The interplay between the genome and the exposome in psychosis spectrum

This thesis presents several studies investigating the processes and mechanisms that underlie the development of psychosis in large epidemiological datasets. The first part of this thesis focuses on understanding symptom dimensions within the trajectories towards clinical outcomes. Mechanisms and processes associated with subclinical and clinical psychosis expression are evaluated. The second part of this thesis focuses on the environmental and genetic factors affecting the development of psychosis expression across the psychosis spectrum. The thesis presents the first systematic analyses of gene-environmental interaction using a cumulative molecular genetic score (polygenic risk score) for schizophrenia. Further, a new methodological tool, the exposome score for schizophrenia (a cumulative environmental score including exposures such as childhood adversities and cannabis use) was developed and applied to study environmental effects on psychosis phenotypes in the general population and in clinical samples. The thesis substantially contributes to the understanding of genetic and environmental effects on psychosis across the spectrum

Context v. algorithm: Evidence that a transdiagnostic framework of contextual clinical characterization is of more clinical value than categorical diagnosis

Background A transdiagnostic and contextual framework of 'clinical characterization', combining clinical, psychopathological, sociodemographic, etiological, and other personal contextual data, may add clinical value over and above categorical algorithm-based diagnosis. Methods Prediction of need for care and health care outcomes was examined prospectively as a function of the contextual clinical characterization diagnostic framework in a prospective general population cohort (n = 6646 at baseline), interviewed four times between 2007 and 2018 (NEMESIS-2). Measures of need, service use, and use of medication were predicted as a function of any of 13 DSM-IV diagnoses, both separately and in combination with clinical characterization across multiple domains: social circumstances/demographics, symptom dimensions, physical health, clinical/etiological factors, staging, and polygenic risk scores (PRS). Effect sizes were expressed as population attributable fractions. Results Any prediction of DSM-diagnosis in relation to need and outcome in separate models was entirely reducible to components of contextual clinical characterization in joint models, particularly the component of transdiagnostic symptom dimensions (a simple score of the number of anxiety, depression, mania, and psychosis symptoms) and staging (subthreshold, incidence, persistence), and to a lesser degree clinical factors (early adversity, family history, suicidality, slowness at interview, neuroticism, and extraversion), and sociodemographic factors. Clinical characterization components in combination predicted more than any component in isolation. PRS did not meaningfully contribute to any clinical characterization model. Conclusion A transdiagnostic framework of contextual clinical characterization is of more value to patients than a categorical system of algorithmic ordering of psychopathology

Resilience Against Traumatic Stress: Current Developments and Future Directions

Given the high prevalence of stress-related mental disorders, their impact on person, family, and society and the paucity of treatment options for most of these disorders, there is currently a pressing need for innovative approaches to deal with these issues and enhance well-being. One approach which has received increasing attention over the last decade is to shift our scientific and clinical focus from risk factors for psychopathology to factors promoting resilience and mental well-being. In order to summarize and evaluate the current state of scientific affairs on the biological basis of resilience, we provide an overview of the literature on animal and human studies of resilience. Because resilience can only truly be operationalized through longitudinal data collection and analyses, we focus primarily on longitudinal studies. This review shows that the concept of resilience is currently being operationalized, measured and even defined in widely variable manners, both within animal and human studies. We further provide an overview of existing and new strategies that could help promote resilience and which are proposed to be implemented more often in clinical situations. Finally, we summarize the challenges the field is facing and provide recommendations for future research

Association between exposome score for schizophrenia and functioning in first-episode psychosis: results from the Athens first-episode psychosis research study

BACKGROUND: Evidence suggests that environmental factors not only increase psychosis liability but also influence the prognosis and outcomes of psychotic disorders. We investigated temporal and cross-sectional associations of a weighted score of cumulative environmental liability for schizophrenia - the exposome score for schizophrenia (ES-SCZ) - with functioning in first-episode psychosis (FEP). METHODS: Data were derived from the baseline and 1-month assessments of the Athens FEP Research Study that enrolled 225 individuals with FEP. The Global Assessment of Functioning (GAF) and the Personal and Social Performance Scale (PSP) were used to measure social, occupational, and psychological functioning. The ES-SCZ was calculated based on the previously validated method. RESULTS: ES-SCZ was associated with the total scores of GAF and PSP at baseline and 1-month assessments. These findings remained significant when accounting for several associated alternative explanatory variables, including other environmental factors (obstetric complications, migration, ethnic minority), clinical characteristics (duration of untreated psychosis, symptom severity, previous antipsychotic use), and family history of psychosis, demonstrating that the association between ES-SCZ and functioning is over and above other risk factors and cannot be explained by symptom severity alone. Functioning improved from baseline to 1-month assessment, but no significant ES-SCZ-by-time interaction was found on functioning, indicating that functioning changes were not contingent on ES-SCZ. CONCLUSIONS: Our findings suggest that rather than a predictor of functional improvement, ES-SCZ represents a stable severity indicator that captures poor functioning in early psychosis. Environmental risk loading for schizophrenia (ES-SCZ) can be beneficial for clinical characterization and incorporated into transdiagnostic staging models

Gene-environment interaction study on the polygenic risk score for neuroticism, childhood adversity, and parental bonding

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRSN), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRSN was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRSN. Multilevel mixed-effects models were used to analyze the main and interacting associations of PRSN, childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene-environment correlation. PRSN thresholds of.005 and.2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRSN from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene-environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism

Gender differences in the associations between childhood adversity and psychopathology in the general population

PURPOSE: To explore gender differences of the associations between childhood adversity (CA) subtypes and psychiatric symptoms in the general population. METHODS: Data of 791 participants were retrieved from a general population twin cohort. The Symptom Checklist-90 Revised (SCL-90) and the Childhood Trauma Questionnaire were used to assess overall psychopathology with nine symptom domains scores and total CA with exposure to five CA subtypes, respectively. The associations between CA and psychopathology were analyzed in men and women separately and were subsequently compared. RESULTS: Total CA was associated with total SCL-90 and all symptom domains without significant gender differences. However, the analyses of CA subtypes showed that the association between emotional abuse and total SCL-90 was stronger in women compared to men [χ 2(1) = 4.10, P = 0.043]. Sexual abuse was significantly associated with total SCL-90 in women, but emotional neglect and physical neglect were associated with total SCL-90 in men. Exploratory analyses of CA subtypes and SCL-90 subdomains confirmed the pattern of gender-specific associations. In women, emotional abuse was associated with all symptom domains, and sexual abuse was associated with all except phobic anxiety and interpersonal sensitivity. In men, emotional neglect was associated with depression, and physical neglect was associated with phobic anxiety, anxiety, interpersonal sensitivity, obsessive-compulsive, paranoid ideation, and hostility subdomains. CONCLUSION: CA is a trans-syndromal risk factor regardless of gender. However, differential associations between CA subtypes and symptom manifestation might exist. Abuse might be particularly associated with psychopathology in women, whereas neglect might be associated with psychopathology in men

Gene–environment interaction study on the polygenic risk score for neuroticism, childhood adversity, and parental bonding

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRSN), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRSN was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRSN. Multilevel mixed-effects models were used to analyze the main and interacting associations of PRSN, childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene–environment correlation. PRSN thresholds of .005 and .2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRSN from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene–environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism

Age- and sex-specific associations between risk scores for schizophrenia and self-reported health in the general population

Purpose The health correlates of polygenic risk (PRS-SCZ) and exposome (ES-SCZ) scores for schizophrenia may vary depending on age and sex. We aimed to examine age- and sex-specific associations of PRS-SCZ and ES-SCZ with self-reported health in the general population. Methods Participants were from the population-based Netherlands Mental Health Survey and Incidence Study–2 (NEMESIS-2). Mental and physical health were measured with the 36-item Short Form Survey 4 times between 2007 and 2018. The PRS-SCZ and ES-SCZ were respectively calculated from common genetic variants and exposures (cannabis use, winter birth, hearing impairment, and five childhood adversity categories). Moderation by age and sex was examined in linear mixed models. Results For PRS-SCZ and ES-SCZ analyses, we included 3099 and 6264 participants, respectively (age range 18–65 years; 55.7–56.1% female). Age and sex did not interact with PRS-SCZ. Age moderated the association between ES-SCZ and mental (interaction: p = 0.02) and physical health (p = 0.0007): at age 18, + 1.00 of ES-SCZ was associated with − 0.10 of mental health and − 0.08 of physical health, whereas at age 65, it was associated with − 0.21 and − 0.23, respectively (all units in standard deviations). Sex moderated the association between ES-SCZ and physical health (p < .0001): + 1.00 of ES-SCZ was associated with − 0.19 of physical health among female and − 0.11 among male individuals. Conclusion There were larger associations between higher ES-SCZ and poorer health among female and older individuals. Accounting for these interactions may increase ES-SCZ precision and help uncover populational determinants of environmental influences on health

Replicated evidence that endophenotypic expression of schizophrenia polygenic risk is greater in healthy siblings of patients compared to controls, suggesting gene-environment interaction. The EUGEI study

Background First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes. Methods We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS. Results In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group. Conclusions The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder