findings support the neuroprotective effects of Li, which were sufficiently pronounced to affect a complex, multivariate measure of brain structure. The association between Li treatment and BrainAGE was independent of long-term thymoprophylactic response and thus may generalize beyond bipolar disorders, to neurodegenerative disorders.

• MeSH
• bipolární porucha diagnostické zobrazování   farmakoterapie   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• multivariační analýza MeSH
• neuroprotektivní látky farmakologie   MeSH
• sloučeniny lithia farmakologie   MeSH
• strojové učení MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

• MeSH
• bipolární porucha klasifikace   genetika   MeSH
• celogenomová asociační studie MeSH
• depresivní porucha unipolární genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetické lokusy * MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• psychotické poruchy genetika   MeSH
• schizofrenie genetika   MeSH
• studie případů a kontrol MeSH
• systémová biologie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

OBJECTIVE: This study aimed to examine differences in the clinical presentation of very-early-onset (VEO) and early-onset (EO) bipolar disorder (BD) not fully explored previously. METHODS: We selected two groups of subjects with BD from the Maritime Bipolar Registry based on age at onset of first major mood episode (VEO with onset prior to age 15 years; EO ranging from 15 to 18 years) and compared them with a reference group (onset after 18 years of age). There were 363 subjects (240 with bipolar I disorder and 123 with bipolar II disorder; mean age 44.2 ± 12.8 (SD) years), with 41 subjects in the VEO and 95 in the EO groups. RESULTS: In comparison with the EO and reference groups, more subjects in the VEO group developed major depression as an index episode (88% for the VEO group versus 61% for the EO group and 54% for the reference group), and had an unremitting clinical course (65% versus 42% and 42%, respectively), rapid cycling (54% versus 34% and 28%, respectively), and comorbid attention-deficit hyperactivity disorder (17% versus 1% and 3%, respectively); a higher proportion of the VEO group had first-degree relatives with affective disorders compared with the EO and reference groups (0.41 versus 0.32 and 0.29, respectively), and they had lower scores on the Global Assessment of Functioning scale (mean scores of 64 versus 70 and 70). Overall, the EO group was similar to the reference group on most measures, except for increased suicidal behavior VEO 53%, EO 44% and reference group 25%). The results of polychotomous logistic regression also support the view that VEO BD represents a rather specific subtype of BD. CONCLUSIONS: Our results suggest the recognized correlates of early-onset BD may be driven by subjects at the lowest end of the age at onset spectrum.

• MeSH
• bipolární porucha * diagnóza   epidemiologie   psychologie   MeSH
• depresivní porucha unipolární diagnóza   epidemiologie   psychologie   MeSH
• dospělí MeSH
• hyperkinetická porucha * diagnóza   epidemiologie   psychologie   MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• poruchy nálady diagnóza   epidemiologie   psychologie   MeSH
• psychiatrické posuzovací škály MeSH
• psychopatologie MeSH
• rodina psychologie   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Kanada MeSH