Association between psychiatric admissions in patients with schizophrenia and IL-6 plasma levels polygenic score.

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.

Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders.

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.

Recent natural selection conferred protection against schizophrenia by non-antagonistic pleiotropy.

Schizophrenia is a debilitating psychiatric disorder associated with a reduced fertility and decreased life expectancy, yet common predisposing variation substantially contributes to the onset of the disorder, which poses an evolutionary paradox. Previous research has suggested balanced selection, a mechanism by which schizophrenia risk alleles could also provide advantages under certain environments, as a reliable explanation. However, recent studies have shown strong evidence against a positive selection of predisposing loci. Furthermore, evolutionary pressures on schizophrenia risk alleles could have changed throughout human history as new environments emerged. Here in this study, we used 1000 Genomes Project data to explore the relationship between schizophrenia predisposing loci and recent natural selection (RNS) signatures after the human diaspora out of Africa around 100,000 years ago on a genome-wide scale. We found evidence for significant enrichment of RNS markers in derived alleles arisen during human evolution conferring protection to schizophrenia. Moreover, both partitioned heritability and gene set enrichment analyses of mapped genes from schizophrenia predisposing loci subject to RNS revealed a lower involvement in brain and neuronal related functions compared to those not subject to RNS. Taken together, our results suggest non-antagonistic pleiotropy as a likely mechanism behind RNS that could explain the persistence of schizophrenia common predisposing variation in human populations due to its association to other non-psychiatric phenotypes.

Common genetic variants contribute to heritability of age at onset of schizophrenia.

Schizophrenia (SCZ) is a complex disorder that typically arises in late adolescence or early adulthood. Age at onset (AAO) of SCZ is associated with long-term outcomes of the disease. We explored the genetic architecture of AAO with a genome-wide association study (GWAS), heritability, polygenic risk score (PRS), and copy number variant (CNV) analyses in 4 740 subjects of European ancestry. Although no genome-wide significant locus was identified, SNP-based heritability of AAO was estimated to be between 17 and 21%, indicating a moderate contribution of common variants. We also performed cross-trait PRS analyses with a set of mental disorders and identified a negative association between AAO and common variants for SCZ, childhood maltreatment and attention-deficit/hyperactivity disorder. We also investigated the role of copy number variants (CNVs) in AAO and found an association with the length and number of deletions (P-value = 0.03), whereas the presence of CNVs previously reported in SCZ was not associated with earlier onset. To our knowledge, this is the largest GWAS of AAO of SCZ to date in individuals from European ancestry, and the first study to determine the involvement of common variants in the heritability of AAO. Finally, we evidenced the role played by higher SCZ load in determining AAO but discarded the role of pathogenic CNVs. Altogether, these results shed light on the genetic architecture of AAO, which needs to be confirmed with larger studies.

Genetic susceptibility for schizophrenia after adjustment by genetic susceptibility for smoking: implications in identification of risk genes and genetic correlation with related traits.

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.

Polygenic risk scores for schizophrenia and treatment resistance: New data, systematic review and meta-analysis.

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.

Oxytocin Exposure in Labor and its Relationship with Cognitive Impairment and the Genetic Architecture of Autism.

Whether there is a relationship between oxytocin (OXT) use in labor and the risk of autism (ASD), and the nature of such relationship, is unclear. By integrating genetic and clinical data in a sample of 176 ASD participants, we tested the hypothesis that OXT is a marker for abnormal prenatal development which leads to impairments in the process of labor. OXT-exposed ASD had more obstetric complications (P = 0.031), earlier onset of symptoms (P = 0.027), poorer cognitive development (P = 0.011), higher mutation burden across neurodevelopment genes (P = 0.020; OR = 5.33) and lower transmission of polygenic risk for ASD (P = 0.0319), than non-exposed ASD. OXT seems to constitute a risk indicator rather than a risk factor for ASD, which is relevant for diagnostic and genetic counselling.

Association between psychiatric hospitalizations of patients with schizophrenia and polygenic risk scores based on genes with altered expression by antipsychotics.

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.

Polygenic contribution to the relationship of loneliness and social isolation with schizophrenia.

Previous research suggests an association of loneliness and social isolation (LNL-ISO) with schizophrenia. Here, we demonstrate a LNL-ISO polygenic score contribution to schizophrenia risk in an independent case-control sample (N = 3,488). We then subset schizophrenia predisposing variation based on its effect on LNL-ISO. We find that genetic variation with concordant effects in both phenotypes shows significant SNP-based heritability enrichment, higher polygenic contribution in females, and positive covariance with mental disorders such as depression, anxiety, attention-deficit hyperactivity disorder, alcohol dependence, and autism. Conversely, genetic variation with discordant effects only contributes to schizophrenia risk in males and is negatively correlated with those disorders. Mendelian randomization analyses demonstrate a plausible bi-directional causal relationship between LNL-ISO and schizophrenia, with a greater effect of LNL-ISO liability on schizophrenia than vice versa. These results illustrate the genetic footprint of LNL-ISO on schizophrenia.

A polygenic approach to the association between smoking and schizophrenia.

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.

Genetic predisposition to alcohol dependence: The combined role of polygenic risk to general psychopathology and to high alcohol consumption.

BACKGROUND: High alcohol consumption and alcohol dependence are only partly genetically correlated and they differ considerably in their correlations with other traits. The existence of genetic correlation among alcohol dependence and psychiatric disorders may be attributed to the presence of a general psychopathology factor, the p factor. This study investigates the relationship of polygenic risk to general psychopathology and to high alcohol consumption on alcohol dependence. METHODS: Participants were 524 alcohol-dependent patients and 729 controls. Polygenic risk scores (PRS) were computed for alcohol consumption (drinks per week) and nine psychiatric disorders. Principal component analysis (PCA) applied to the psychiatric PRS was used to calculate the first principal component as a proxy of the polygenic p factor. RESULTS: Both the polygenic p factor and the drinks per week PRS were associated with alcohol dependence in our sample. Both variables are only weakly correlated, contributing additively to the risk for alcohol dependence. Sensitivity analyses showed that the polygenic p factor was also associated with alcohol dependence in the subset of patients without any psychiatric or substance use comorbidity. CONCLUSIONS: Polygenic risk for alcohol dependence can be split at least into two components, involved in general psychopathology and high alcohol consumption. The first component of PCA based on PRS for different psychiatric disorders allows estimation of the contribution of the polygenic p factor to alcohol dependence. The pleiotropic effects of genetic variants across psychiatric disorders are mainly manifested as alcohol dependence in some patients.

Colocalization of association signals at nicotinic acetylcholine receptor genes between schizophrenia and smoking traits.

BACKGROUND: Epidemiological data suggest that smoking may be a risk factor for schizophrenia (SCZ), but more evidence is needed. Two regions coding nicotinic acetylcholine receptor (nAchR) subunits, atCHRNA2 and the CHRNA5/A3/B4 cluster, were associated with SCZ in genome-wide association studies (GWAS). Additionally, a signal at CHRNA4 is near significance. CHRNA2 was also associated with cannabis use disorder (CUD). These regions were also associated with smoking behaviors. If tobacco is a risk factor, the GWAS signals at smoking behaviors and SCZ have to be due to the same causal variants, i.e. they have to colocalize, although colocalization does not necessarily imply causality. Here, we present colocalization analysis at these loci between SCZ and smoking behaviors. METHODS: The Bayesian approach implemented in coloc was used to check for posterior probability of colocalization versus independent signals at the three loci with some evidence of association with SCZ and smoking behaviors, using GWAS summary statistics. Colocalization was also assessed for positive control traits and CUD. Three different sensibility analyses were used to confirm the results. A visualization tool, LocusCompare, was used to facilitate interpretation of the coloc results. RESULTS: Evidence for colocalization of GWAS signals between SCZ and smoking behaviors was found for CHRNA2. Evidence for independent causal variants was found for the other two loci. CUD GWAS signal at CHRNA2 colocalizes with SCZ and smoking behaviors. CONCLUSIONS: Overall, the results indicate that the association between some nAchR subunit genes and SCZ cannot be solely explained by their effect on smoking behaviors.

Substance use during pregnancy and personality dimensions. / Consumo de substancias durante el embarazo y dimensiones de personalidad.

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.

Psychiatric comorbidities in Asperger syndrome are related with polygenic overlap and differ from other Autism subtypes.

There is great phenotypic heterogeneity within autism spectrum disorders (ASD), which has led to question their classification into a single diagnostic category. The study of the common genetic variation in ASD has suggested a greater contribution of other psychiatric conditions in Asperger syndrome (AS) than in the rest of the DSM-IV ASD subtypes (Non_AS). Here, using available genetic data from previously performed genome-wide association studies (GWAS), we aimed to study the genetic overlap between five of the most related disorders (schizophrenia (SCZ), major depression disorder (MDD), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorders (OCD) and anxiety (ANX)), and AS, comparing it with the overlap in Non_AS subtypes. A Spanish cohort of autism trios (N = 371) was exome sequenced as part of the Autism Sequencing Consortium (ASC) and 241 trios were extensively characterized to be diagnosed with AS following DSM-IV and Gillberg's criteria (N = 39) or not (N = 202). Following exome imputation, polygenic risk scores (PRS) were calculated for ASD, SCZ, ADHD, MDD, ANX, and OCD (from available summary data from Psychiatric Genomic Consortium (PGC) repository) in the Spanish trios' cohort. By using polygenic transmission disequilibrium test (pTDT), we reported that risk for SCZ (Pscz = 0.008, corrected-PSCZ = 0.0409), ADHD (PADHD = 0.021, corrected-PADHD = 0.0301), and MDD (PMDD = 0.039, corrected-PMDD = 0.0501) is over-transmitted to children with AS but not to Non_AS. Indeed, agnostic clustering procedure with deviation values from pTDT tests suggested two differentiated clusters of subjects, one of which is significantly enriched in AS (P = 0.025). Subsequent analysis with S-Predixcan, a recently developed software to predict gene expression from genotype data, revealed a clear pattern of correlation between cortical gene expression in ADHD and AS (P < 0.001) and a similar strong correlation pattern between MDD and AS, but also extendable to another non-brain tissue such as lung (P < 0.001). Altogether, these results support the idea of AS being qualitatively distinct from Non_AS autism and consistently evidence the genetic overlap between AS and ADHD, MDD, or SCZ.

Screen-printed electrodes-based technology: Environmental application to real time monitoring of phenolic degradation by phytoremediation with horseradish roots.

The following is a description of a simple strategy for monitoring phenolic pollutants from highly-contaminated water samples. These phenolic compounds are removed from tap water using horseradish roots (Raphanus sativus) that contain peroxidase as catalyst and H2O2 to generate hydroxyl radicals. The later (•OH) acts on the aromatic structure, causing them to degrade to non-toxic by-products. The tool used to follow up the evolution of the process is based on screen-printed carbon electrodes (SPCEs) as electrochemical sensor for simultaneous detection of hydroquinone (Epa at 0.047 V), m-cresol (Epa at 0.506 V) and 4-nitrophenol (Epa at 0.696 V) by differential pulse voltammetry (DPV). This electroanalytical methodology enables close monitoring of the situation and rapid sensor response time. Furthermore, this direct methodology works for opaque and heterogeneous samples, as tap water with chopped horseradish roots, without any treatment of samples previously to the analysis. For better knowledge of the electrodic-transfer process, the electrochemical behavior of these phenolic compounds by cyclic voltammetry (CV) is also included. This simple methodology shows a low detection limit (below to 5 µM) and an excellent selectivity (peak potential separation between them up to 200 mV or greater) in a linear range of three orders of concentration (from 1-5 µM to 1 mM) for all of the analytes studied. The DPV responses of the phenolic compounds during the phytoremediation process are simultaneously monitored by this direct, cheap, reproducible (RSD < 2.3%) and rapid DPV-SPCE electroanalytical methodology. Portable device as electrochemical sensor with this optimized and validated technology can be applied for decentralized analysis, on-site assays and rapid screening purposes. The use of the horseradish roots achieves the total elimination of phenolic pollutants in concentrations 1000 times higher than the legal limits in less than 1 h.

Clock gene polygenic risk score and seasonality in major depressive disorder and bipolar disorder.

Seasonal changes in mood and diurnal preference are two well-characterized chronobiological phenotypes in major depressive disorder (MDD) and bipolar disorder (BD). The biological mechanisms regulating physiological changes related to seasonality and chronotype involve several genes known as "clock" or circadian genes. Our goal was to study the relationship between the polygenic risk score (PRS) obtained from a set of clock genes and chronobiological traits in patients with mood disorders. The sample included 445 patients with mood disorders (256 MDD; 189 BD). Seasonality was assessed using the Seasonal Pattern Assessment Questionnaire (SPAQ), and chronotype was assessed using the Horne and Östberg Morningness-Eveningness Questionnaire. We selected 248 single nucleotide polymorphisms located within 19 genes. PRS for both MDD and BD was calculated using the Psychiatric Genetics Consortium latest datasets as discovery samples. Another PRS was calculated using results from a genome-wide association study focusing on chronotype. SPAQ results were significantly associated with MDD-PRS (p = 0.037) and chronotype-PRS (p = 0.019), which also showed a significant interaction with age (p = 0.039). No significant association was observed between the measured PRS and chronotype. Our results reflect that small effect variants associated with MDD and chronotype within clock genes are associated with seasonality traits in patients with mood disorders, further explaining the mechanism through which the circadian system might influence mood disorder clinical presentation. Future studies measuring PRS from specific gene sets and focusing on biological endophenotypes will help to elucidate the pathways from genetic variations to clinical outcome.

Interaction between the functional SNP rs2070951 in NR3C2 gene and high levels of plasma corticotropin-releasing hormone associates to postpartum depression.

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.

Identification of relevant hub genes for early intervention at gene coexpression modules with altered predicted expression in schizophrenia.

Genetic risk for schizophrenia is due to the joint effect of multiple genes acting mainly at two different processes, prenatal/perinatal neurodevelopment and adolescence/early adulthood synapse maturation. Identification of important genes at the second process is of relevance for early intervention. The aim of this work was to identify gene co-expression modules with altered expression in schizophrenia during adolescence/early adulthood. To this goal, we predicted frontal cortex gene expression in one discovery sample, the largest GWAS of schizophrenia from the Psychiatric Genomics Consortium, using S-prediXcan, and in one target sample, consisting of 625 schizophrenic patients and 819 controls from Spain, using prediXcan. Prediction models were trained on GTEx frontal cortex expression dataset. In parallel, we identified brain co-expression modules from BrainSpan using WGCNA. Then, we estimated polygenic risk scores based on predicted expression (PE-PRS) for each co-expression module in the target sample, based on PE-PRS model from the discovery sample. This analysis led to the identification of a module with mainly adolescence/adulthood expression whose PE-PRS was significantly associated with schizophrenia. The module was significantly enriched in synaptic processes. Several hub genes at this module are drugabble, according to the drug-gene interaction database, and/or involved in synaptic transmission, such as the voltage-gated ion channels SCN2B and KCNAB2, the calcium calmodulin kinases CAMK2A and CAMK1G, or genes involved in synaptic vesicle cycle, such as DNM1, or SYNGR1. Therefore, identification of this module may be the first step in patient stratification based on biology, as well as in drug design and drug repurposing efforts.

BDNF genetic variants and methylation: effects on cognition in major depressive disorder.

Brain-derived neurotrophic factor (BDNF) gene regulation has been linked to the pathophysiology of major depressive disorder (MDD). MDD patients show cognitive deficits, and altered BDNF regulation has a relevant role in neurocognitive functions. Our goal was to explore the association between BDNF genetic and epigenetic variations with neurocognitive performance in a group of MDD patients and healthy controls considering possible modulating factors. The sample included 134 subjects, 64 MDD patients, and 70 healthy controls. Clinical data, childhood maltreatment, and neurocognitive performance were assessed in all participants. Eleven single nucleotide polymorphisms (SNPs) and two promoter regions in the BDNF gene were selected for genotype and methylation analysis. The role of interactions between BDNF genetic and epigenetic variations with MDD diagnosis, sex, and Childhood Trauma Questionnaire (CTQ) scores was also explored. We observed significant associations between neurocognitive performance and two BDNF SNPs (rs908867 and rs925946), an effect that was significantly mediated by methylation values at specific promoter I sites. We identified significant associations between neurocognitive results and methylation status as well as its interactions with MDD diagnosis, sex, and CTQ scores. Our results support the hypothesis that BDNF gene SNPs and methylation status, as well as their interactions with modulating factors, can influence cognition. Further studies are required to confirm the effect of BDNF variations and cognitive function in larger samples.