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1.
Psychiatr Danub ; 32(3-4): 325-333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370729

RESUMO

Major depressive disorder is the greatest burden of developed countries in the context of morbidity caused by mental disorders. Until recent, ketamine has been mostly used for anesthesia, analgesia, sedation and treatment of chronic pain syndromes. However, unique pharmacodynamic properties of ketamine have increased interests in it's use for treatment of depression. It is assumed that ketamine reverses synaptic chronic stress pathology within one day of administration by postsynaptic glutamate activation, providing synaptic connectivity restoration that last for days or weeks. Potential glutamatergic agents, in context of treatment of major depressive disorder are not entirely novel phenomenon. Considering the aforementioned, current neurobiological view of depression as a solely monoaminergic phenomenon should be reassessed in order to prompt discovery of putative antidepressant drugs of novel generation. Acute side effects, such as increased salivation, increase in heart rate, systemic arterial pressure and intracranial pressure necessitate careful monitoring during intravenous administration of ketamine, even in subanesthetic doses. However, major burden of ketamine administration lies in it's ability to produce psychotomimetic side effects and emergence delirium. Esketamine nasal spray has now been widely approved and is considered safe in terms of acute side effects, tolerability and consistent therapeutic benefit.


Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Interações Medicamentosas , Epigênese Genética/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Humanos , Ketamina/efeitos adversos , Ketamina/química
3.
PLoS Genet ; 16(9): e1009015, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956347

RESUMO

Evidence from both GWAS and clinical observation has suggested that certain psychiatric, metabolic, and autoimmune diseases are heterogeneous, comprising multiple subtypes with distinct genomic etiologies and Polygenic Risk Scores (PRS). However, the presence of subtypes within many phenotypes is frequently unknown. We present CLiP (Correlated Liability Predictors), a method to detect heterogeneity in single GWAS cohorts. CLiP calculates a weighted sum of correlations between SNPs contributing to a PRS on the case/control liability scale. We demonstrate mathematically and through simulation that among i.i.d. homogeneous cases generated by a liability threshold model, significant anti-correlations are expected between otherwise independent predictors due to ascertainment on the hidden liability score. In the presence of heterogeneity from distinct etiologies, confounding by covariates, or mislabeling, these correlation patterns are altered predictably. We further extend our method to two additional association study designs: CLiP-X for quantitative predictors in applications such as transcriptome-wide association, and CLiP-Y for quantitative phenotypes, where there is no clear distinction between cases and controls. Through simulations, we demonstrate that CLiP and its extensions reliably distinguish between homogeneous and heterogeneous cohorts when the PRS explains as low as 3% of variance on the liability scale and cohorts comprise 50, 000 - 100, 000 samples, an increasingly practical size for modern GWAS. We apply CLiP to heterogeneity detection in schizophrenia cohorts totaling > 50, 000 cases and controls collected by the Psychiatric Genomics Consortium. We observe significant heterogeneity in mega-analysis of the combined PGC data (p-value 8.54 × 0-4), as well as in individual cohorts meta-analyzed using Fisher's method (p-value 0.03), based on significantly associated variants. We also apply CLiP-Y to detect heterogeneity in neuroticism in over 10, 000 individuals from the UK Biobank and detect heterogeneity with a p-value of 1.68 × 10-9. Scores were not significantly reduced when partitioning by known subclusters ("Depression" and "Worry"), suggesting that these factors are not the primary source of observed heterogeneity.


Assuntos
Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Algoritmos , Transtorno Bipolar/genética , Estudos de Casos e Controles , Bases de Dados Genéticas , Transtorno Depressivo Maior/genética , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Modelos Teóricos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Esquizofrenia/genética
4.
Compr Psychiatry ; 102: 152199, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32911381

RESUMO

BACKGROUND: The human serotonin transporter (SERT) gene polymorphism (5HTTLPR) has been associated with multiple psychiatric disorders, including major depression, anxiety disorders, and substance use disorders. This study investigated the association between 5HTTLPR and psychiatric morbidity and comorbidity in a psychiatrist-examined population sample. METHODS: 628 participants, mean age 48.3 years old, were assessed by psychiatrists using the Schedules for Clinical Assessment in Neuropsychiatry. Associations between 5HTTLPR and the prevalence, comorbidity, and time-to-diagnoses for 16 psychiatric conditions were evaluated, using several analytical approaches. RESULTS: The SERT S allele was significantly associated with an increased lifetime prevalence of panic disorder. There was a "protective" association between SERT gene S allele carrier status and the risk of obsessive-compulsive disorder (OCD) in time-to-event analysis. Carriers of the S allele had a significant increased risk of two specific comorbid disorder pairs: major depressive disorder (MDD) and social phobia, and MDD and agoraphobia. Overall, there was no increased risk of receiving an initial or an additional diagnosis for a mental disorder in the SERT S allele carriers CONCLUSIONS: The findings suggest that the S allele carrier status is associated with an increased prevalence of panic disorder in a community sample. There was an increased risk for comorbidity in a more homogeneous subgroup of cases with MDD and social phobia, as well as or agoraphobia. Our findings suggest a specific effect of the SERT promoter gene polymorphism on a subgroup of individuals identifiable by their comorbidity.


Assuntos
Transtorno Depressivo Maior , Proteínas da Membrana Plasmática de Transporte de Serotonina , Baltimore , Comorbidade , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Seguimentos , Humanos , Pessoa de Meia-Idade , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
5.
Proc Natl Acad Sci U S A ; 117(40): 25138-25149, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958675

RESUMO

Major depressive disorder emerges from the complex interactions of biological systems that span genes and molecules through cells, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to depression requires a multiscale approach, encompassing measures of brain structure and function as well as genetic and cell-specific transcriptional data. Here, we examine anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Brain Genomics Superstruct Project, and Enhancing NeuroImaging through Meta Analysis (ENIGMA; combined n ≥ 23,723). Integrative analyses incorporate measures of cortical gene expression, postmortem patient transcriptional data, depression genome-wide association study (GWAS), and single-cell gene transcription. Neuroimaging correlates of depression and negative affect were consistent across three independent datasets. Linking ex vivo gene down-regulation with in vivo neuroimaging, we find that transcriptional correlates of depression imaging phenotypes track gene down-regulation in postmortem cortical samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data reveal somatostatin interneurons and astrocytes to be consistent cell associates of depression, through both in vivo imaging and ex vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS-derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multiscale approaches, the transcriptional correlates of depression-linked brain function and structure were enriched for disorder-relevant molecular pathways. These findings bridge levels to connect specific genes, cell classes, and biological pathways to in vivo imaging correlates of depression.


Assuntos
Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Transtorno Depressivo Maior/genética , Regulação da Expressão Gênica/genética , Somatostatina/genética , Astrócitos/metabolismo , Astrócitos/patologia , Autopsia , Encéfalo/patologia , Córtex Cerebral/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/fisiopatologia , Feminino , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes/genética , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Herança Multifatorial/genética , Neuroimagem/métodos , Transdução de Sinais/genética , Análise de Célula Única/métodos
6.
Psychiatry Res ; 292: 113313, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32738552

RESUMO

Psychopathology research has increasingly sought to study the etiology and treatment of individual symptoms, rather than categorical diagnoses. However, it is unclear whether commonly used measures have adequate psychometric properties for assessing individual symptoms. This study examined the test-retest reliability and familial concordance (an indicator of validity) of the symptoms of Major Depressive Disorder (MDD), a disorder consisting of nine core symptoms, most of which are aggregated (e.g., symptom 7 of the DSM criteria for MDD is worthlessness or guilt). Lifetime MDD symptoms were measured in 504 young adults (237 sibling pairs) using the Structured Clinical Interview for DSM-5 (SCID). Fifty-one people completed a second SCID within three weeks of their first SCID. Results indicated that aggregated and unaggregated symptoms demonstrated moderate to substantial test-retest reliability and generally significant, but slight to fair familial concordance (with the highest familial concordance being for markedly diminished interest or pleasure and its unaggregated components - decreased interest and decreased pleasure). Given the increasing focus on the differential validity of individual MDD symptoms, the present study suggests that interview-based assessments of depression can assess most individual symptoms with adequate levels of reliability and validity.


Assuntos
Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/genética , Entrevista Psicológica/normas , Psicometria/normas , Adolescente , Adulto , Transtorno Depressivo Maior/psicologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Entrevista Psicológica/métodos , Masculino , Psicometria/métodos , Reprodutibilidade dos Testes , Adulto Jovem
7.
Neurology ; 95(14): e1963-e1970, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32817390

RESUMO

OBJECTIVE: To explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer disease (AD). METHODS: We conducted bidirectional 2-sample Mendelian randomization analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (n = 446,118), Psychiatric Genomics Consortium (n = 18,759), and International Genomics of Alzheimer's Project (n = 63,926). We used the inverse variance-weighted Mendelian randomization method to estimate causal effects and weighted median and Mendelian randomization-Egger for sensitivity analyses to test for pleiotropic effects. RESULTS: We found that higher risk of AD was significantly associated with being a "morning person" (odds ratio [OR] 1.01, p = 0.001), shorter sleep duration (self-reported: ß = -0.006, p = 1.9 × 10-4; accelerometer based: ß = -0.015, p = 6.9 × 10-5), less likely to report long sleep (ß = -0.003, p = 7.3 × 10-7), earlier timing of the least active 5 hours (ß = -0.024, p = 1.7 × 10-13), and a smaller number of sleep episodes (ß = -0.025, p = 5.7 × 10-14) after adjustment for multiple comparisons. We also found that higher risk of AD was associated with lower risk of insomnia (OR 0.99, p = 7 × 10-13). However, we did not find evidence that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and risk of AD. CONCLUSION: We found that AD may causally influence sleep patterns. However, we did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between MDD and AD.


Assuntos
Doença de Alzheimer/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Sono , Doença de Alzheimer/genética , Transtorno Depressivo Maior/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Fenótipo , Sono/genética
8.
BMC Psychiatry ; 20(1): 408, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32795354

RESUMO

BACKGROUND: Variation in genes implicated in homocysteine and lipid metabolism systems may influence antidepressant response for patients with major depressive disorder (MDD). This study aimed to investigate whether association of polymorphisms on the MTHFR, ApoE and ApoA4 genes with the treatment response in MDD subjects. METHODS: A total of 281 Han Chinese MDD patients received a single antidepressant drug (SSRI or SNRI) for at least 6 weeks, among whom 275 were followed up for 8 weeks. Their response to 6 weeks' treatment and remission to 8 weeks' treatment with antidepressant drugs was determined by changes in the 17-item Hamilton Depression Rating Scale (HARS-17) score. Single SNP and haplotype associations with treatment response were analyzed by UNPHASED 3.0.13. Logistic regression analysis was used to explore the interactions between genotypes and gender or drug type on treatment outcome, only those SNPs that had interactional association with gender or drug type were subjected to further stratified analysis. RESULTS: In total group, the haplotype (C-A) in MTHFR (rsl801133 and rs1801131) and the ApoE rs405509 AA genotype were significantly associated with better efficacy of antidepressants; In gender subgroups, only haplotype (C-A) in MTHFR (rsl801133 and rs1801131) was significantly associated with better efficacy of antidepressants in male subgroup; In drug type subgroup, the haplotype (C-A) in MTHFR (rsl801133 and rs1801131) and haplotype (G-C) in ApoE (rs7412 and rs405509) were associated with better efficacy of antidepressants in SNRI treated subgroup; The ApoA4 rs5092 G allele and GG genotype were associated with worse efficacy of antidepressants in SNRI treated subgroup. CONCLUSIONS: Genetic polymorphisms in homocysteine and lipid metabolism systems are associated with antidepressant response, particularly for the interactions of the certain genetic with gender or drug type.


Assuntos
Transtorno Depressivo Maior , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Genótipo , Homocisteína , Humanos , Metabolismo dos Lipídeos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética
10.
Sci Rep ; 10(1): 12649, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724131

RESUMO

To elucidate the genetic underpinnings of the antidepressant efficacy of S-ketamine (esketamine) nasal spray in major depressive disorder (MDD), we performed a genome-wide association study (GWAS) in cohorts of European ancestry (n = 527). This analysis was followed by a polygenic risk score approach to test for associations between genetic loading for psychiatric conditions, symptom profiles and esketamine efficacy. We identified a genome-wide significant locus in IRAK3 (p = 3.57 × 10-8, rs11465988, ß = - 51.6, SE = 9.2) and a genome-wide significant gene-level association in NME7 (p = 1.73 × 10-6) for esketamine efficacy (i.e. percentage change in symptom severity score compared to baseline). Additionally, the strongest association with esketamine efficacy identified in the polygenic score analysis was from the genetic loading for depressive symptoms (p = 0.001, standardized coefficient ß = - 3.1, SE = 0.9), which did not reach study-wide significance. Pathways relevant to neuronal and synaptic function, immune signaling, and glucocorticoid receptor/stress response showed enrichment among the suggestive GWAS signals.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Ketamina/uso terapêutico , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/psicologia , Feminino , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
11.
Biol Pharm Bull ; 43(7): 1067-1072, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612069

RESUMO

Major depressive disorder (MDD) is one of the most common psychiatric diseases. However, early detection and diagnosis of MDD is difficult, largely because there is no known biomarker or objective diagnostic examination, and its diagnosis is instead based on a clinical interview. The aim of this study was to develop a novel diagnostic tool using DNA methylation as a blood biomarker. We sought to determine whether unmedicated patients with MDD showed significant differences in DNA methylation in the promoter region of the SHATI/N-acetyltransferase 8 like (SHATI/NAT8L) gene compared to healthy controls. Sixty participants with MDD were recruited from all over Japan. They were diagnosed and assessed by at least two trained psychiatrists according to DSM-5 criteria. DNA was extracted from peripheral blood. We then assessed DNA methylation of the SHATI/NAT8L promoter regions in patients with MDD by pyrosequencing. Methylation levels of the SHATI/NAT8L promoter region at CpG sites in peripheral blood from unmedicated patients were significantly higher than in healthy controls. In contrast, medicated patients with MDD showed significantly lower methylation levels in the same region compared to healthy controls. Since previous studies of DNA methylation in MDD only assessed medicated patients, the methylation status of the SHATI/NAT8L promoter region in unmedicated patients presented herein may prove useful for the diagnosis of MDD. To our knowledge, this is the first attempt to measure methylation of the SHATI/NAT8L gene in drug-naïve patients with psychiatric diseases. Based on our findings, methylation of SHATI/NAT8L DNA might be a diagnostic biomarker of MDD.


Assuntos
Acetiltransferases/genética , Metilação de DNA , Transtorno Depressivo Maior/genética , Regiões Promotoras Genéticas , Adolescente , Adulto , Biomarcadores , Criança , Transtorno Depressivo Maior/diagnóstico , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Depress Anxiety ; 37(9): 862-875, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32627298

RESUMO

BACKGROUND: Perinatal depression carries adverse effects on maternal health and child development, but genetic underpinnings remain unclear. We investigated the polygenic risk of perinatal depressive symptoms. METHODS: About 742 women from the prospective Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction cohort were genotyped and completed the Center for Epidemiologic Studies Depression scale 14 times during the prenatal period and twice up to 12 months postpartum. Polygenic risk scores for major depressive disorder, bipolar disorder, schizophrenia, and cross-disorder were calculated using multiple p-value thresholds. RESULTS: Polygenic risk scores for major depressive disorder, schizophrenia, and cross-disorder, but not bipolar disorder, were associated with higher prenatal and postpartum depressive symptoms (0.8%-1% increase per one standard deviation increase in polygenic risk scores). Prenatal depressive symptoms accounted for and mediated the associations between the polygenic risk scores and postpartum depressive symptoms (effect size proportions-mediated: 52.2%-88.0%). Further, the polygenic risk scores were associated with 1.24-1.45-fold odds to belong to the group displaying consistently high compared with consistently low depressive symptoms through out the prenatal and postpartum periods. CONCLUSIONS: Polygenic risk scores for major depressive disorder, schizophrenia, and cross-disorder in non-perinatal populations generalize to perinatal depressive symptoms and may afford to identify women for timely preventive interventions.


Assuntos
Transtorno Bipolar , Depressão Pós-Parto , Transtorno Depressivo Maior , Complicações na Gravidez , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Criança , Depressão , Depressão Pós-Parto/epidemiologia , Depressão Pós-Parto/genética , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Feminino , Humanos , Herança Multifatorial/genética , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética , Estudos Prospectivos , Fatores de Risco
13.
PLoS Med ; 17(6): e1003137, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32479557

RESUMO

BACKGROUND: Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm. METHODS AND FINDINGS: Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder [MDD], attention deficit/hyperactivity disorder [ADHD], bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10-35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-reported, and the limited power of some of the included GWASs, potentially leading to possible type II error. CONCLUSIONS: In addition to confirming the role of MDD, we demonstrate that ADHD and schizophrenia likely play a role in the aetiology of self-harm using multivariate genetic designs for causal inference. Among the many individual risk factors we simultaneously considered, our findings suggest that systematic detection and treatment of core psychiatric symptoms, including psychotic and impulsivity symptoms, may be beneficial among people at risk for self-harm.


Assuntos
Comportamento Autodestrutivo/genética , Idoso , Idoso de 80 Anos ou mais , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Bipolar/complicações , Transtorno Bipolar/genética , Bases de Dados como Assunto , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fatores de Risco , Esquizofrenia , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/etiologia , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/genética , Inquéritos e Questionários , Reino Unido/epidemiologia
14.
Gene ; 755: 144901, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32554045

RESUMO

BACKGROUND: The genetic basis of suicide attempts (SA) remains unclear. Especially the role of copy number variations (CNVs) remains to be elucidated. The present study aimed to identify susceptibility variants associated with SA among Chinese with major depressive disorder (MDD), covering both CNVs and single-nucleotide polymorphisms (SNPs). METHODS: We conducted a genome-wide association study (GWAS) on MDD patients with and without SA and top results were tested in a replication study. A genome-wide CNV study was also performed. Subsequently, a validation assay using qRT-PCR technology was performed to confirm any associated CNVs and then applied to the entire cohort to examine the association. RESULTS: Although GWAS did not identify any SNPs reaching genome-wide significance, we identified TPH2 as the top susceptibility gene (p-value = 2.75e-05) in gene-based analysis, which is a strong biological candidate for its role in the serotonergic system. As for CNV analysis, we found that the global rate of CNV was higher in SA than that in non-SA subjects (p-value = 0.023). Genome-wide CNV study revealed an SA-associated CNV region that achieved genome-wide significance (corrected p-value = 0.014). The associated CNV was successfully validated with a more rigorous qRT-PCR assay and identified to be a common variant in this cohort. Its deletion rate was higher in SA subjects [OR = 2.05 (1.02-4.12), adjusted p-value = 0.045]. Based on the GTEx database, genetic variants that probed this CNV were significantly associated with the expression level of ZNF33B in two brain regions (p-value < 4.2e-05). In stratified analysis, the CNV showed a significant effect [OR = 2.58 (1.06-6.27), p-value = 0.039] in those with high neuroticism but not in those with average or low neuroticism. CONCLUSIONS: We identified a new common CNV likely involved in the etiology of SA. This finding sheds light on an important role of common CNVs in the pathophysiology of SA, suggesting a new promising avenue for investigating its genetic architecture.


Assuntos
Transtorno Depressivo Maior/genética , Tentativa de Suicídio/psicologia , Fatores de Transcrição/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , China , Cromossomos Humanos Par 10 , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Suicídio/psicologia , Triptofano Hidroxilase/genética
15.
Psychiatry Res ; 290: 113017, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32485484

RESUMO

Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism. Here, we evaluated the ability of individual pharmacokinetic genes (CYP2C19, CYP2D6, CYP3A4) and a combinatorial pharmacogenomic test (GeneSight Psychotropic®; weighted assessment of all three genes) to predict citalopram/escitalopram blood levels in patients with MDD. Patients from the Genomics Used to Improve DEpression Decisions (GUIDED) trial who were taking citalopram/escitalopram at screening and had available blood level data were included (N=191). In multivariate analysis of the individual genes and combinatorial pharmacogenomic test separately (adjusted for age, smoking status), the F statistic for the combinatorial pharmacogenomic test was 1.7 to 2.9-times higher than the individual genes, showing that it explained more variance in citalopram/escitalopram blood levels. In multivariate analysis of the individual genes and combinatorial pharmacogenomic test together, only the combinatorial pharmacogenomic test remained significant. Overall, this demonstrates that the combinatorial pharmacogenomic test was a superior predictor of citalopram/escitalopram blood levels compared to individual genes.


Assuntos
Antidepressivos/sangue , Antidepressivos/farmacocinética , Citalopram/sangue , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Transtorno Depressivo Maior/tratamento farmacológico , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/farmacocinética , Adulto , Algoritmos , Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Testes Farmacogenômicos , Inibidores de Captação de Serotonina/uso terapêutico , Resultado do Tratamento
16.
PLoS Genet ; 16(5): e1008185, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32392212

RESUMO

Psychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up. Here we conducted a hypothesis-free phenome-wide association study in about 330,000 participants from the UK Biobank to examine associations of polygenic risk scores (PRS) for five psychiatric disorders (major depression (MDD), bipolar disorder (BP), schizophrenia (SCZ), attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)) with 23,004 outcomes in UK Biobank, using the open-source PHESANT software package. There was evidence after multiple testing (p<2.55x10-06) for associations of PRSs with 294 outcomes, most of them attributed to associations of PRSMDD (n = 167) and PRSSCZ (n = 157) with mental health factors. Among others, we found strong evidence of association of higher PRSADHD with 1.1 months younger age at first sexual intercourse [95% confidence interval [CI]: -1.25,-0.92] and a history of physical maltreatment; PRSASD with 0.01% lower erythrocyte distribution width [95%CI: -0.013,-0.007]; PRSSCZ with 0.95 lower odds of playing computer games [95%CI:0.95,0.96]; PRSMDD with a 0.12 points higher neuroticism score [95%CI:0.111,0.135] and PRSBP with 1.03 higher odds of having a university degree [95%CI:1.02,1.03]. We were able to show that genetic liabilities for five major psychiatric disorders associate with long-term aspects of adult life, including socio-demographic factors, mental and physical health. This is evident even in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Estudo de Associação Genômica Ampla/métodos , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Estudos de Coortes , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos , Masculino , Herança Multifatorial , Fenótipo , Fatores de Risco , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Fatores Socioeconômicos , Reino Unido/epidemiologia
17.
Psychiatry Res Neuroimaging ; 301: 111101, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32447184

RESUMO

A single nucleotide polymorphism (SNP) rs12415800 of the silent mating type information regulation 2 homolog 1 gene (SIRT1) has shown a genome-wide significant association with major depression disorder (MDD) in a recent GWAS using a large sample. Subsequent studies of SIRT1's biological functions were supportive of a possible role in the pathophysiology of MDD. However, SIRT1-mediated physiopathology of MDD may be brain region specific. In the present study, we investigated the impact of SIRT1 rs12415800 genotypes on gray matter volumes (GMV) among different brain regions in both MDD patients and healthy controls. The rs12415800 was genotyped in 170 patients with first-episode medication-naïve MDD (cases) and 170 healthy controls. Magnetic resonance imaging was conducted and the voxel-based morphometry (VBM) approach was employed to analyze obtained images. When compared with the cases carrying GG genotype, the cases carrying GA or AA genotypes (A for risk allele) showed decreased GMV in right precuneus, left cuneus/precuneus, and right frontal superior. In contrast, the rs12415800-associated GMV abnormalities were not observed in controls. The SIRT1-rs12415800 polymorphism may be associated with the changes of GMV in MDD patients.


Assuntos
Transtorno Depressivo Maior/genética , Substância Cinzenta/patologia , Polimorfismo de Nucleotídeo Único/genética , Sirtuína 1/sangue , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/patologia , Feminino , Genótipo , Substância Cinzenta/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/genética , Adulto Jovem
18.
Psychiatr Genet ; 30(4): 101-109, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32459709

RESUMO

OBJECTIVES: Massive research has examined the cause of major depressive disorder (MDD) and accumulating evidence has revealed that the gene for the norepinephrine transporter (NET) is involved in MDDs etiology as well as the antidepressant response. The G1287A (rs5569, GRCh38, Chromosome 16, 55697923) is located in the exon 9 region of the SLC6A2 gene. It was found to be connected with MDD and antidepressant response in people of different genetic ancestries. However, the results are still inconsistent. METHODS: A meta-analysis was conducted to evaluate the overall association of rs5569 polymorphisms with MDD and the antidepressant response. RESULTS: Sixteen articles that studied the connection between the G1287A polymorphism and MDD or antidepressant response were identified, and their outcomes revealed there was a significant connection between the polymorphisms and MDD and antidepressant response. Our study indicated that the GG genotype may be a protection factor against the development of MDD [odds ratio (OR = 0.78, 95% confidence interval (CI) = 0.64-0.96, P = 0.02 for Asian population; OR = 0.79, 95% CI = 0.63-0.98, P = 0.03 for Han Chinese population] while the GG genotype had a worse antidepressant response (OR = 0.49, 95% CI = 0.25-0.94, P = 0.03). CONCLUSIONS: NET G1287A polymorphisms are involved in the etiology of MDD and antidepressant response.


Assuntos
Transtorno Depressivo Maior/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Biomarcadores Farmacológicos/sangue , Estudos de Casos e Controles , China , Éxons , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética
19.
Depress Anxiety ; 37(9): 834-841, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32383277

RESUMO

BACKGROUND: Cohort and cost-effectiveness studies suggest that measuring variation in genes that influence metabolism of common drugs could improve antidepressant treatment outcomes. Prior randomized trials have yielded inconsistent results. METHOD: Multicenter randomized double-blind (subject and rater), controlled trial of pharmacogenomic testing among outpatients with nonpsychotic major depressive disorder. Study participants (n = 304) were randomized 1:1 to assay-guided treatment (AGT; N = 151) or treatment-as-usual (TAU; N = 153). Participants and raters were blinded to study arm; unblinded clinicians received results of a pharmacogenomic test and adjusted treatment in light of the test report. Primary outcome was change over 8 weeks in Hamilton Depression Rating Scale (SIGH-D-17). RESULTS: For the primary comparison of interest, change in SIGH-D-17, no significant difference was detected between AGT and TAU at Week 8 (p = .53). Rates of study completion also did not differ between the arms (AGT 92.7%, TAU 92.2% (χ2 = 0.03, df = 1, p = .86). Exploratory analyses suggested significantly fewer individuals experienced worsening of depressive symptoms following AGT, and that treatment concordant with assay results was associated with greater likelihood of remission. CONCLUSION: Pharmacogenomic testing using a panel of pharmacokinetic and pharmacodynamic variants was not associated with significant improvement in the primary efficacy outcome when providers were unconstrained by the assay results. Further investigation is needed to understand the discordance with cost-effectiveness results and among randomized trials.


Assuntos
Transtorno Depressivo Maior , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Método Duplo-Cego , Humanos , Farmacogenética , Testes Farmacogenômicos , Resultado do Tratamento
20.
Nat Genet ; 52(4): 437-447, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231276

RESUMO

Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Transtorno Bipolar/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Sensibilidade e Especificidade
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