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Schizophrenia diagnosis and admission history were associated with a polygenic score (PGS) for schizophrenia based on a subset of variants that act by modifying the expression of genes whose expression is also modified by antipsychotics. This gene set was enriched in cytokine production. Interleukin-6 (IL-6) is the only cytokine whose plasma levels were associated both with schizophrenia diagnosis and with acute decompensations in the largest meta-analysis. Therefore, we hypothesized that an IL-6 PGS, but not other cytokines PGSs, would be associated with schizophrenia chronicity/psychiatric admissions. Using the IL-6 PGS model from The PGS Catalog, IL-6 PGS was calculated in 427 patients with schizophrenia and data regarding admission history. Association between IL-6 PGS and chronicity, measured as number and duration of psychiatric admissions, or ever readmission was analyzed by multivariate ordinal and logistic regression, respectively. Specificity of results was assessed by analysis of PGSs from the other cytokines at The PGS Catalog with meta-analytic evidence of association with schizophrenia diagnosis or acute decompensations, IL-1RA, IL-4, IL-8, and IL-12. IL-6 PGS was associated with schizophrenia chronicity, explaining 1.51% of variability (OR = 1.29, 95% CI 1.07-1.55, P = 0.007). There was no association with ever readmission. Other cytokines PGSs were not associated with chronicity. Association with IL-6 PGS was independent of association with schizophrenia PGS. Our results provide evidence that genetically regulated higher levels of IL-6 are involved in schizophrenia chronicity, highlighting the relevance of immunity processes for a subgroup of patients.
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Interleucina-6 , Herencia Multifactorial , Esquizofrenia , Humanos , Esquizofrenia/sangre , Interleucina-6/sangre , Femenino , Masculino , Adulto , Persona de Mediana EdadRESUMEN
BACKGROUND: Prevalence of smoking in schizophrenia (SCZ) is larger than in general population. Genetic studies provided some evidence of a causal effect of smoking on SCZ. We aim to characterize the genetic susceptibility to SCZ affected by genetic susceptibility to smoking. METHODS: Multi-trait-based conditional and joint analysis was applied to the largest European SCZ genome-wide association studies (GWAS) to remove genetic effects on SCZ driven by smoking, estimated by generalized summary data-based Mendelian randomization. Enrichment analysis was performed to compare original v. conditional GWAS. Change in genetic correlation between SCZ and relevant traits after conditioning was assessed. Colocalization analysis was performed to identify specific loci confirming general findings. RESULTS: Conditional analysis identified 19 new risk loci for SCZ and 42 lost loci whose association with SCZ may be partially driven by smoking. These results were strengthened by colocalization analysis. Enrichment analysis indicated a higher association of differentially expressed genes at prenatal brain stages after conditioning. Genetic correlation of SCZ with substance use and dependence, attention deficit-hyperactivity disorder, and several externalizing traits significantly changed after conditioning. Colocalization of association signal between SCZ and these traits was identified for some of the lost loci, such as CHRNA2, CUL3, and PCDH7. CONCLUSIONS: Our approach led to identification of potential new SCZ loci, loci partially associated to SCZ through smoking, and a shared genetic susceptibility between SCZ and smoking behavior related to externalizing phenotypes. Application of this approach to other psychiatric disorders and substances may lead to a better understanding of the role of substances on mental health.
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OBJECTIVE: To test whether a schizophrenia polygenic risk score (PRS) based on the subset of polymorphisms that affect brain expression of genes with altered expression by antipsychotics (exprAP PRS) is associated with psychiatric readmission of patients with schizophrenia. METHODS: The study involved 427 patients with schizophrenia. Genes with altered expression by antipsychotics were extracted from the Comparative Toxigenomics Database. ExprAP PRS was estimated using the clumping and thresholding (p < 0.05) method. Two additional PRS were tested based on subsets of exprAP polymorphisms whose schizophrenia risk allele has the same (unrestored PRS) or opposite (restored PRS) direction of effect on gene expression than antipsychotics. A general SCZ PRS was tested for comparison. Logistic and ordinal regression were used to test for association of each PRS with ever readmission and admission history, an outcome based on length and number of admissions, respectively. Webgestalt was used for Gene Ontology enrichment analysis. RESULTS: ExprAP PRS was associated with ever readmission (OR = 1.48, 95%CI:1.10-1.97) and admission history (OR = 1.30, 95%CI 1.07-1.57). SCZ PRS (OR = 1.22, 95%CI: 1.01-1.48) and unrestored PRS (OR = 1.26, 95%CI 1.04-1.53) were only associated with admission history. Genes at exprAP PRS were enriched in regulation of cytokine production. CONCLUSION: Our findings suggest that PRS based on genes with altered expression by antipsychotics may be better predictors of readmission than SCZ PRS, warranting further investigation in larger cohorts of patients. The action of antipsychotics may be related to brain gene expression, mainly in genes involved in immunity.
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Antipsicóticos , Esquizofrenia , Antipsicóticos/uso terapéutico , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Hospitalización , Humanos , Herencia Multifactorial , Factores de Riesgo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genéticaRESUMEN
Smoking prevalence in schizophrenia is considerably larger than in general population, playing an important role in early mortality. We compared the polygenic contribution to smoking in schizophrenic patients and controls to assess if genetic factors may explain the different prevalence. Polygenic risk scores (PRSs) for smoking initiation and four genetically correlated traits were calculated in 1108 schizophrenic patients (64.4% smokers) and 1584 controls (31.1% smokers). PRSs for smoking initiation, educational attainment, body mass index and age at first birth were associated with smoking in patients and controls, explaining a similar percentage of variance in both groups. Attention-deficit hyperactivity disorder (ADHD) PRS was associated with smoking only in schizophrenia. This association remained significant after adjustment by psychiatric cross-disorder PRS. A PRS combining all the traits was more explanative than smoking initiation PRS alone, indicating that genetic susceptibility to the other traits plays an additional role in smoking behaviour. Smoking initiation PRS was also associated with schizophrenia in the whole sample, but the significance was lost after adjustment for smoking status. This same pattern was observed in the analysis of specific SNPs at the CHRNA5-CHRNA3-CHRNB4 cluster associated with both traits. Overall, the results indicate that the same genetic factors are involved in smoking susceptibility in schizophrenia and in general population and are compatible with smoking acting, directly or indirectly, as a risk factor for schizophrenia that contributes to the high prevalence of smoking in these patients. The contrasting results for ADHD PRS may be related to higher ADHD symptomatology in schizophrenic patients.
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Esquizofrenia/genética , Fumar Tabaco/genética , Adulto , Trastorno por Déficit de Atención con Hiperactividad/genética , Índice de Masa Corporal , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Herencia Multifactorial , Proteínas del Tejido Nervioso/genética , Fenotipo , Receptores Nicotínicos/genética , Factores de Riesgo , Factores SociodemográficosRESUMEN
Postpartum depression (PPD) is a common mood disorder that occurs after delivery with a prevalence of approximately 10%. Recent reports have related placental corticotropin-releasing hormone (pCRH) to postpartum depressive symptoms. The aim of this study was to determine whether pCRH, ACTH, and cortisol (measured 48 h after delivery) and glucocorticoid and mineralocorticoid receptor genotypes (NR3C1 and NR3C2) and their interaction are associated with PPD. A longitudinal 32-week prospective study of five hundred twenty-five Caucasian depression-free women that were recruited from obstetric units at two Spanish general hospitals immediately after delivery. Of the women included in the sample, forty-two (8%) developed PPD. A strong association between PPD and the interaction between the pCRH and NR3C2 rs2070951 genotype was observed. The mean level of pCRH in rs2070951GG carriers with PPD was 56% higher than the mean in the CG and CC genotype groups (P < 0.00005). Carriers of the rs2070951GG genotype with high levels of pCRH had a higher risk of developing PPD (OR = 1.020, 95% CI 1.007-1.034, P = 0.002). This association remained even after controlling for variables such as neuroticism, obstetric complications and the number of stressful life events during pregnancy. There is an important interaction between pCRH 48 h postpartum and the NR3C2 rs2070951GG genotype. This interaction moderately associates with the presence of PPD. These results may open a new line of research and, if confirmed in other settings, will help to identify better risk predictors and the treatment for PPD.
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Hormona Liberadora de Corticotropina/sangre , Depresión Posparto/diagnóstico , Depresión Posparto/genética , Receptores de Mineralocorticoides/genética , Hormona Adrenocorticotrópica/sangre , Adulto , Femenino , Genotipo , Humanos , Hidrocortisona/sangre , Estudios Longitudinales , Placenta/fisiopatología , Periodo Posparto , Embarazo , Estudios Prospectivos , Factores de Riesgo , EspañaRESUMEN
Our aim was to assess personality traits associated with substance use during pregnancy in a population-based, multicentre study of 1804 pregnant women. On day 2-3 postpartum, participants completed a semi-structured interview, including self-reported drug use (alcohol, tobacco, caffeine, cannabis, cocaine, opioids) during pregnancy, and socio-demographic, reproductive and obstetric variables, personal and family psychiatric history, social support, and the Eysenck personality questionnaire, short version (EPQ-RS). Logistic regression models were conducted. Fifty per cent of women reported substance use during pregnancy: 40% caffeine, 21% tobacco, 3.5% alcohol, and 0.3 % cannabis. Mean T-scores (SD) for personality dimensions were 51.1 (9.6) for extraversion, 48 (8.9) for psychoticism, and 43.6 (8.5) for neuroticism. Extroversion (p = .029) and psychoticism (p = .009) were identified as risk factors after adjustment by age, level of education, employment status during pregnancy, low social support, and previous psychiatric history. For each increment of 10 units in their scores, the odds of substance use increased by 12% and 16% respectively. Low education, being on leave during pregnancy, and previous psychiatric history were independent factors (p < .05) associated with substance use during pregnancy. Primiparity was a protective factor (p = .001). The final models showed a good fit (p = .26). The screening of substance use during pregnancy should include personality dimensions apart from psychosocial variables and history of psychiatric disorders. It is important to identify the associated risk factors for substance use during pregnancy to prevent and improve foetal/neonatal and maternal health during perinatal period.
Este estudio evalúa los patrones de consumo de substancias durante el embarazo y las dimensiones de personalidad asociadas, en una muestra multicéntrica de 1804 mujeres de población general. En el 2-3 día posparto, completaron una entrevista auto-administrada sobre el consumo de alcohol, tabaco, cafeína, cannabis, cocaína, opiáceos, drogas de diseño, además de variables socio-demográficas, obstétricas/reproductivas, historia psiquiátrica previa, apoyo social durante el embarazo y el cuestionario de personalidad de Eysenck (EPQ-RS). Se generaron modelos de regresión logística múltiple. La prevalencia del consumo fue del 50% (N=909): 40% cafeína, 21% tabaco, 3,5% alcohol, y 0,3 cannabis. Las puntuaciones T medias (DE) de personalidad fueron: extraversión 51,1 (9,6), psicoticismo 48 (8,9) y neuroticismo 43,6 (8,5). Las dimensiones de extraversión (p=0,029) y psicoticismo (p=0,009), fueron identificadas como factores de riesgo tras ajustar por edad, nivel educación, estatus laboral durante el embarazo, bajo apoyo social, e historia psiquiátrica previa. Para cada incremento de 10 unidades en sus puntuaciones, el odds de consumo de substancias durante el embarazo se incrementó un 12% y un 16% respectivamente. Menor educación, estar de baja, y antecedentes psiquiátricos fueron también factores independientes (p<0,05) asociados al consumo. Ser primípara fue factor protector (p=0,001). El modelo final mostró un ajuste satisfactorio (p=0,26). El cribaje de las mujeres con riesgo de consumo de substancias durante el embarazo debería incluir la personalidad además de variables psicosociales y antecedentes psiquiátricos. Identificar los factores de riesgo asociados es importante para prevenir y mejorar la salud materna y fetal/neonatal durante el embarazo y posparto.
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The transcriptome profiles of the cingulate gyrus region from the postmortem brain tissues of a set of well-characterized patients with schizophrenia (SCZ) and matched controls were investigated using an integrated approach that analyzed both the alterations in transcription expression pattern and rare genetic variants in expressed genes. We demonstrated increased expression of astrocyte-related genes using spatiotemporal co-expression modules that have previously been established for developing human brain, and showed these results are independent of medication dosage. The relationship between genetic variants and expression pattern in the context of neurodevelopment was further investigated, and we identified an enrichment of rare genetic variants in a set of signature genes that were specific to astrocytes and up-regulated in the patients with SCZ. Our result suggested the involvement of astrocyte malfunction in SCZ pathophysiology. In addition, our approach indicated a novel strategy of narrowing down genetic variants that might contribute to the pathophysiology in the patients with SCZ to a subset of genes that are highly expressed in an affected brain region.
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Astrocitos/metabolismo , Giro del Cíngulo/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Adulto , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Masculino , Transcriptoma , Regulación hacia ArribaRESUMEN
Copy number variants (CNVs) conferring risk of schizophrenia present incomplete penetrance, suggesting the existence of second genetic hits. Identification of second hits may help to find genes with rare variants of susceptibility to schizophrenia. The aim of this work was to search for second hits of moderate/high risk in schizophrenia carriers of risk CNVs and resequencing of the relevant genes in additional samples. To this end, ten patients with risk CNVs at cytobands 15q11.2, 15q11.2-13.1, 16p11.2, or 16p13.11, were subjected to whole-exome sequencing. Rare single nucleotide variants, defined as those absent from main public databases, were classified according to bioinformatic prediction of pathogenicity by CADD scores. The average number of rare predicted pathogenic variants per sample was 13.6 (SD 2.01). Two genes, BFAR and SYNJ1, presented rare predicted pathogenic variants in more than one sample. Follow-up resequencing of these genes in 432 additional cases and 432 controls identified a significant excess of rare predicted pathogenic variants in case samples at SYNJ1. Taking into account its function in clathrin-mediated synaptic vesicle endocytosis at presynaptic terminals, our results suggest an impairment of this process in schizophrenia.
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Variaciones en el Número de Copia de ADN/genética , Secuenciación del Exoma/métodos , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Monoéster Fosfórico Hidrolasas/genética , Esquizofrenia/genética , Predisposición Genética a la Enfermedad , Humanos , RiesgoRESUMEN
INTRODUCTION: The Edinburgh Postnatal Depression Scale (EPDS) is considered the gold standard in screening for postpartum depression. Although the Spanish version has been widely used, its factorial structure has not yet been studied . METHODS: A total of 1,204 women completed the EPDS 32 weeks after delivery. To avoid multiple testing, we split the sample into two halves, randomly drawing two subsamples of 602 participants each. We conducted exploratory factor analysis (EFA), followed by an oblimin rotation with the first sub-sample. Confirmatory factor analysis (CFA) was conducted using a Weighted Least Squares Means and Variance (WLSMV) estimation of the data. We explored different solutions between two and four factors. We compared the factors between two groups with depression and non-depression (evaluated with the Diagnostic Interview for Genetic Studies (DIGS) for the DSM-IV). RESULTS: The EFA indicated a three-factor model consisting of anxiety, depression and anhedonia. The results of the CFA confirmed the three-factor model (χ2=99.203, p<0.001; RMSEA=0.06, 90% CI=0.04/0.07, CFI=0.87 and TLI=0.82). Women with depression in the first 32 weeks obtained higher scores for anxiety, depression and anhedonia dimensions (p<0.001). CONCLUSIONS: This is the first study of confirmatory analysis with the Spanish version of EPDS in a large sample of women without psychiatric care during pregnancy. A three-factor model consisting of anxiety, depression and anhedonia was used. Women with depression had a higher score in the three dimensions of the EPDS.
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Depresión Posparto/diagnóstico , Escalas de Valoración Psiquiátrica , Adulto , Autoevaluación Diagnóstica , Análisis Factorial , Femenino , Humanos , TraduccionesRESUMEN
There is a long way from the initial discovery of a genome-wide significant signal to mechanistic understanding of the association. Identification of the gene and causal polymorphism usually requires an extensive additional effort. The schizophrenia genome-wide significant locus at 4q24 may be a rare exception to this pattern. As discussed in this review, the association at this locus is most probably driven by a functional missense variant at the metal cations transporter SLC39A8. The variant, rs13107325, is almost exclusive of European populations and is one of the most pleiotropic variants of the genome, being associated at genome-wide significant level with several additional traits, such as body mass index, Crohn's disease, blood pressure related-traits, and serum levels of manganese, N-terminal pro-B-type natriuretic peptide and HDL-cholesterol. SLC39A8 seems to be subject to recent natural selection in Europeans. It is almost ubiquitously expressed and its physiological role is beginning to be elucidated, mainly in relation to immunity. This manuscript presents arguments in favor of the rs13107325 variant as the functional variant responsible for the association of this locus with schizophrenia, reviews the genetic associations with this gene, the evidences of natural selection on the gene, and the known aspects about its structure and physiological functions. Finally, some hypotheses about putative mechanisms for its association with schizophrenia are presented based on this knowledge, including impaired immunity/inflammation, interference with glutamatergic neurotransmission, homeostasis of essential metals in brain, such as iron, zinc or manganese, or neurotoxicity by heavy metals, such as cadmium or lead.
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Proteínas de Transporte de Catión/genética , Esquizofrenia/genética , Esquizofrenia/patología , Proteínas de Transporte de Catión/fisiología , Pleiotropía Genética/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Patología Molecular/métodos , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The transition to motherhood is stressful as it requires several important changes in family dynamics, finances, and working life, along with physical and psychological adjustments. This study aimed at determining whether some forms of coping might predict postpartum depressive symptomatology. A total of 1626 pregnant women participated in a multi-centric longitudinal study. Different evaluations were performed 8 and 32 weeks after delivery. Depression was assessed using the Edinburgh Postnatal Depression Scale (EPDS) and the structured Diagnostic Interview for Genetic Studies (DIGS). The brief Coping Orientation for Problem Experiences (COPE) scale was used to measure coping strategies 2-3 days postpartum. Some coping strategies differentiate between women with and without postpartum depression. A logistic regression analysis was used to explore the relationships between the predictors of coping strategies and major depression (according to DSM-IV criteria). In this model, the predictor variables during the first 32 weeks were self-distraction (OR 1.18, 95 % CI 1.04-1.33), substance use (OR 0.58, 95 % CI 0.35-0.97), and self-blame (OR 1.18, 95 % CI 1.04-1.34). In healthy women with no psychiatric history, some passive coping strategies, both cognitive and behavioral, are predictors of depressive symptoms and postpartum depression and help differentiate between patients with and without depression.
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Adaptación Psicológica , Depresión Posparto/psicología , Trastorno Depresivo Mayor/psicología , Periodo Posparto/psicología , Adulto , Depresión Posparto/diagnóstico , Trastorno Depresivo Mayor/diagnóstico , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Estudios Longitudinales , Tamizaje Masivo , Embarazo , Escalas de Valoración Psiquiátrica , Análisis de Regresión , Factores de Riesgo , Estrés Psicológico/complicaciones , Estrés Psicológico/diagnóstico , Encuestas y CuestionariosRESUMEN
Schizophrenia may be considered a human-specific disorder arisen as a maladaptive by-product of human-specific brain evolution. Therefore, genetic variants involved in susceptibility to schizophrenia may be identified among those genes related to acquisition of human-specific traits. NPAS3, a transcription factor involved in central nervous system development and neurogenesis, seems to be implicated in the evolution of human brain, as it is the human gene with most human-specific accelerated elements (HAEs), i.e., .mammalian conserved regulatory sequences with accelerated evolution in the lineage leading to humans after human-chimpanzee split. We hypothesize that any nucleotide variant at the NPAS3 HAEs may lead to altered susceptibility to schizophrenia. Twenty-one variants at these HAEs detected by the 1000 genomes Project, as well as five additional variants taken from psychiatric genome-wide association studies, were genotyped in 538 schizophrenic patients and 539 controls from Galicia. Analyses at the haplotype level or based on the cumulative role of the variants assuming different susceptibility models did not find any significant association in spite of enough power under several plausible scenarios regarding direction of effect and the specific role of rare and common variants. These results suggest that, contrary to our hypothesis, the special evolution of the NPAS3 HAEs in Homo relaxed the strong constraint on sequence that characterized these regions during mammalian evolution, allowing some sequence changes without any effect on schizophrenia risk.
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Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Factores de Transcripción/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Estudios de Casos y Controles , Evolución Molecular , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Haplotipos , Humanos , Masculino , Neurogénesis/genética , Polimorfismo de Nucleótido SimpleRESUMEN
It has been reported that certain genetic factors involved in schizophrenia could be located in the mitochondrial DNA (mtDNA). Therefore, we hypothesized that mtDNA mutations and/or variants would be present in schizophrenia patients and may be related to schizophrenia characteristics and mitochondrial function. This study was performed in three steps: (1) identification of pathogenic mutations and variants in 14 schizophrenia patients with an apparent maternal inheritance of the disease by sequencing the entire mtDNA; (2) case-control association study of 23 variants identified in step 1 (16 missense, 3 rRNA, and 4 tRNA variants) in 495 patients and 615 controls, and (3) analyses of the associated variants according to the clinical, psychopathological, and neuropsychological characteristics and according to the oxidative and enzymatic activities of the mitochondrial respiratory chain. We did not identify pathogenic mtDNA mutations in the 14 sequenced patients. Two known variants were nominally associated with schizophrenia and were further studied. The MT-RNR2 1811A > G variant likely does not play a major role in schizophrenia, as it was not associated with clinical, psychopathological, or neuropsychological variables, and the MT-ATP6 9110T > C p.Ile195Thr variant did not result in differences in the oxidative and enzymatic functions of the mitochondrial respiratory chain. The patients with apparent maternal inheritance of schizophrenia did not exhibit any mutations in their mtDNA. The variants nominally associated with schizophrenia in the present study were not related either to phenotypic characteristics or to mitochondrial function. We did not find evidence pointing to a role for mtDNA sequence variation in schizophrenia.
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ADN Mitocondrial/genética , Bases de Datos Genéticas , Variación Genética/genética , Haplotipos/genética , Mitocondrias/patología , Mutación/genética , Esquizofrenia/genética , Adulto , Estudios de Casos y Controles , Europa (Continente) , Femenino , Estudios de Seguimiento , Humanos , Patrón de Herencia/genética , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Pruebas Neuropsicológicas , Fosforilación Oxidativa , PronósticoRESUMEN
Background: Epidemiological studies have linked low birth weight to psychiatric disorders, including substance use disorders. Genomic analyses suggest a role of placental physiology on psychiatric risk. We investigated whether this association is causally related to impaired trophoblast function. Methods: We conducted a two-sample summary-data Mendelian randomization study using as instrumental variables those genetic variants strongly associated with birth weight, whose effect is exerted through the fetal genome, and are located near genes with differential expression in trophoblasts. Eight psychiatric and substance use disorders with >10,000 samples were included as outcomes. The inverse variance weighted method was used as the main analysis and several sensitivity analyses were performed for those significant results. Results: The inverse variance weighted estimate, based on 14 instrumental variables, revealed an association, after correction for multiple tests, between birth weight and broadly defined depression (ß = -0.165, 95% CI = -0.282 to -0.047, P = 0.0059). Sensitivity analyses revealed the absence of heterogeneity in the effect of instrumental variables, confirmed by leave-one-out analysis, MR_Egger intercept, and MR_PRESSO. The effect was consistent using robust methods. Reverse causality was not detected. The effect was specifically linked to genetic variants near genes involved in trophoblast physiology instead of genes with fetal effect on birth weight or involved in placenta development. Conclusion: Impaired trophoblast functioning, probably leading to reduced fetal brain oxygen and nutrient supply, is causally related to broadly defined depression. Considering the therapeutic potential of some agents to treat fetal growth restriction, further research on the effect of trophoblast physiology on mental disorders may have future implications in prevention.
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Cumulative evidence suggests that zebrafish is a useful model in psychiatric research. Weighted Gene Co-expression Network Analysis (WGCNA) enables the reduction of genome-wide expression data to modules of highly co-expressed genes, which are hypothesized to interact within molecular networks. In this study, we first applied WGCNA to zebrafish brain expression data across different experimental conditions. Then, we characterized the different co-expression modules by gene-set enrichment analysis and hub gene-phenotype association. Finally, we analyzed association of polygenic risk scores (PRSs) based on genes of some interesting co-expression modules with alcohol dependence in 524 patients and 729 controls from Galicia, using competitive tests. Our approach revealed 34 co-expression modules in the zebrafish brain, with some showing enrichment in human synaptic genes, brain tissues, or brain developmental stages. Moreover, certain co-expression modules were enriched in psychiatry-related GWAS and comprised hub genes associated with psychiatry-related traits in both human GWAS and zebrafish models. Expression patterns of some co-expression modules were associated with the tested experimental conditions, mainly with substance withdrawal and cold stress. Notably, a PRS based on genes from co-expression modules exclusively associated with substance withdrawal in zebrafish showed a stronger association with human alcohol dependence than PRSs based on randomly selected brain-expressed genes. In conclusion, our analysis led to the identification of co-expressed gene modules that may model human brain gene networks involved in psychiatry-related traits. Specifically, we detected a cluster of co-expressed genes whose expression was exclusively associated with substance withdrawal in zebrafish, which significantly contributed to alcohol dependence susceptibility in humans.
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Alcoholismo , Encéfalo , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo , Pez Cebra , Animales , Encéfalo/metabolismo , Alcoholismo/genética , Humanos , Herencia Multifactorial , Modelos Animales de Enfermedad , Expresión Génica/genéticaRESUMEN
Evidence suggests a remarkable shared genetic susceptibility between psychiatric disorders. However, sex-dependent differences have been less studied. We explored the contribution of schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) polygenic scores (PGSs) on the risk for psychotic disorders and whether sex-dependent differences exist (CIBERSAM sample: 1826 patients and 1372 controls). All PGSs were significantly associated with psychosis. Sex-stratified analyses showed that the variance explained in psychotic disorders risk was significantly higher in males than in females for all PGSs. Our results confirm the shared genetic architecture across psychotic disorders and demonstrate sex-dependent differences in the vulnerability to psychotic disorders.
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Trastorno Bipolar , Trastorno Depresivo Mayor , Predisposición Genética a la Enfermedad , Herencia Multifactorial , Trastornos Psicóticos , Esquizofrenia , Caracteres Sexuales , Humanos , Masculino , Femenino , Herencia Multifactorial/genética , Trastornos Psicóticos/genética , Trastornos Psicóticos/epidemiología , Predisposición Genética a la Enfermedad/genética , Adulto , Trastorno Bipolar/genética , Esquizofrenia/genética , Esquizofrenia/epidemiología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/epidemiología , Persona de Mediana EdadRESUMEN
BACKGROUND: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. Studies have reported a shared genetic basis between schizophrenia and cortical thickness. However, no genes whose expression is related to abnormal cortical thinning in schizophrenia have been identified. METHODS: We conducted linear mixed models to estimate the rates of accelerated cortical thinning across 68 regions from the Desikan-Killiany atlas in individuals with schizophrenia compared with healthy control participants from a large longitudinal sample (ncases = 169 and ncontrols = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning. RESULTS: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit this accelerated thinning were downregulated in several psychiatric disorders and were enriched for both common and rare disrupting variation for schizophrenia and neurodevelopmental disorders. In contrast, none of these enrichments were observed for baseline cross-sectional cortical thickness differences. CONCLUSIONS: Our findings suggest that accelerated cortical thinning, rather than cortical thickness alone, serves as an informative phenotype for neurodevelopmental disruptions in schizophrenia. We highlight the genetic and transcriptomic correlates of this accelerated cortical thinning, emphasizing the need for future longitudinal studies to elucidate the role of genetic variation and the temporal-spatial dynamics of gene expression in brain development and aging in schizophrenia.
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Trastornos del Neurodesarrollo , Esquizofrenia , Humanos , Esquizofrenia/genética , Esquizofrenia/patología , Esquizofrenia/diagnóstico por imagen , Adulto , Persona de Mediana Edad , Masculino , Femenino , Adolescente , Adulto Joven , Anciano , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Trastornos del Neurodesarrollo/diagnóstico por imagen , Adelgazamiento de la Corteza Cerebral/genética , Adelgazamiento de la Corteza Cerebral/diagnóstico por imagen , Adelgazamiento de la Corteza Cerebral/patología , Imagen por Resonancia Magnética , Estudios Longitudinales , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Esquizofrenia/genética , Factores de Transcripción/genética , Alelos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Riesgo , Factor de Transcripción 4RESUMEN
A balanced translocation affecting DISC1 cosegregates with several psychiatric disorders, including schizophrenia, in a Scottish family. DISC1 is a hub protein of a network of protein-protein interactions involved in multiple developmental pathways within the brain. Gene set-based analysis has been proposed as an alternative to individual analysis of single nucleotide polymorphisms (SNPs) to get information from genome-wide association studies. In this work, we tested for an overrepresentation of the DISC1 interacting proteins within the top results of our ranked list of genes based on our previous genome-wide association study of missense SNPs in schizophrenia. Our data set consisted of 5100 common missense SNPs genotyped in 476 schizophrenic patients and 447 control subjects from Galicia, NW Spain. We used a modification of the Gene Set Enrichment Analysis adapted for SNPs, as implemented in the GenGen software. The analysis detected an overrepresentation of the DISC1 interacting proteins (permuted P-value=0.0158), indicative of the role of this gene set in schizophrenia risk. We identified seven leading-edge genes, MACF1, UTRN, DST, DISC1, KIF3A, SYNE1, and AKAP9, responsible for the overrepresentation. These genes are involved in neuronal cytoskeleton organization and intracellular transport through the microtubule cytoskeleton, suggesting that these processes may be impaired in schizophrenia.
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Proteínas Portadoras/metabolismo , Estudio de Asociación del Genoma Completo , Mutación Missense , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Polimorfismo de Nucleótido Simple , Esquizofrenia/genética , Esquizofrenia/metabolismo , Biología Computacional , Conjuntos de Datos como Asunto , Epistasis Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Unión Proteica , RiesgoRESUMEN
Although treatment-resistant schizophrenia (TRS) is an important and frequent problem with a specific treatment, clozapine, its biological determinants are poorly understood. At the genetic level, most studies of association between schizophrenia polygenic risk score (SCZ PRS) and TRS did not reach statistical significance. However, no systematic review or meta-analysis of this type of study has been conducted. In this work, we first performed an association study between SCZ PRS and TRS in a sample of 427 patients with schizophrenia. Then, we carried out a systematic review and meta-analysis of all available data. PubMed was searched for articles reporting association between SCZ PRS and TRS, defined as use of clozapine or failure of two sequentially prescribed antipsychotics. The association in our sample was not statistically significant. Five studies met the inclusion criteria, involving 7309 patients, 2386 (33 %) with TRS. Fixed effect model meta-analysis revealed a statistically significant association with TRS status (OR = 1.090, 95 % CI = 1.0301.154; P = 0.0027; I2 = 0.00 %). The robustness of the result was demonstrated by maintaining a statistically significant association in all sensitivity analyses, such as a leave-one-out approach or use of a random effects model. Therefore, at least part of the genetic susceptibility to TRS is shared with that of schizophrenia. However, our results did not support the clinical utility of the SCZ PRS in its current stage due to the small effect size. Improvements in PRS estimation and combination with other predictors may lead to future use in stratification of patients.