RESUMO
This review aims to explore the intricate relationship among epigenetic mechanisms, stress, and affective disorders, focusing on how early life experiences and coping mechanisms contribute to susceptibility to mood disorders. Epigenetic factors play a crucial role in regulating gene expression without altering the DNA (deoxyribonucleic acid) sequence, and recent research has revealed associations between epigenetic changes and maladaptive responses to stress or psychiatric disorders. A scoping review of 33 studies employing the PRISMA-S (Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Statement) guidelines investigates the role of stress-induced epigenetic mechanisms and coping strategies in affective disorder occurrence, development, and progression. The analysis encompasses various stress factors, including childhood trauma, work-related stress, and dietary deficiencies, alongside epigenetic changes, such as DNA methylation and altered gene expression. Findings indicate that specific stress-related genes frequently exhibit epigenetic changes associated with affective disorders. Moreover, the review examines coping mechanisms in patients with bipolar disorder and major depressive disorder, revealing mixed associations between coping strategies and symptom severity. While active coping is correlated with better outcomes, emotion-focused coping may exacerbate depressive or manic episodes. Overall, this review underscores the complex interplay among genetic predisposition, environmental stressors, coping mechanisms, and affective disorders. Understanding these interactions is essential for developing targeted interventions and personalized treatment strategies for individuals with mood disorders. However, further research is needed to elucidate specific genomic loci involved in affective disorders and the clinical implications of coping strategies in therapeutic settings.
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Adaptação Psicológica , Epigênese Genética , Transtornos do Humor , Estresse Psicológico , Humanos , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Transtornos do Humor/psicologia , Transtornos do Humor/genética , Metilação de DNARESUMO
Genes involved in the hypothalamic-pituitary-adrenal axis may be a robust biomarker of psychiatric disorders. Genetic polymorphisms of the SKA2 gene are associated with several behavioral disorders. In this study, we embarked on a systematic search of all possible reports of genetic association with SKA2 and affective disorder, post-traumatic stress disorder, and suicide behavior; the functional consequences of nsSNPs were explored through computational tools with an in silico analysis. Eight eligible articles were included. Our study identified that SKA2 did not show association with risk of Major Depression Disorder. Epigenetic variation at SKA2 mediates vulnerability to Post-Traumatic Stress Disorder. Studies provide strong preliminary evidence that alterations at the SKA2 gene covary with types of suicide behavior, including suicidal ideation, attempts, and completions. Results from in silico analysis predicted that I22S, I22G, I78T, A15L, D18R, R25L, N42I, Y21S, K14I, K14L, and L60R were the most structurally and functionally significant nsSNPs in SKA2. Amino acid conservation analysis revealed that the amino acids were highly conserved and some dissimilarities of mutant type amino acids from wild-type amino acids such as charge, size, and hydrophobicity were observed. In the future, SKA2 gene have the potential to be evaluated as prognostic biomarkers for diagnosis and research.
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Proteínas Cromossômicas não Histona , Simulação por Computador , Transtornos de Estresse Pós-Traumáticos , Suicídio , Humanos , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/psicologia , Proteínas Cromossômicas não Histona/genética , Suicídio/psicologia , Transtornos do Humor/genética , Transtornos do Humor/psicologia , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença/genéticaRESUMO
OBJECTIVES: Previous results demonstrated that CYP2D6 and CYP2C19 gene variants affect serum concentrations of antidepressants. We implemented a PGx service determining gene variants in CYP2D6 and CYP2C19 in our clinical routine care and report on our first patient cohort. METHODS: We analysed CYP2D6 and CYP2C19 allele, genotype, and phenotype frequencies, and actionable pharmacogenetic variants in this German psychiatric inpatient cohort. Two-tailed z-test was used to investigate for differences in CYP2D6 and CYP2C19 phenotypes and actionable/non-actionable genetic variant frequencies between our cohort and reference cohorts. RESULTS: Out of the 154 patients included, 44.8% of patients were classified as CYP2D6 normal metabolizer, 38.3% as intermediate metabolizers, 8.4% as poor metabolizers, and 2.6% as ultrarapid metabolizers. As for CYP2C19, 40.9% of patients were classified as normal metabolizers, 19.5% as intermediate metabolizers, 2.6% as poor metabolizers, 31.2% as rapid metabolizers, and 5.8% as ultrarapid metabolizers. Approximately, 80% of patients had at least one actionable PGx variant. CONCLUSION: There is a high prevalence of actionable PGx variants in psychiatric inpatients which may affect treatment response. Physicians should refer to PGx-informed dosing guidelines in carriers of these variants. Pre-emptive PGx testing in general may facilitate precision medicine also for other drugs metabolised by CYP2D6 and/or CYP2C19.
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Antidepressivos , Transtornos de Ansiedade , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Transtornos do Humor , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2C19/genética , Feminino , Masculino , Alemanha , Adulto , Pessoa de Meia-Idade , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/tratamento farmacológico , Antidepressivos/uso terapêutico , Transtornos do Humor/genética , Transtornos do Humor/tratamento farmacológico , Pacientes Internados , Genótipo , Alelos , Fenótipo , Frequência do Gene , Variantes Farmacogenômicos , Idoso , Estudos de CoortesRESUMO
Mood disorders, particularly major depressive disorder (MDD) and bipolar disorder (BD), are often underdiagnosed, leading to substantial morbidity. Harnessing the potential of emerging methodologies, we propose a novel multimodal fusion approach that integrates patient-oriented brain structural magnetic resonance imaging (sMRI) scans with DNA whole-exome sequencing (WES) data. Multimodal data fusion aims to improve the detection of mood disorders by employing established deep-learning architectures for computer vision and machine-learning strategies. We analyzed brain imaging genetic data of 321 East Asian individuals, including 147 patients with MDD, 78 patients with BD, and 96 healthy controls. We developed and evaluated six fusion models by leveraging common computer vision models in image classification: Vision Transformer (ViT), Inception-V3, and ResNet50, in conjunction with advanced machine-learning techniques (XGBoost and LightGBM) known for high-dimensional data analysis. Model validation was performed using a 10-fold cross-validation. Our ViT â XGBoost fusion model with MRI scans, genomic Single Nucleotide polymorphism (SNP) data, and unweighted polygenic risk score (PRS) outperformed baseline models, achieving an incremental area under the curve (AUC) of 0.2162 (32.03% increase) and 0.0675 (+8.19%) and incremental accuracy of 0.1455 (+25.14%) and 0.0849 (+13.28%) compared to SNP-only and image-only baseline models, respectively. Our findings highlight the opportunity to refine mood disorder diagnostics by demonstrating the transformative potential of integrating diverse, yet complementary, data modalities and methodologies.
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Transtorno Bipolar , Transtorno Depressivo Maior , Humanos , Transtornos do Humor/diagnóstico por imagem , Transtornos do Humor/genética , Transtornos do Humor/patologia , Transtorno Depressivo Maior/genética , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/genética , Encéfalo/patologia , Neuroimagem/métodos , Imageamento por Ressonância Magnética/métodosRESUMO
OBJECTIVE: To examine the risk of anxiety disorders in offspring of parents with mood disorders. METHOD: We conducted a systematic review and meta-analysis. We searched 4 electronic databases (Medline, Embase, PsycINFO, and Web of Science [core collection]) to identify cross-sectional and cohort studies that examined the association between parental mood disorders (including bipolar disorder and unipolar depression) and risk of anxiety disorders in offspring. Pooled risk ratios (RRs) of overall and specific anxiety disorders were synthesized using a random effects model. Subgroup analyses and meta-regression were performed to identify moderation factors. RESULTS: A total of 35 studies were included in the final analysis. Our results showed higher risks of all types of anxiety disorders in the offspring of parents with mood disorders (any anxiety disorder, RR = 1.82, 95% CI = 1.47-2.26), except for agoraphobia (RR = 1.08, 95% CI = 0.56-2.08), and with an especially elevated risk of panic disorder (RR = 3.07, 95% CI = 2.19-4.32). Subgroup analysis demonstrated no significant difference between the risks of anxiety disorders across the offspring of parents with bipolar disorder as opposed to unipolar depression. The absence of anxiety disorders in control parents, younger offspring age, and specific parent/offspring sex were associated with higher RRs for some anxiety disorders in offspring of parents with mood disorders. CONCLUSION: Our findings suggest a robust relationship between parental mood disorders and offspring anxiety disorders, and highlight the potential value of prevention and early intervention for anxiety disorders in this context. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. STUDY PREREGISTRATION INFORMATION: Anxiety Disorders in Offspring of Parents with Mood Disorders: A Systematic Review; https://www.crd.york.ac.uk/prospero/; CRD42021215058.
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Filho de Pais com Deficiência , Transtorno Depressivo , Humanos , Transtornos do Humor/epidemiologia , Transtornos do Humor/genética , Estudos Transversais , Transtornos de Ansiedade/epidemiologia , PaisRESUMO
BACKGROUND: Risk preference is often defined as the tendency to engage in risky activities. Increasing evidence shows that risk preference is associated with mood disorders. However, the causality and direction of this association are not clear. METHODS: Genome-wide association study summary data of risk preference in 939,908 participants from UK Biobank and 23andMe were used to identify general risk preference. Data for 413,466 individuals taken from The Psychiatric Genomics Consortium were used to identify bipolar disorder (BP). Data for 807,553 individuals taken from The Psychiatric Genomics Consortium were used to identify major depressive disorder (MDD). The weighted median, inverse-variance weighting, and Mendelian randomization-Egger methods were used for the Mendelian randomization analysis to estimate a causal effect and detect directional pleiotropy. RESULTS: GWAS summary data were obtained from three combined samples, containing 939,908, 413,466 and 807,553 individuals of European ancestry. Mendelian randomization evidence suggested that risk preference increased the onset of BP, and BP also increased risk preference (P < 0.001). In contrast, there were no reliable results to describe the relationship of risk preference with MDD (P > 0.05). Furthermore, there was no significant relationship between MDD and risk preference. CONCLUSION: Using large-scale GWAS data, robust evidence supports a mutual relationship between risk preference and BP, but no relationship between risk preference and MDD was observed. This study indicates a potential marker for the early identification of MDD and BP. Additionally, it shows that reducing risk preferences for patients with BP may be a valuable intervention for treating BP.
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Transtorno Bipolar , Transtorno Depressivo Maior , Humanos , Transtornos do Humor/epidemiologia , Transtornos do Humor/genética , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The Ndufs4 knockout (KO) mouse is a validated and robust preclinical model of mitochondrial diseases (specifically Leigh syndrome), that displays a narrow window of relative phenotypical normality, despite its inherent mitochondrial complex I dysfunction and severe phenotype. Preclinical observations related to psychiatric comorbidities that arise in patients with mitochondrial diseases and indeed in Leigh syndrome are, however, yet to be investigated in this model. Strengthening this narrative is the fact that major depression and bipolar disorder are known to present with deficits in mitochondrial function. We therefore screened the behavioural profile of male and female Ndufs4 KO mice (relative to heterozygous; HET and wildtype; WT mice) between postnatal days 28 and 35 for locomotor, depressive- and anxiety-like alterations and linked it with selected brain biomarkers, viz. serotonin, kynurenine, and redox status in brain areas relevant to psychiatric pathologies (i.e., prefrontal cortex, hippocampus, and striatum). The Ndufs4 KO mice initially displayed depressive-like behaviour in the tail suspension test on PND31 but not on PND35 in the forced swim test. In the mirror box test, increased risk resilience was observed. Serotonin levels of KO mice, compared to HET controls, were increased on PND36, together with increased tryptophan to serotonin and kynurenine turnover. Kynurenine to kynurenic acid turnover was however decreased, while reduced versus oxidized glutathione ratio (GSH/GSSG) was increased. When considering the comorbid psychiatric traits of patients with mitochondrial disorders, this work elaborates on the neuropsychiatric profile of the Ndufs KO mouse. Secondly, despite locomotor differences, Ndufs4 KO mice present with a behavioural profile not unlike rodent models of bipolar disorder, namely variable mood states and risk-taking behaviour. The model may elucidate the bio-energetic mechanisms underlying mood disorders, especially in the presence of mitochondrial disease. Studies are however required to further validate the model's translational relevance.
Assuntos
Doença de Leigh , Doenças Mitocondriais , Humanos , Masculino , Feminino , Animais , Camundongos , Doença de Leigh/genética , Doença de Leigh/patologia , Cinurenina , Serotonina , Camundongos Knockout , Transtornos do Humor/genética , Doenças Mitocondriais/genética , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismoRESUMO
Major depressive disorder (MDD) and bipolar disorder (BD), are globally prevalent, contributing to significant disease burden and adverse health outcomes. These mood disorders are associated with changes in many aspects of brain reward pathways, yet cellular and molecular changes in the brain are not readily available in clinical populations. Therefore, the use of biomarkers as proxies for changes in the brain are necessary. The proliferation of mitochondria in blood has emerged as a potentially useful biomarker, yet a clear consensus on how these mood disorders impact mitochondrial DNA copy number (mtDNAcn) has not been reached. To determine the current available consensus on the relationship of mood disorder diagnosis and blood mtDNcn, we performed a meta-analysis of available literature measuring this biomarker. Following PRISMA guidelines for a systematic search, 22 papers met inclusion criteria for meta-analysis (10 MDD, 10 BD, 2 both MDD and BD). We extracted demographic, disorder, and methodological information with mtDNAcn. Using the metafor package for R, calculated effect sizes were used in random effects or meta regression models for MDD and BD. Overall, our data suggest blood mtDNAcn may be a useful biomarker for mood disorders, with MDD and BD Type II associated with higher mtDNAcn, and BD Type I associated with lower mtDNAcn. Initially, we observed a trending increase in mtDNAcn in patients with MDD, which reached significance when one study with outlying demographic characteristics was excluded. Subgroup and meta-regression analysis indicated the relationship between mtDNAcn and diagnosis in patients with BD is dependent on BD type, while no relationship is detectable when BD types are mixed. Further study of blood mtDNAcn could predict downstream health outcomes or treatment responsivity in individuals with mood disorders.
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Transtorno Depressivo Maior , Transtornos do Humor , Humanos , Transtornos do Humor/genética , Transtornos do Humor/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Biomarcadores , MitocôndriasRESUMO
Adolescence is a particularly important period for brain development and is also when mood disorders typically emerge. Several psychiatric illnesses exhibit mitochondrial dysfunction, elevated inflammation, and impaired white matter integrity. This study explored the intersection of mitochondrial health, NLRP3 inflammasome activation, and white matter integrity in a small cohort of 29 adolescent patients with mood disorders (bipolar disorder (BD): n = 11, major depressive disorder (MDD): n = 19) and 19 healthy controls. In this sample, adolescents with mood disorders showed lower fractional anisotropy of the ventral cingulum bundle than healthy controls. Across all adolescents, we demonstrated a significant relationship between mitochondrial electron transport chain gene expression, and NLRP3 inflammasome gene expression and activation. Furthermore, circulating cell free mitochondrial DNA was associated with lower white matter integrity in the anterior thalamic radiation. Exploratory subgroup analyses revealed that adolescents with bipolar disorder exhibited lower levels of mitochondrial gene expression and volume, along with increased sensitivity to NLRP3 inflammasome activation compared to adolescents with unipolar depression. Overall, our results reveal relationships between peripherally-measured endpoints of mitochondrial health and NLRP3 inflammasome activation, and centrally measured endpoints of white matter integrity in adolescents. Together with subtle patterns of aberrant neural and biological structure and function in association with mood disorder diagnoses, these results may shed light on the pathophysiology of disease in this early phase of illness.
Assuntos
Transtorno Depressivo Maior , Substância Branca , Humanos , Adolescente , Transtornos do Humor/genética , Substância Branca/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/genética , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Projetos Piloto , Mitocôndrias , AnisotropiaRESUMO
Neurobiological disorders are highly prevalent medical conditions that contribute to significant morbidity and mortality. Single-cell RNA sequencing (scRNA-seq) is a technique that measures gene expression in individual cells. In this review, we survey scRNA-seq studies of tissues from patients suffering from neurobiological disease. This includes postmortem human brains and organoids derived from peripheral cells. We highlight a range of conditions, including epilepsy, cognitive disorders, substance use disorders, and mood disorders. These findings provide new insights into neurobiological disease in multiple ways, including discovering novel cell types or subtypes involved in disease, proposing new pathophysiological mechanisms, uncovering novel drug targets, or identifying potential biomarkers. We discuss the quality of these findings and suggest potential future directions and areas open for additional research, including studies of non-cortical brain regions and additional conditions such as anxiety disorders, mood disorders, and sleeping disorders. We argue that additional scRNA-seq of tissues from patients suffering from neurobiological disease could advance our understanding and treatment of these conditions.
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Transtornos de Ansiedade , Transtornos do Humor , Humanos , Transtornos do Humor/genética , Encéfalo , Biomarcadores , Análise de Sequência de RNA/métodosRESUMO
BACKGROUND: Copy number variants (CNVs) have been associated with the risk of schizophrenia, autism and intellectual disability. However, little is known about their spectrum of psychopathology in adulthood. METHODS: We investigated the psychiatric phenotypes of adult CNV carriers and compared probands, who were ascertained through clinical genetics services, with carriers who were not. One hundred twenty-four adult participants (age 18-76), each bearing one of 15 rare CNVs, were recruited through a variety of sources including clinical genetics services, charities for carriers of genetic variants, and online advertising. A battery of psychiatric assessments was used to determine psychopathology. RESULTS: The frequencies of psychopathology were consistently higher for the CNV group compared to general population rates. We found particularly high rates of neurodevelopmental disorders (NDDs) (48%), mood disorders (42%), anxiety disorders (47%) and personality disorders (73%) as well as high rates of psychiatric multimorbidity (median number of diagnoses: 2 in non-probands, 3 in probands). NDDs [odds ratio (OR) = 4.67, 95% confidence interval (CI) 1.32-16.51; p = 0.017) and psychotic disorders (OR = 6.8, 95% CI 1.3-36.3; p = 0.025) occurred significantly more frequently in probands (N = 45; NDD: 39[87%]; psychosis: 8[18%]) than non-probands (N = 79; NDD: 20 [25%]; psychosis: 3[4%]). Participants also had somatic diagnoses pertaining to all organ systems, particularly conotruncal cardiac malformations (in individuals with 22q11.2 deletion syndrome specifically), musculoskeletal, immunological, and endocrine diseases. CONCLUSIONS: Adult CNV carriers had a markedly increased rate of anxiety and personality disorders not previously reported and high rates of psychiatric multimorbidity. Our findings support in-depth psychiatric and medical assessments of carriers of CNVs and the establishment of multidisciplinary clinical services.
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Transtornos Psicóticos , Esquizofrenia , Humanos , Variações do Número de Cópias de DNA/genética , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Transtornos Psicóticos/epidemiologia , Psicopatologia , Transtornos do Humor/epidemiologia , Transtornos do Humor/genéticaRESUMO
Prescription of PCSK9-inhibitors has increased in recent years but not much is known about its off-target effects. PCSK9-expression is evident in non-hepatic tissues, notably the brain, and genetic variation in the PCSK9 locus has recently been shown to be associated with mood disorder-related traits. We investigated whether PCSK9 inhibition, proxied by a genetic reduction in expression of PCSK9 mRNA, might have a causal adverse effect on mood disorder-related traits. We used genetic variants in the PCSK9 locus associated with reduced PCSK9 expression (eQTLs) in the European population from GTEx v8 and examined the effect on PCSK9 protein levels and three mood disorder-related traits (major depressive disorder, mood instability, and neuroticism), using summary statistics from the largest European ancestry genome-wide association studies. We conducted summary-based Mendelian randomization analyses to estimate the causal effects, and attempted replication using data from eQTLGen, Brain-eMETA, and the CAGE consortium. We found that genetically reduced PCSK9 gene-expression levels were significantly associated with reduced PCSK9 protein levels but not with increased risk of mood disorder-related traits. Further investigation of nearby genes demonstrated that reduced USP24 gene-expression levels was significantly associated with increased risk of mood instability (p-value range = 5.2x10-5-0.03), and neuroticism score (p-value range = 2.9x10-5-0.02), but not with PCSK9 protein levels. Our results suggest that genetic variation in this region acts on mood disorders through a PCSK9-independent pathway, and therefore PCSK9-inhibitors are unlikely to have an adverse impact on mood disorder-related traits.
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Transtorno Depressivo Maior , Transtornos do Humor , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/genética , Inibidores de PCSK9 , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9/genética , Ubiquitina Tiolesterase/genética , Locos de Características QuantitativasRESUMO
Background PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are important therapeutic options for reducing cardiovascular disease risk; however, questions remain regarding potential differences in the neuropsychiatric impact of long-term PCSK9 inhibition between men and women. Methods and Results Using PCSK9 gene single-nucleotide polymorphisms from European ancestry-based genome-wide association studies of low-density lipoprotein cholesterol (N=1 320 016), circulating PCSK9 protein levels (N=10 186), tissue-specific PCSK9 gene expression, sex-specific genome-wide association studies of anxiety, depression, cognition, insomnia, and dementia (ranging from 54 321 to 194 174), we used drug-target inverse variance-weighted Mendelian randomization (MR) and complementary MR methods (MR Egger, weighted median, and weighted mode) to investigate potential neuropsychiatric consequences of genetically proxied PCSK9 inhibition in men and women. We failed to find evidence surpassing correction for multiple comparisons of relationships between genetically proxied PCSK9 inhibition and the risk for the 12 neuropsychiatric end points in either men or women. Drug-target analyses were generally well-powered to detect effect estimates at several hypothesized thresholds for both combined-sex and sex-specific end points, especially analyses using PCSK9 instruments derived from protein and expression quantitative trait loci. Further, MR estimates across complementary MR methods and additional models using genetic instruments derived from circulating PCSK9 protein levels and tissue-specific PCSK9 expression were in alignment, strengthening causal inference. Conclusions Genetically proxied PCSK9 inhibition showed a neutral neuropsychiatric side effect profile with no major sex-specific differences. Given statistical power considerations, replication with larger samples, as well as data from other ancestral populations, are necessary. These findings may have important clinical implications for lipid-lowering drug-prescribing practices and side effect monitoring of approved and future PCSK9 therapies.
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Transtornos Cognitivos , Demência , Transtornos do Humor , Pró-Proteína Convertase 9 , Feminino , Humanos , Masculino , Cognição , Transtornos Cognitivos/genética , Demência/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos do Humor/genética , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismoRESUMO
Stigmatizing attitudes toward children with psychopathology represent a barrier to treatment and well-being, yet almost no research has investigated what contributes to these attitudes. This study examines the effects of medication treatment and genetic etiology on stigmatizing attitudes toward a relatively new and controversial disorder-Disruptive Mood Dysregulation Disorder (DMDD). Participants (159 parents, 225 non-parents) completed a vignette study on Amazon's Mechanical Turk (MTurk) in which a child displayed behaviors consistent with DMDD. The child was described as either taking psychiatric medication or not, and the vignette described the child's condition as either genetic or did not mention etiology. Participants who were parents reported greater stigma when the etiology (genetic prime vs. no prime) matched the perceived appropriate treatment (medication vs. no medication). Among parents, a child treated with medication who had a genetic disorder, and a child who was not treated with medication and for whom genetic etiology was not primed, were most stigmatized. No differences emerged among non-parents. These findings highlight the importance of considering multiple factors (parental status, congruence between treatment and perceived disorder etiology) when investigating mental health stigma and underscore the need to further investigate such nuances to inform anti-stigma interventions.
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Transtornos de Deficit da Atenção e do Comportamento Disruptivo , Humor Irritável , Causalidade , Criança , Humanos , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/genética , PaisRESUMO
Mood disorders are mental health class that health professionals use to broadly describe all types of depression and bipolar disorders. Heritability of both bipolar and depressive disorder is in the range of 50%, which means that genes alone are not sufficient to explain all the cases of mood disorders, but they confer a substantial risk which is combined with environmental stressors to determine the final illness. In the recent years, a number of studies considered the idea to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders.
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Transtorno Bipolar , Transtornos do Humor , Transtorno Bipolar/genética , Humanos , Saúde Mental , Transtornos do Humor/genéticaRESUMO
Mood disorders and suicidal behavior have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT1A) brain binding. However, it is unclear whether this reflects genetic effects or epigenetic effects of childhood adversity, compensatory mechanisms, or illness stress-related changes. We sought to separate such effects on 5-HT1A binding by examining high familial risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset with and without developing mood disorder or suicidal behavior. PET imaging quantified 5-HT1A binding potential BPND using [11C]CUMI-101 in healthy volunteers (HV, N = 23) and three groups with one or more relatives manifesting early-onset mood disorder and suicide attempt: 1. unaffected HR (N = 23); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 26); and 3. HR-MOOD with previous suicide attempt (HR-MOOD + SA, N = 20). Findings were tested in an independent cohort not selected for family history (HV, MOOD, and MOOD + SA, total N = 185). We tested for regional BPND differences and whether brain-wide patterns distinguished between groups. Low ventral prefrontal 5-HT1A BPND was associated with lifetime mood disorder diagnosis and suicide attempt, but only in subjects with a family history of mood disorder and suicide attempt. Brain-wide 5-HT1A BPND patterns including low ventral prefrontal and mesiotemporal cortical binding distinguished HR-MOOD + SA from HV. A biological endophenotype associated with resilience was not observed. Low ventral prefrontal 5-HT1A BPND may reflect familial mood disorder and suicide-related pathology. Further studies are needed to determine if higher ventral prefrontal 5-HT1A BPND confers resilience, reducing risk of suicidal behavior in the context of familial risk, and thereby offer a potential prevention target.
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Receptor 5-HT1A de Serotonina , Ideação Suicida , Humanos , Receptor 5-HT1A de Serotonina/genética , Predisposição Genética para Doença , Serotonina , Transtornos do Humor/genéticaRESUMO
Objective: Mood disorders often co-occur with attention-deficit/hyperactive disorder (ADHD), disruptive behavior disorders (DBDs), and aggression. We aimed to determine if polygenic risk scores (PRSs) based on external genome-wide association studies (GWASs) of these disorders could improve genetic identification of mood disorders.Methods: We combined 6 independent family studies that had genetic data and diagnoses for mood disorders that were made using different editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). We identified mood disorders, either concurrently or in the future, in participants between 6 and 17 years of age using PRSs calculated using summary statistics of GWASs for ADHD, ADHD with DBD, major depressive disorder (MDD), bipolar disorder (BPD), and aggression to compute PRSs.Results: In our sample of 485 youths, 356 (73%) developed a subthreshold or full mood disorder and 129 (27%) did not. The cross-validated mean areas under the receiver operating characteristic curve (AUCs) for the 7 models identifying participants with any mood disorder ranged from 0.552 in the base model of age and sex to 0.648 in the base model + all 5 PRSs. When included in the base model individually, the ADHD PRS (OR = 1.65, P < .001), Aggression PRS (OR = 1.27, P = .02), and MDD PRS (OR = 1.23, P = .047) were significantly associated with the development of any mood disorder.Conclusions: Using PRSs for ADHD, MDD, BPD, DBDs, and aggression, we could modestly identify the presence of mood disorders. These findings extend evidence for transdiagnostic genetic components of psychiatric illness and demonstrate that PRSs calculated using traditional diagnostic boundaries can be useful within a transdiagnostic framework.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno Depressivo Maior , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Humanos , Transtornos do Humor/diagnóstico , Transtornos do Humor/epidemiologia , Transtornos do Humor/genética , Herança Multifatorial/genética , Fatores de RiscoRESUMO
There has recently been marked progress in identifying genetic risk factors for major depression (MD) and bipolar disorder (BD); however, few systematic efforts have been made to elucidate heterogeneity that exists within and across these diagnostic taxa. The Affective disorders, Environment, and Cognitive Trait (AFFECT) study presents an opportunity to identify and associate the structure of cognition and symptom-level domains across the mood disorder spectrum in a prospective study from a diverse US population.Participants were recruited from the 23andMe, Inc research participant database and through social media; self-reported diagnosis of MD or BD by a medical professional and medication status data were used to enrich for mood-disorder cases. Remote assessments were used to acquire an extensive range of phenotypes, including mood state, transdiagnostic symptom severity, task-based measures of cognition, environmental exposures, personality traits. In this paper we describe the study design, and the demographic and clinical characteristics of the cohort. In addition we report genetic ancestry, SNP heritability, and genetic correlations with other large cohorts of mood disorders.A total of 48,467 participants were enrolled: 14,768 with MD, 9864 with BD, and 23,835 controls. Upon enrollment, 47% of participants with MD and 27% with BD indicated being in an active mood episode. Cases reported early ages of onset (mean = 13.2 and 14.3 years for MD and BD, respectively), and high levels of recurrence (78.6% and 84.9% with >5 episodes), psychotherapy, and psychotropic medication use. SNP heritability on the liability scale for the ascertained MD participants (0.19-0.21) was consistent with the high level of disease severity in this cohort, while BD heritability estimates (0.16-0.22) were comparable to reports in other large scale genomic studies of mood disorders. Genetic correlations between the AFFECT cohort and other large-scale cohorts were high for MD but not for BD. By incorporating transdiagnostic symptom assessments, repeated measures, and genomic data, the AFFECT study represents a unique resource for dissecting the structure of mood disorders across multiple levels of analysis. In addition, the fully remote nature of the study provides valuable insights for future virtual and decentralized clinical trials within mood disorders.