Polygenic risk score for schizophrenia was not associated with glycemic level (HbA1c) in patients with non-affective psychosis: Genetic Risk and Outcome of Psychosis (GROUP) cohort study

Introduction: Type 2 diabetes (T2D) is a common comorbidity in patients with schizophrenia (SCZ). The underlying pathophysiologic mechanisms are yet to be fully elucidated, although it can be argued that shared genes, environmental factors or their interaction effect are involved. This study investigated the association between polygenic risk score of SCZ (PRSSCZ) and glycated haemoglobin (HbA1c) while adjusting for polygenic risk score of T2D (PRST2D), and clinical and demographic covariables. Methods: Genotype, clinical and demographic data of 1129 patients with non-affective psychosis were extracted from Genetic Risk and Outcome of Psychosis (GROUP) cohort study. The glycated haemoglobin (HbA1c) was the outcome. PRS was calculated using standard methods. Univariable and multivariable linear regression analyses were applied to estimate associations. Additionally, sensitivity analysis based on multiple imputation was done. After correction for multiple testing, a two-sided p-value ≤.003 was considered to discover evidence for an association. Results: Of 1129 patients, 75.8% were male with median age of 29 years. The mean (standard deviation) HbA1c level was 35.1 (5.9) mmol/mol. There was no evidence for an association between high HbA1c level and increased PRSSCZ (adjusted regression coefficient (aβ) = 0.69, standard error (SE) = 0.77, p-value =.37). On the other hand, there was evidence for an association between high HbA1c level and increased PRST2D (aβ = 0.93, SE = 0.32, p-value =.004), body mass index (aβ = 0.20, SE = 0.08, p-value =.01), diastolic blood pressure (aβ = 0.08, SE = 0.04, p-value =.03), late age of first psychosis onset (aβ = 0.19, SE = 0.05, p-value =.0004) and male gender (aβ = 1.58, SE = 0.81, p-value =.05). After multiple testing correction, there was evidence for an association between high HbA1c level and late age of first psychosis onset. Evidence for interaction effect between PRSscz and antipsychotics was not observed. The multiple imputation-based sensitivity analysis provided consistent results with complete case analysis. Conclusions: Glycemic dysregulation in patients with SCZ was not associated with PRSSCZ. This suggests that the mechanisms of hyperglycemia or diabetes are at least partly independent from genetic predisposition to SCZ. Our findings show that the change in HbA1c level can be caused by at least in part due to PRST2D, late age of illness onset, male gender, and increased body mass index and diastolic blood pressure

Psychosis Endophenotypes:A Gene-Set-Specific Polygenic Risk Score Analysis

BACKGROUND AND HYPOTHESIS: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes. STUDY DESIGN: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score. STUDY RESULTS: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores. CONCLUSIONS: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models

Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

Background Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. Methods We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltag

Feedback based on experience sampling data: examples of current approaches and considerations for future research

Methodologies such as the Experience Sampling Method (ESM) or Ecological Momentary Assessment allow the gathering of fine-graded, dynamic, personal data within a patient's daily life. Currently, it is studied whether feedback based on experience sampling data (ESM-based feedback) can be used as a clinical tool to inform shared decision-making in clinical practice. Although the potential of feedback is recognized, little is known on how to generate, use, and implement it. This article (i) presents n = 15 ongoing ESM projects within the Belgian-Dutch network for ESM research wherein ESM-based feedback is provided to various patient populations, and (ii) summarizes qualitative data on experiences with ESM-based feedback of researchers (n = 8) with extensive expertise with ESM (average of 10 years) involved in these ongoing studies. The following aspects appear to be of relevance when providing ESM-based feedback: training for healthcare professionals and researchers, the use of online interfaces and graphical visualizations to present data, and interacting with patients in a face-to-face setting when discussing the contextual relevance and potential implications. Prospectively, research may build on these aspects and create coherent consensus-based guidelines for the use of ESM-based feedback.info:eu-repo/semantics/publishedVersio

Association of cognitive performance with clinical staging in schizophrenia spectrum disorders:a prospective 6-year follow-up study

Background: Clinical staging has been developed to capture the large heterogeneity in schizophrenia spectrum disorders. Including cognitive performance in the staging model may improve its clinical validity. Moreover, cognitive functioning could predict transition across stages. However, current evidence of the association between cognition and clinical staging is inconsistent. Therefore, we aim to assess whether cognitive parameters are associated with clinical stages in a large sample of patients with schizophrenia spectrum disorders and to identify cognitive markers at baseline that are associated with stage-transition at three and six-year follow-up. Methods: We applied the staging model of Fusar-Poli et al. (2017) in 927 patients with non-affective psychotic disorders, assessed at baseline, and after three and six-year follow-up. Cognitive performance was assessed with a standard test battery. Generalized linear mixed models were used to analyze associations of cognitive performance with staging and stage-transition at follow-up. Results: Findings showed that higher stages of illness were significantly associated with lower processing speed (F = 3.688, p = 0.025) and deficits in working memory (F = 6.365, p = 0.002) across assessments. No associations between cognitive parameters at baseline and stage-transition at three- and six-year follow-up were found. Conclusion: We conclude that processing speed and working memory were modestly associated with higher stages of illness in schizophrenia spectrum disorders, thereby slightly improving its clinical validity. However, associations were small and we found no evidence for predictive validity

Subjective quality of life in psychosis : Evidence for an association with real world functioning?

Subjective quality of life (SQOL) is an established patient-reported outcome in psychosis. However, current self-report measures of SQOL may be affected by recall bias and may not fully capture dynamic changes in SQOL over time. This study aimed to examine the ecological validity of self-reported and momentary assessment measures of SQOL, and their association with emotional experience, social interaction and activity in real life, in both patients with psychotic disorder (n = 56) and controls (n = 71). Self-reported QOL was assessed with the WHO-QOL, momentary QOL and real life experiences were assessed with the Experience Sampling Method (ESM). Results show that both measures were significantly associated in patients and controls, and associations with emotional experience were most relevant, momentary QOL being a stronger predictor than self-reported QOL. The association between momentary QOL and negative affect was stronger in patients than in controls. Overall, momentary QOL was more consistently associated with affect, social interaction and activity, while self-reported QOL displayed a more narrow association with mostly affect. Concluding, concurrent assessment of self-reported QOL and momentary QOL showed that momentary QOL may enhance the ecological validity of SQOL measurement. Experience sampling research may broaden our perspective on SQOL and its associations with real life functioning

Autistic Symptoms and Social Functioning in Psychosis:A Network Approach

Psychotic and autistic symptoms are related to social functioning in individuals with psychotic disorders (PD). The present study used a network approach to (1) evaluate the interactions between autistic symptoms, psychotic symptoms, and social functioning, and (2) investigate whether relations are similar in individuals with and without PD. We estimated an undirected network model in a sample of 504 PD, 572 familial risk for psychosis (FR), and 337 typical comparisons (TC), with a mean age of 34.9 years. Symptoms were assessed with the Autism Spectrum Quotient (AQ; 5 nodes) and the Community Assessment of Psychic Experiences (CAPE; 9 nodes). Social functioning was measured with the Social Functioning Scale (SFS; 7 nodes). We identified statistically significant differences between the FR and PD samples in global strength (P <. 001) and network structure (P <. 001). Our results show autistic symptoms (social interaction nodes) are negatively and more closely related to social functioning (withdrawal, interpersonal behavior) than psychotic symptoms. More and stronger connections between nodes were observed for the PD network than for FR and TC networks, while the latter 2 were similar in density (P =. 11) and network structure (P =. 19). The most central items in strength for PD were bizarre experiences, social skills, and paranoia. In conclusion, specific autistic symptoms are negatively associated with social functioning across the psychosis spectrum, but in the PD network symptoms may reinforce each other more easily. These findings emphasize the need for increased clinical awareness of comorbid autistic symptoms in psychotic individuals