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.

High blood levels of brain-derived neurotrophic factor (BDNF) mRNA in early psychosis are associated with inflammatory markers.

The brain-derived neurotrophic factor (BDNF) single nucleotide polymorphism (SNP) rs6265C > T, Val66Met, affects BDNF secretion and has been related to inflammatory processes. Both the rs6265 and BDNF protein levels have been widely investigated in neuropsychiatric disorders with conflicting results. In the present study we examined BDNF mRNA expression in blood considering the SNP rs6265 and its relationship with inflammatory markers in the early stages of psychosis. The rs6265 genotype and blood BDNF mRNA levels were measured in 34 at-risk mental states (ARMS) individuals, 37 patients with first-episode psychosis (FEP) and 42 healthy controls (HCs) by quantitative PCR and reverse transcription (RT)-qPCR using validated TaqMan assays. We also obtained measures of interleukin-6 (IL6) mRNA levels, fibrinogen, neutrophil-to-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein. We identified that BDNF mRNA levels were associated with the rs6265 genotype in an allele-dose-dependent manner, with low expression levels associated with the T allele (Met substitution). Thus, we controlled for the rs6265 genotype in all analyses. Blood BDNF mRNA levels differed between diagnostic groups: patients with FEP exhibited higher blood BDNF mRNA levels than ARMS individuals, and the lowest levels were observed in HC. In addition, we observed significant correlations between BDNF mRNA levels and inflammatory markers (IL6 mRNA levels and NLR), controlled by the rs6265 genotype, in ARMS and FEP groups. This exploratory study suggests that the rs6265 genotype is associated with differential blood mRNA expression of BDNF that increases with illness progression and correlated with inflammation in the early stages of psychosis.

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.

Gradual Increase in Inflammation-Linked Glycoproteins and a Proatherogenic Lipoprotein Profile in the Early Stages of Psychosis as Characterized by 1H NMR Blood Analysis.

Minimally invasive prognostic markers of inflammation and dyslipidemia in individuals with a risk of psychosis, also called "at-risk mental state" (ARMS), or in the first episode of psychosis (FEP) are of utmost clinical importance to prevent cardiovascular disorders. We analyzed the plasma concentration of inflammation-linked glycoproteins (Glycs) and lipoprotein subclasses by proton nuclear magnetic resonance (1H NMR) in a single acquisition. Study participants were healthy controls (HCs, N = 67) and patients with ARMS (N = 58), FEP (N = 110), or early psychosis diagnosis with ≥2 episodes (critical period (CP), N = 53). Clinical biomarkers such as high-sensitivity C-reactive protein, interleukin 6, fibrinogen, insulin, and lipoproteins were also measured. Although all participants had normal lipoprotein profiles and no inflammation according to conventional biomarkers, a gradual increase in the Glyc 1H NMR levels was observed from HCs to CP patients; this increase was statistically significant for GlycA (CP vs HC). In parallel, a progressive and significant proatherogenic 1H NMR lipoprotein profile was also identified across stages of psychosis (ARMS and CP vs HC). These findings highlight the potential of using 1H NMR Glyc and lipoprotein profiling to identify blood changes in individuals with ARMS or FEP and pave the way for applications using this technology to monitor metabolic and cardiovascular risks in clinical psychiatry.

Metabolic Overlap between Alzheimer's Disease and Metabolic Syndrome Identifies the PVRL2 Gene as a New Modulator of Diabetic Dyslipidemia.

BACKGROUND: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share metabolic alterations such as abnormal insulin and lipid metabolism and have some common genetic factors such as APOE genotype. Taking this into account, we hypothesized that we could identify common genetic factors involved in the development of diabetes and cardiovascular diseases. METHODOLOGY: We first genotyped 48 single nucleotide polymorphisms (SNPs) previously associated with AD in a cohort composed of 330 patients with cognitive impairment (CI) to assess their association with plasma lipids. Second, we conducted pleiotropy-informed conjunctional false discovery rate (FDR) analysis designed to identify shared variants between AD and plasma lipid levels. Finally, we used the SNPs to be found associated with lipid parameters and AD to search for associations with lipoprotein parameters in 281 patients with cardiometabolic risk. RESULTS: Five SNPs were significantly associated with lower levels of cholesterol transported in remnant lipoprotein particles (RLPc) in subjects with CI; among these SNPs was the rs73572039 variant in PVRL2. Stratified QQ-plots were conducted on GWAS designed for AD and triglycerides (TG). The cross-trait analysis resulted in a total of 22 independent genomic loci associated with both AD and TG levels with a conjFDR < 0.05. Among these loci, two pleiotropic variants were located in PVRL2 (rs12978931 and rs11667640). The three SNPs in PVRL2 were significantly associated with RLPc, TG, and number of circulating VLDL and HDL particles in subjects with cardiometabolic risk. CONCLUSIONS: We have identified three variants in PVRL2 that predispose individuals to AD that also influence the lipid profile that confers cardiovascular risk in T2DM subjects. PVRL2 is a potential new modulating factor of atherogenic dyslipidemia.

Shared genetic architecture between attention-deficit/hyperactivity disorder and lifespan.

There is evidence linking ADHD to a reduced life expectancy. The mortality rate in individuals with ADHD is twice that of the general population and it is associated with several factors, such as unhealthy lifestyle behaviors, social adversity, and mental health problems that may in turn increase mortality rates. Since ADHD and lifespan are heritable, we used data from genome-wide association studies (GWAS) of ADHD and parental lifespan, as proxy of individual lifespan, to estimate their genetic correlation, identify genetic loci jointly associated with both phenotypes and assess causality. We confirmed a negative genetic correlation between ADHD and parental lifespan (rg = -0.36, P = 1.41e-16). Nineteen independent loci were jointly associated with both ADHD and parental lifespan, with most of the alleles that increased the risk for ADHD being associated with shorter lifespan. Fifteen loci were novel for ADHD and two were already present in the original GWAS on parental lifespan. Mendelian randomization analyses pointed towards a negative causal effect of ADHD liability on lifespan (P = 1.54e-06; Beta = -0.07), although these results were not confirmed by all sensitivity analyses performed, and further evidence is required. The present study provides the first evidence of a common genetic background between ADHD and lifespan, which may play a role in the reported effect of ADHD on premature mortality risk. These results are consistent with previous epidemiological data describing reduced lifespan in mental disorders and support that ADHD is an important health condition that could negatively affect future life outcomes.

Polygenic risk scores enhance prediction of body mass index increase in individuals with a first episode of psychosis.

BACKGROUND: Individuals with a first episode of psychosis (FEP) show rapid weight gain during the first months of treatment, which is associated with a reduction in general physical health. Although genetics is assumed to be a significant contributor to weight gain, its exact role is unknown. METHODS: We assembled a population-based FEP cohort of 381 individuals that was split into a Training (n = 224) set and a Validation (n = 157) set to calculate the polygenic risk score (PRS) in a two-step process. In parallel, we obtained reference genome-wide association studies for body mass index (BMI) and schizophrenia (SCZ) to examine the pleiotropic landscape between the two traits. BMI PRSs were added to linear models that included sociodemographic and clinical variables to predict BMI increase (∆BMI) in the Validation set. RESULTS: The results confirmed considerable shared genetic susceptibility for the two traits involving 449 near-independent genomic loci. The inclusion of BMI PRSs significantly improved the prediction of ∆BMI at 12 months after the onset of antipsychotic treatment by 49.4% compared to a clinical model. In addition, we demonstrated that the PRS containing pleiotropic information between BMI and SCZ predicted ∆BMI better at 3 (12.2%) and 12 months (53.2%). CONCLUSIONS: We prove for the first time that genetic factors play a key role in determining ∆BMI during the FEP. This finding has important clinical implications for the early identification of individuals most vulnerable to weight gain and highlights the importance of examining genetic pleiotropy in the context of medically important comorbidities for predicting future outcomes.

Maladaptive personality traits in patients with recent-onset psychosis: A case-control study using the Personality Inventory for the DSM-5 (PID-5).

BACKGROUND: The relationship between maladaptive personality traits and psychotic disorders in the early stages of disease has not been thoroughly investigated, even though it is essential for developing prevention and early intervention strategies. METHODS: The five domains and the 25 facets of the Personality Inventory for DSM-5 (PID-5) were compared between 102 patients with recent-onset psychosis (ROP) and 116 community subjects (C) with a general linear model including age and sex in the analyses. In addition, multiple linear regression models were used to identify which factors associated with the PID-5 domains in ROP, and correlation analyses were used to explore the relationship between personality traits. RESULTS: Patients with ROP, compared to C, exhibited higher scores in four out of the five domains with medium effect sizes (Cohen's f2 ≥ 0.15) in two of them: negative affect (NA, p = 0.013, f2 = 0.04), detachment (DET, p < 0.001, f2 = 0.15), disinhibition (DIS, p < 0.001, f2 = 0.14) and psychoticism (PSY, p < 0.001, f2 = 0.16). Significant group differences were observed in 15 of the 25 facets and the largest effects were observed in the facets of withdrawal (p ≤ 0.001, f2 = 0.20), irresponsibility (p < 0.001, f2 = 0.23) and unusual beliefs (p = 0.001, f2 = 0.22). Interestingly, being on antidepressants and high scores on the positive subscale of the Positive and Negative Syndrome Scale (PANSS) were associated with high scores of NA, antagonism (ANT) and PSY. CONCLUSIONS: Maladaptive personality traits were prominent in persons with ROP. These findings suggest that personality traits might play a role in vulnerability to psychosis and highlight the importance of evaluating personality in the early stages of psychosis.

DDR1 and Its Ligand, Collagen IV, Are Involved in In Vitro Oligodendrocyte Maturation.

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor expressed in epithelial cells from different tissues in which collagen binding activates pleiotropic functions. In the brain, DDR1 is mainly expressed in oligodendrocytes (OLs), the function of which is unclear. Whether collagen can activate DDR1 in OLs has not been studied. Here, we assessed the expression of DDR1 during in vitro OL differentiation, including collagen IV incubation, and the capability of collagen IV to induce DDR1 phosphorylation. Experiments were performed using two in vitro models of OL differentiation: OLs derived from adult rat neural stem cells (NSCs) and the HOG16 human oligodendroglial cell line. Immunocytofluorescence, western blotting, and ELISA were performed to analyze these questions. The differentiation of OLs from NSCs was addressed using oligodendrocyte transcription factor 2 (Olig2) and myelin basic protein (MBP). In HOG16 OLs, collagen IV induced DDR1 phosphorylation through slow and sustained kinetics. In NSC-derived OLs, DDR1 was found in a high proportion of differentiating cells (MBP+/Olig2+), but its protein expression was decreased in later stages. The addition of collagen IV did not change the number of DDR1+/MBP+ cells but did accelerate OL branching. Here, we provide the first demonstration that collagen IV mediates the phosphorylation of DDR1 in HOG16 cells and that the in vitro co-expression of DDR1 and MBP is associated with accelerated branching during the differentiation of primary OLs.

Cross-sectional and longitudinal assessment of the association between DDR1 variants and processing speed in patients with early psychosis and healthy controls.

Recent evidence indicates that DDR1 participates in myelination and that variants of DDR1 are associated with decreased cognitive processing speed (PS) in schizophrenia (SZ). Here, we explored whether DDR1 variants were associated with PS in subjects diagnosed with an early psychosis (EP), a condition often preceding SZ. Data from two Spanish independent samples (from Reus and Santander) including patients with EP (n = 75 and n = 312, respectively) and healthy controls (HCs; n = 57 and n = 160) were analyzed. The Trail Making Test part A was used to evaluate PS. Participants underwent genotyping to identify DDR1 variants rs1264323 and rs2267641. Cross-sectional data were analyzed with general linear models and longitudinal data were analyzed using mixed models. We examined the combined rs1264323AA-rs2267641AC/CC genotypes (an SZ-risk combination) on PS. The SZ-risk combined genotypes were associated with increased PS in EP patients but not in HCs in the cross-sectional analysis. In the longitudinal analysis, the SZ-risk combined genotypes were significantly associated with increased PS in both HCs and EP patients throughout the 10-year follow-up but no genotype × time interaction was observed. These results provide further evidence that DDR1 is involved in cognition and should be replicated with other samples.

Risk factors for metabolic syndrome in individuals with recent-onset psychosis at disease onset and after 1-year follow-up.

Metabolic syndrome (MetS) is a cluster of parameters encompassing the most dangerous heart attack risk factors, associated with increased morbidity and mortality. It is highly prevalent in recent-onset psychosis (ROP) patients. In this pilot study, we evaluated MetS parameters (fasting glucose, high-density lipoprotein (HDL) cholesterol (HDL-c), fasting triglycerides, waist circumference, and systolic and diastolic blood pressure), clinical symptoms, pharmacological treatment, lifestyle, and inflammatory markers in 69 patients with ROP and 61 healthy controls (HCs). At baseline, waist circumference (p = 0.005) and fasting triglycerides (p = 0.007) were higher in patients with ROP than in HCs. At the 1-year follow-up, patients showed clinical improvement, with a reduction in the positive and negative syndrome scale (PANSS) score (p < 0.001), dietary intake (p = 0.001), and antipsychotic medication dose (p < 0.001); however, fasting glucose (p = 0.011), HDL-c (p = 0.013) and waist circumference worsened (p < 0.001). We identified sex, age, BMI, dietary intake, physical activity, daily tobacco use, daily cannabis use, and antipsychotic doses as risk factors contributing to baseline MetS parameters. After 1-year follow-up, those factors plus the PANSS and Calgary Depression Scale for Schizophrenia (CDSS) scores were associated with MetS parameters. Further studies are needed to understand the contributions of the studied risk factors in patients with ROP at onset and during disease progression.

Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review.

BACKGROUND: Mitochondrial DNA (mtDNA) encodes 37 genes necessary for synthesizing 13 essential subunits of the oxidative phosphorylation system. mtDNA alterations are known to cause mitochondrial disease (MitD), a clinically heterogeneous group of disorders that often present with neuropsychiatric symptoms. Understanding the nature and frequency of mtDNA alterations in health and disease could be a cornerstone in disentangling the relationship between biochemical findings and clinical symptoms of brain disorders. This systematic review aimed to summarize the mtDNA alterations in human brain tissue reported to date that have implications for further research on the pathophysiological significance of mtDNA alterations in brain functioning. METHODS: We searched the PubMed and Embase databases using distinct terms related to postmortem human brain and mtDNA up to June 10, 2021. Reports were eligible if they were empirical studies analysing mtDNA in postmortem human brains. FINDINGS: A total of 158 of 637 studies fulfilled the inclusion criteria and were clustered into the following groups: MitD (48 entries), neurological diseases (NeuD, 55 entries), psychiatric diseases (PsyD, 15 entries), a miscellaneous group with controls and other clinical diseases (5 entries), ageing (20 entries), and technical issues (5 entries). Ten entries were ascribed to more than one group. Pathogenic single nucleotide variants (pSNVs), both homo- or heteroplasmic variants, have been widely reported in MitD, with heteroplasmy levels varying among brain regions; however, pSNVs are rarer in NeuD, PsyD and ageing. A lower mtDNA copy number (CN) in disease was described in most, but not all, of the identified studies. mtDNA deletions were identified in individuals in the four clinical categories and ageing. Notably, brain samples showed significantly more mtDNA deletions and at higher heteroplasmy percentages than blood samples, and several of the deletions present in the brain were not detected in the blood. Finally, mtDNA heteroplasmy, mtDNA CN and the deletion levels varied depending on the brain region studied. INTERPRETATION: mtDNA alterations are well known to affect human tissues, including the brain. In general, we found that studies of MitD, NeuD, PsyD, and ageing were highly variable in terms of the type of disease or ageing process investigated, number of screened individuals, studied brain regions and technology used. In NeuD and PsyD, no particular type of mtDNA alteration could be unequivocally assigned to any specific disease or diagnostic group. However, the presence of mtDNA deletions and mtDNA CN variation imply a role for mtDNA in NeuD and PsyD. Heteroplasmy levels and threshold effects, affected brain regions, and mitotic segregation patterns of mtDNA alterations may be involved in the complex inheritance of NeuD and PsyD and in the ageing process. Therefore, more information is needed regarding the type of mtDNA alteration, the affected brain regions, the heteroplasmy levels, and their relationship with clinical phenotypes and the ageing process. FUNDING: Hospital Universitari Institut Pere Mata; Institut d'Investigació Sanitària Pere Virgili; Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (PI18/00514).

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.

DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes.

Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results:DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion:DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

The role of childhood trauma, HPA axis reactivity and FKBP5 genotype on cognition in healthy individuals.

Cognitive impairment has been associated with both childhood adversity and abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function. An interaction exists between the functional polymorphism rs1360780 in the FKBP5 gene and childhood maltreatment, influencing a variety of clinical outcomes. Our goal was to study the relationship between different types of childhood trauma, HPA axis functionality, rs1360780 genotype and cognitive function in 198 healthy individuals who participated in the study. We obtained clinical data, childhood maltreatment scores and neurocognitive performance by clinical assessment; HPA negative feedback was analysed using the dexamethasone suppression test ratio (DSTR) after administration of 0.25 mg of dexamethasone; and the FKBP5 rs1360780 polymorphism was genotyped in DNA obtained from blood samples. The results showed a significant influence of physical neglect on measures of neurocognition as well as an interaction between the DSTR and physical and emotional neglect. Regarding social cognition, a significant association was found with sexual and physical abuse as well as with rs1360780 risk-allele carrier status. Moreover, an interaction between the rs1360780 genotype and the presence of physical abuse was significantly associated with social cognition results. Our results suggest a specific impact of different kinds of childhood maltreatment on measures of neurocognition and social cognition, which might be influenced by HPA axis reactivity and genetic variants in HPA axis-related genes such as FKBP5. Disentangling the relationship between these elements and their influence on cognitive performance might help identify susceptible individuals with higher stress vulnerability and develop preventive interventions.

The shared genetic architecture of schizophrenia, bipolar disorder and lifespan.

Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap-pleiotropy-between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder.

Perceived stress, social functioning and quality of life in first-episode psychosis: A 1-year follow-up study.

AIM: Quality of life (QoL) has been widely studied in people with schizophrenia. In the early phases of psychosis, it remains often impaired even after the remission of psychotic symptoms. The aim of this study was to explore QoL and social functioning during the first year after a first-episode psychosis (FEP), and to study potential moderating effects of stress measures. METHODS: Here, 61 FEP subjects and 55 healthy controls (HCs) were included. Sociodemographic data and clinical variables were collected through a semi-structured interview. Stress measures, social functioning and QoL were assessed with the Holmes-Rahe Social Readjustment Rating Scale, the Perceived Stress Scale, the Social Adaptation Self-Scale and the Euro-QoL-5D, respectively. Analysis of variance was employed with repeated measures and a mediation analysis at baseline and at 1-year follow-up was carried out. RESULTS: Patients reported lower QoL, poorer social functioning and more stress than HC. FEP patients significantly improved in QoL and stress measures over time, but not in social functioning. Perceived stress mediated the association between poorer social functioning and lower QoL. CONCLUSIONS: Social functioning at baseline may determine QoL over a 1-year follow-up period. Despite the improvement in most measures, patients do not achieve the level of well-being as the healthy group.