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Background: Studies have shown associations between polygenic risk scores for educational attainment (PRS EA ), cognitive reserve (CR), cognition, negative symptoms (NS), and psychosocial functioning in first-episode psychosis (FEP). However, their specific interactions remain unclear. This study aimed to investigate the mediating roles of CR, cognition, and NS in the relationship between PRS EA and psychosocial functioning one year after a FEP. Additionally, we sought to explore the impact of two NS subtypes on this relationship: diminished Expression (EXP-NS) and Motivation and Pleasure (MAP-NS)., Methods: A total of 138 FEP participants, predominantly male (70%), with a mean age of 24.77 years (SD = 5.29), underwent genetic, clinical, and cognitive assessments two months after study enrollment. Functioning evaluation followed at one-year follow-up. To investigate the mediating role of CR, cognition, and NS in the relationship between PRS EA and functioning, a serial mediation model was employed. Two further mediation models were tested to explore the differential impact of EXP-NS and MAP-NS. Mediation analysis was performed using the PROCESS macro version 4.1 within SPSS version 26., Results: The serial mediation model revealed a causal chain for PRS EA  > CR > cognition > NS > Functioning (β = -3.08, 95%CI [-5.73, -0.43], p = 0.023). When differentiating by type of NS, only EXP-NS were significantly associated in the casual chain (β = -0.17, 95% CI [-0.39, -0.01], p < 0.05)., Conclusions: CR, cognition and NS -specifically EXP-NS- mediate the association between PRS EA and psychosocial functioning at one-year follow-up in FEP patients. These results highlight the potential for personalized interventions based on genetic predisposition., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Genome-wide association studies (GWAS) have revealed the polygenic nature of treatment-resistant schizophrenia TRS. Gene expression imputation allowed the translation of GWAS results into regulatory mechanisms and the construction of gene expression (GReX) risk scores (GReX-RS).  In the present study we computed GReX-RS from the largest GWAS of TRS to assess its association with clinical features. We perform transcriptome imputation in the largest GWAS of TRS to find GReX associated with TRS using brain tissues. Then, for each tissue, we constructed a GReX-RS of the identified genes in a sample of 254 genotyped first episode of psychosis (FEP) patients to test its association with clinical phenotypes, including clinical symptomatology, global functioning and cognitive performance. Our analysis provides evidence that the polygenic basis of TRS includes genetic variants that modulate the expression of certain genes in certain brain areas (substantia nigra, hippocampus, amygdala and frontal cortex), which at the same time are related to clinical features in FEP patients, mainly persistence of negative symptoms and cognitive alterations in sustained attention, which have also been suggested as clinical predictors of TRS. Our results provide a clinical explanation of the polygenic architecture of TRS and give more insight into the biological mechanisms underlying TRS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Menarini, Rovi and Takeda. The rest of the authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Polygenic risk scores for educational attainment (PRS EA ), cognitive reserve (CR), and clinical symptoms are associated with functioning in first-episode psychosis (FEP). Nevertheless, the mechanisms underlying their complex interaction are yet to be explored. This study assessed the mediating role of CR and clinical symptoms, both negative (NS) and positive (PS), on the interrelationship between PRS EA and functionality, one year after a FEP., Methods: A total of 162 FEP patients underwent clinical, functional, and genetic assessments. Using genome-wide association study summary results, PRS EA were constructed for each individual. Two mediation models were performed. The parallel mediation model explored the relationship of PRS EA with functionality through CR and clinical symptoms. The serial mediation model tested a causal chain of the three mediators: CR, NS, and PS. Mediation analysis was performed using the PROCESS function V.4.1 in SPSS V.22., Results: A serial mediation model revealed a causal chain for PRS EA  > CR > NS > Functionality ( β  = -0.35, 95%CI [-0.85, -0.04], p  < 0.05). The model fit the data satisfactorily (CFI = 1.00; RMSEA = 0.00; SRMR = 7.2 × 10 -7 ). Conversely, no parallel mediation was found between the three mediators, PRS EA and functionality and the model poorly fit the data (CFI = 0.30; RMSEA = 0.25; SRMR = 0.11)., Conclusions: Both CR and NS mediate the relationship between PRS EA and functionality at one-year follow-up, using serial mediation analysis. This may be relevant for prevention and personalized early intervention to reduce illness impact and improve functional outcomes in FEP patients.

Little is known about genetic predisposition to relapse. Previous studies have linked cognitive and psychopathological (mainly schizophrenia and bipolar disorder) polygenic risk scores (PRS) with clinical manifestations of the disease. This study aims to explore the potential role of PRS from major mental disorders and cognition on schizophrenia relapse. 114 patients recruited in the 2EPs Project were included (56 patients who had not experienced relapse after 3 years of enrollment and 58 patients who relapsed during the 3-year follow-up). PRS for schizophrenia (PRS-SZ), bipolar disorder (PRS-BD), education attainment (PRS-EA) and cognitive performance (PRS-CP) were used to assess the genetic risk of schizophrenia relapse.Patients with higher PRS-EA, showed both a lower risk (OR=0.29, 95% CI [0.11-0.73]) and a later onset of relapse (30.96± 1.74 vs. 23.12± 1.14 months, p=0.007. Our study provides evidence that the genetic burden of neurocognitive function is a potentially predictors of relapse that could be incorporated into future risk prediction models. Moreover, appropriate treatments for cognitive symptoms appear to be important for improving the long-term clinical outcome of relapse., Competing Interests: Conflict of interest A. Ibáñez has received research support from or served as speaker or advisor for Janssen-Cilag, Lundbeck and Otsuka. A. Gonzalez-Pinto has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Sanofi-Aventis, Exeltis, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), and the Basque Government, J. Saiz-Ruiz has been as speaker for and on the advisory boards of Adamed, Lundbeck, Servier, Medtronic, Casen Recordati, Neurofarmagen, Otsuka, Indivior, Lilly, Schwabe, Janssen and Pfizer, outside the submitted work. M. Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Menarini, Rovi and Takeda, Pilar A. Saiz has been a consultant to and/or has received honoraria or grants from Adamed, CIBERSAM, European Comission, Government of the Principality of Asturias, Instituto de Salud Carlos III, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Plan Nacional Sobre Drogas and Servier. R. Rodriguez-Jimenez has been a consultant for, spoken in activities of, or received  grants from: Instituto de Salud Carlos III,  Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/ BMD-2422 AGES; S2017/BMD-3740), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen-Recordati, Angelini. The rest of the authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The main objective of the present study was to investigate the association between several epigenetic clocks, covering different aspects of aging, with schizophrenia relapse evaluated over a 3-year follow-up period in a cohort of ninety-one first-episode schizophrenia patients. Genome-wide DNA methylation was profiled and four epigenetic clocks, including epigenetic clocks of chronological age, mortality and telomere length were calculated. Patients that relapsed during the follow-up showed epigenetic acceleration of the telomere length clock (p = 0.030). Shorter telomere length was associated with cognitive performance (working memory, r = 0.31 p = 0.015; verbal fluency, r = 0.28 p = 0.028), but no direct effect of cognitive function or symptom severity on relapse was detected. The results of the present study suggest that epigenetic age acceleration could be involved in the clinical course of schizophrenia and could be a useful marker of relapse when measured in remission stages., (© 2022. The Author(s).)

Objective: Metabolic syndrome is a health-threatening condition suffered by approximately one third of schizophrenia patients and largely attributed to antipsychotic medication. Previous evidence reports a common genetic background of psychotic and metabolic disorders. In this study, we aimed to assess the role of polygenic risk scores (PRSs) on the progression of the metabolic profile in a first-episode psychosis (FEP) cohort., Method: Of the 231 FEP individuals included in the study, 192-220 participants were included in basal analysis and 118-179 in longitudinal 6-month models. Eleven psychopathologic and metabolic PRSs were constructed. Basal and longitudinal PRSs association with metabolic measurements was assessed by statistical analyses., Results: No major association of psychopathological PRSs with the metabolic progression was found. However, high risk individuals for depression and cholesterol-related PRSs reported a higher increase of cholesterol levels during the follow-up (FDR ≤ 0.023 for all analyses). Their effect was comparable to other well-established pharmacological and environmental risk factors (explaining at least 1.2% of total variance)., Conclusion: Our findings provide new evidence of the effects of metabolic genetic risk on the development of metabolic dysregulation. The future establishment of genetic profiling tools in clinical procedures could enable practitioners to better personalize antipsychotic treatment selection and dosage., (Copyright © 2022. Published by Elsevier B.V.)

A better understanding of schizophrenia subtypes is necessary to stratify the patients according to clinical attributes. To explore the genomic architecture of schizophrenia symptomatology, we analyzed blood co-expression modules and their association with clinical data from patients in remission after a first episode of schizophrenia. In total, 91 participants of the 2EPS project were included. Gene expression was assessed using the Clariom S Human Array. Weighted-gene co-expression network analysis (WGCNA) was applied to identify modules of co-expressed genes and to test its correlation with global functioning, clinical symptomatology, and premorbid adjustment. Among the 25 modules identified, six modules were significantly correlated with clinical data. These modules could be clustered in two groups according to their correlation with clinical data. Hub genes in each group showing overlap with risk genes for schizophrenia were enriched in biological processes related to metabolic processes, regulation of gene expression, cellular localization and protein transport, immune processes, and neurotrophin pathways. Our results indicate that modules with significant associations with clinical data showed overlap with gene sets previously identified in differential gene-expression analysis in brain, indicating that peripheral tissues could reveal pathogenic mechanisms. Hub genes involved in these modules revealed multiple signaling pathways previously related to schizophrenia, which may represent the complex interplay in the pathological mechanisms behind the disease. These genes could represent potential targets for the development of peripheral biomarkers underlying illness traits in clinical remission stages after a first episode of schizophrenia., (© 2022. The Author(s).)