Genetic overlap between psychotic experiences in the community across age and with psychiatric disorders

This study explores the degree to which genetic influences on psychotic experiences are stable across adolescence and adulthood, and their overlap with psychiatric disorders. Genome-wide association results were obtained for adolescent psychotic experiences and negative symptom traits (N = 6297–10,098), schizotypy (N = 3967–4057) and positive psychotic experiences in adulthood (N = 116,787–117,794), schizophrenia (N = 150,064), bipolar disorder (N = 41,653), and depression (N = 173,005). Linkage disequilibrium score regression was used to estimate genetic correlations. Implicated genes from functional and gene-based analyses were compared. Mendelian randomization was performed on trait pairs with significant genetic correlations. Results indicated that subclinical auditory and visual hallucinations and delusions of persecution during adulthood were significantly genetically correlated with schizophrenia (rg = 0.27–0.67) and major depression (rg = 0.41–96) after correction for multiple testing. Auditory and visual subclinical hallucinations were highly genetically correlated (rg = 0.95). Cross-age genetic correlations for psychotic experiences were not significant. Gene mapping and association analyses revealed 14 possible genes associated with psychotic experiences that overlapped across age for psychotic experiences or between psychotic experiences and psychiatric disorders. Mendelian randomization indicated bidirectional associations between auditory and visual hallucinations in adults but did not support causal relationships between psychotic experiences and psychiatric disorders. These findings indicate that psychotic experiences in adulthood may be more linked genetically to schizophrenia and major depression than psychotic experiences in adolescence. Our study implicated specific genes that are associated with psychotic experiences across development, as well as genes shared between psychotic experiences and psychiatric disorders

Research Review: A guide to computing and implementing polygenic scores in developmental research

The increasing availability of genotype data in longitudinal population- and family-based samples provides opportunities for using polygenic scores (PGS) to study developmental questions in child and adolescent psychology and psychiatry. Here, we aim to provide a comprehensive overview of how PGS can be generated and implemented in developmental psycho(patho)logy, with a focus on longitudinal designs. As such, the paper is organized into three parts: First, we provide a formal definition of polygenic scores and related concepts, focusing on assumptions and limitations. Second, we give a general overview of the methods used to compute polygenic scores, ranging from the classic approach to more advanced methods. We include recommendations and reference resources available to researchers aiming to conduct PGS analyses. Finally, we focus on the practical applications of PGS in the analysis of longitudinal data. We describe how PGS have been used to research developmental outcomes, and how they can be applied to longitudinal data to address developmental questions

Examining intergenerational risk factors for conduct problems using polygenic scores in the Norwegian Mother, Father and Child Cohort Study

The aetiology of conduct problems involves a combination of genetic and environmental factors, many of which are inherently linked to parental characteristics given parents' central role in children's lives across development. It is important to disentangle to what extent links between parental heritable characteristics and children's behaviour are due to transmission of genetic risk or due to parental indirect genetic influences via the environment (i.e., genetic nurture). We used 31,290 genotyped mother-father-child trios from the Norwegian Mother, Father and Child Cohort Study (MoBa), testing genetic transmission and genetic nurture effects on conduct problems using 13 polygenic scores (PGS) spanning psychiatric conditions, substance use, education-related factors, and other risk factors. Maternal or self-reports of conduct problems at ages 8 and 14 years were available for up to 15,477 children. We found significant genetic transmission effects on conduct problems for 12 out of 13 PGS at age 8 years (strongest association: PGS for smoking, β = 0.07, 95% confidence interval = [0.05, 0.08]) and for 4 out of 13 PGS at age 14 years (strongest association: PGS for externalising problems, β = 0.08, 95% confidence interval = [0.05, 0.11]). Conversely, we did not find genetic nurture effects for conduct problems using our selection of PGS. Our findings provide evidence for genetic transmission in the association between parental characteristics and child conduct problems. Our results may also indicate that genetic nurture via traits indexed by our polygenic scores is of limited aetiological importance for conduct problems-though effects of small magnitude or effects via parental traits not captured by the included PGS remain a possibility

The cooccurrence, shared genetic aetiology and causal associations between tobacco use and psychotic experiences

Psychotic experiences (PE) are traits in the general population that resemble psychotic symptoms. PE are associated with an increased risk of psychiatric disorders and those affected by these traits or disorders are more likely to smoke tobacco. However, studies on adolescent smoking behaviours and PE have not considered PE dimensionally, adequately accounted for confounding, or included negative symptom traits. Longitudinal studies suggest that smoking may precede PE, but findings are inconclusive. This thesis presents evidence on the phenotypic and genetic associations between PE and smoking behaviours, with an emphasis on adolescent development. Chapter 2 provides a systematic review of the literature on the association between PE and smoking behaviour. In Chapter 3, regression analyses are conducted on the association between the regularity of tobacco use and domains of PE during adolescence accounting for several confounding factors. Chapter 4 presents the first twin study to explore the degree to which PE share genetic and environmental influences with smoking in a large adolescent sample. Chapter 5 investigates the degree to which adolescent and adult PE, schizophrenia, major depression and bipolar disorder are influenced by overlapping common genetic variants using genome-wide association summary statistics. Chapter 6 investigates genetic associations between smoking behaviours and psychiatric disorders and PE accounting for the genetic influences on covariates. It also investigates causal associations between smoking initiation and PE and psychiatric disorders using Mendelian randomization. This thesis concludes with a discussion of the main findings, broader themes, limitations and conclusions. Evidence from this thesis supports phenotypic and genetic associations between smoking and PE during adolescence. This thesis provides novel insights into the aetiology of PE over the lifespan and the underlying reasons why PE cooccur with smoking behaviour. It strengthens the evidence base for a specific biological link between smoking and psychiatric illness

The cooccurrence, shared genetic aetiology and causal associations between tobacco use and psychotic experiences

Psychotic experiences (PE) are traits in the general population that resemble psychotic symptoms. PE are associated with an increased risk of psychiatric disorders and those affected by these traits or disorders are more likely to smoke tobacco. However, studies on adolescent smoking behaviours and PE have not considered PE dimensionally, adequately accounted for confounding, or included negative symptom traits. Longitudinal studies suggest that smoking may precede PE, but findings are inconclusive. This thesis presents evidence on the phenotypic and genetic associations between PE and smoking behaviours, with an emphasis on adolescent development. Chapter 2 provides a systematic review of the literature on the association between PE and smoking behaviour. In Chapter 3, regression analyses are conducted on the association between the regularity of tobacco use and domains of PE during adolescence accounting for several confounding factors. Chapter 4 presents the first twin study to explore the degree to which PE share genetic and environmental influences with smoking in a large adolescent sample. Chapter 5 investigates the degree to which adolescent and adult PE, schizophrenia, major depression and bipolar disorder are influenced by overlapping common genetic variants using genome-wide association summary statistics. Chapter 6 investigates genetic associations between smoking behaviours and psychiatric disorders and PE accounting for the genetic influences on covariates. It also investigates causal associations between smoking initiation and PE and psychiatric disorders using Mendelian randomization. This thesis concludes with a discussion of the main findings, broader themes, limitations and conclusions. Evidence from this thesis supports phenotypic and genetic associations between smoking and PE during adolescence. This thesis provides novel insights into the aetiology of PE over the lifespan and the underlying reasons why PE cooccur with smoking behaviour. It strengthens the evidence base for a specific biological link between smoking and psychiatric illness

Community Treatment Orders and associations with readmission rates and duration of psychiatric hospital admission:A controlled electronic case register study

OBJECTIVES: Limited evidence is available regarding the effect of community treatment orders (CTOs) on mortality and readmission to psychiatric hospital. We compared clinical outcomes between patients placed on CTOs to a control group of patients discharged to voluntary community mental healthcare. DESIGN AND SETTING: An observational study using deidentified electronic health record data from inpatients receiving mental healthcare in South London using the Clinical Record Interactive Search (CRIS) system. Data from patients discharged between November 2008 and May 2014 from compulsory inpatient treatment under the Mental Health Act were analysed. PARTICIPANTS: 830 participants discharged on a CTO (mean age 40 years; 63% male) and 3659 control participants discharged without a CTO (mean age 42 years; 53% male). OUTCOME MEASURES: The number of days spent in the community until readmission, the number of days spent in inpatient care in the 2 years prior to and the 2 years following the index admission and mortality. RESULTS: The mean duration of a CTO was 3.2 years. Patients receiving care from forensic psychiatry services were five times more likely and patients receiving a long-acting injectable antipsychotic were twice as likely to be placed on a CTO. There was a significant association between CTO receipt and readmission in adjusted models (HR: 1.60, 95% CI 1.42 to 1.80, p<0.001). Compared with controls, patients on a CTO spent 17.3 additional days (95% CI 4.0 to 30.6, p=0.011) in a psychiatric hospital in the 2 years following index admission and had a lower mortality rate (HR: 0.66, 95% CI 0.50 to 0.88, p=0.004). CONCLUSIONS: Many patients spent longer on CTOs than initially anticipated by policymakers. Those on CTOs are readmitted sooner, spend more time in hospital and have a lower mortality rate. These findings merit consideration in future amendments to the UK Mental Health Act

Novel insights into the common heritable liability to addiction: a multivariate genome-wide association study

Addiction to nicotine, alcohol and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability. To elucidate its genetic architecture, we modelled the common liability to addiction, inferred from genetic correlations among six measures of dependence and frequency of use of nicotine, alcohol and cannabis. Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to addiction, of which 67% were novel and not associated with the six phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine D2 gene), and showed enrichment for several components of the central nervous systems (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic) that are thought to modulate drug reinforcement. Genetic correlations with other traits were most prominent for reward-related behaviours (e.g., risk-taking, cocaine and heroin use) and mood (e.g., depression, insomnia). These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of addiction, and help to elucidate the common genetic architecture underlying addiction

Novel Biological Insights Into the Common Heritable Liability to Substance Involvement: A Multivariate Genome-wide Association Study

BACKGROUND: Consumption of nicotine, alcohol, and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability to substance involvement. METHODS: To elucidate its genetic architecture, we modeled a common liability inferred from genetic correlations among 6 measures of dependence and frequency of use of nicotine, alcohol, and cannabis. RESULTS: Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to substance involvement, of which 67% were novel and not associated with the 6 phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine receptor D2 gene) and showed enrichment for several components of the central nervous system (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic [gamma-aminobutyric acidergic]) that are thought to modulate drug reinforcement. Genetic correlations with other traits were most prominent for reward-related behaviors (e.g., risk taking, cocaine use, and opioid use) and mood (e.g., depression, insomnia). CONCLUSIONS: These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of substance involvement and help to elucidate the genetic architecture underlying the use of common psychoactive substances

Intergenerational transmission of polygenic predisposition for neuropsychiatric traits on emotional and behavioural difficulties in childhood

Childhood emotional and behavioural difficulties frequently co-occur and often precede diagnosed neuropsychiatric conditions. Delineating shared and specific risk factors for emotional and behavioural difficulties early in life is therefore essential for prevention strategies. Here, we focus on how a set of key parental risk factors shape their offspring’s behavioural and emotional symptoms. Leveraging data from 14,959 genotyped family trios from the Norwegian Mother, Father and Child Cohort Study (MoBa), we model symptom level data into general and specific domains. We then investigate the direct (genetically transmitted) and indirect (environmentally mediated) contributions of polygenic risk for neuropsychiatric and related traits to those domains. We observe evidence consistent with an environmental route to general symptomatology beyond genetic transmission, while also demonstrating domain-specific direct and indirect genetic contributions. Our findings pave the way for a better identification of early risk pathways that can be targeted in preventive interventions aiming to interrupt the intergenerational cycle of risk transmission