Understanding the relationship between loneliness, substance use traits and psychiatric disorders: A genetically informed approach

Loneliness is a common, yet distressing experience associated with adverse outcomes including substance use problems and psychiatric disorders. To what extent these associations reflect genetic correlations and causal relationships is currently unclear. We applied Genomic Structural Equation Modelling (GSEM) to dissect the genetic architecture between loneliness and psychiatric-behavioural traits. Included were summary statistics from 12 genome-wide association analyses, including loneliness and 11 psychiatric phenotypes (range N: 9,537 – 807,553). We first modelled latent genetic factors amongst the psychiatric traits to then investigate potential causal effects between loneliness and the identified latent factors, using multivariate genome-wide association analyses and bidirectional Mendelian randomization. We identified three latent genetic factors, encompassing neurodevelopmental/mood conditions, substance use traits and disorders with psychotic features. GSEM provided evidence of a unique association between loneliness and the neurodevelopmental/mood conditions latent factor. Mendelian randomization results were suggestive of bidirectional causal effects between loneliness and the neurodevelopmental/mood conditions factor. These results imply that a genetic predisposition to loneliness may elevate the risk of neurodevelopmental/mood conditions, and vice versa. However, results may reflect the difficulty of distiguishing between loneliness and neurodevelopmental/mood conditions, which present in similar ways. We suggest, overall, the importance of addressing loneliness in mental health prevention and policy

Assessing the consequences of cyberbullying on mental health

Advances in technology and the advent of social media have led to the emergence of a new phenomenon — cyberbullying. Although there are some similarities, approaches to tackling traditional bullying are largely ineffective in combating cyberbullying, which has been linked to adverse mental health and, in extreme cases, suicide

Protecting against researcher bias in secondary data analysis: challenges and potential solutions

Analysis of secondary data sources (such as cohort studies, survey data, and administrative records) has the potential to provide answers to science and society’s most pressing questions. However, researcher biases can lead to questionable research practices in secondary data analysis, which can distort the evidence base. While pre-registration can help to protect against researcher biases, it presents challenges for secondary data analysis. In this article, we describe these challenges and propose novel solutions and alternative approaches. Proposed solutions include approaches to (1) address bias linked to prior knowledge of the data, (2) enable pre-registration of non-hypothesis-driven research, (3) help ensure that pre-registered analyses will be appropriate for the data, and (4) address difficulties arising from reduced analytic flexibility in pre-registration. For each solution, we provide guidance on implementation for researchers and data guardians. The adoption of these practices can help to protect against researcher bias in secondary data analysis, to improve the robustness of research based on existing data

Systematic Review and Meta-analysis of Genetically Informed Research: Associations between Parent Anxiety and Offspring Internalizing Problems

OBJECTIVE: Parent anxiety is associated with offspring internalizing problems (emotional problems related to anxiety and depression). This may reflect causal processes, whereby exposure to parent anxiety directly influences offspring internalizing (and/or vice versa). However, parent-offspring associations could also be attributable to their genetic relatedness. We present a systematic review and meta-analysis to investigate whether exposure to parent anxiety is associated with offspring internalizing after controlling for genetic relatedness. METHOD: A literature search in five databases identified 429 records. Publications were retained if they used a quasi-experimental design in a general population sample to control for participant relatedness in associations between parent anxiety and offspring internalizing outcomes. Publications were excluded if they involved an experimental exposure or intervention. Studies of pre- and post-natal anxiety exposure were meta-analysed separately. Pearson's correlation coefficient estimates (r) were pooled using multilevel random effects models. RESULTS: Eight publications were retained. Data were drawn from four population cohorts, each unique to a quasi-experimental design: adoption, sibling-comparison, children-of-twins or in-vitro-fertilisation. Cohorts were located in northern Europe or America. Families were predominantly of European ancestry. Three publications (Nfamilies>11,700; offspring aged 0.5-10 years) showed no association between prenatal anxiety exposure and offspring internalizing outcomes after accounting for participant relatedness (r=.04, CI -.07,.14). Six publications (Nfamilies>12,700; offspring aged 0.75-22 years) showed a small but significant association between concurrent symptoms in parents and offspring, after accounting for participant relatedness (r=.13, CI .04,.21). CONCLUSION: Initial literature, derived from homogenous populations, suggests that prenatal anxiety exposure does not cause offspring internalizing outcomes. However, postnatal anxiety exposure may be causally associated with concurrent offspring internalizing, via non-genetic pathways. Longitudinal stability, child-to-parent effects, and the role of moderators and methodological biases require attention

Identifying risk factors involved in the common versus specific liabilities to substance use: A genetically informed approach

Individuals most often use several rather than one substance among alcohol, cigarettes or cannabis. This widespread co‐occurring use of multiple substances is thought to stem from a common liability that is partly genetic in origin. Genetic risk may indirectly contribute to a common liability to substance use through genetically influenced mental health vulnerabilities and individual traits. To test this possibility, we used polygenic scores indexing mental health and individual traits and examined their association with the common versus specific liabilities to substance use

Continuity of cannabis use and violent offending over the life course

Although the association between cannabis use and violence has been reported in the literature, the precise nature of this relationship, especially the directionality of the association, is unclear. Young males from the Cambridge Study of Delinquent Development (n = 411) were followed up between the ages of 8 and 56 years to prospectively investigate the association between cannabis use and violence. A multi-wave (eight assessments, T1–T8) follow-up design was employed that allowed temporal sequencing of the variables of interest and the analysis of violent outcome measures obtained from two sources: (i) criminal records (violent conviction); and (ii) self-reports. A combination of analytic approaches allowing inferences as to the directionality of associations was employed, including multivariate logistic regression analysis, fixed-effects analysis and cross-lagged modelling. Multivariable logistic regression revealed that compared with never-users, continued exposure to cannabis (use at age 18, 32 and 48 years) was associated with a higher risk of subsequent violent behaviour, as indexed by convictions [odds ratio (OR) 7.1, 95% confidence interval (CI) 2.19–23.59] or self-reports (OR 8.9, 95% CI 2.37–46.21). This effect persisted after controlling for other putative risk factors for violence. In predicting violence, fixed-effects analysis and cross-lagged modelling further indicated that this effect could not be explained by other unobserved time-invariant factors. Furthermore, these analyses uncovered a bi-directional relationship between cannabis use and violence. Together, these results provide strong indication that cannabis use predicts subsequent violent offending, suggesting a possible causal effect, and provide empirical evidence that may have implications for public policy

Combining multivariate genomic approaches to elucidate the comorbidity between autism spectrum disorder and attention deficit hyperactivity disorder

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. METHODS: With the summary data from two GWAS, one on ASD (N = 46,350) and another on ADHD (N = 55,374) individuals, we used genomic structural equation modelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. RESULTS: We found that 37.5% of the SNPs associated with ASD (at p < 1e-6) colocalized with ADHD SNPs and that 19.6% of the SNPs associated with ADHD colocalized with ASD SNPs. We identified genes mapped to SNPs that are specific to ASD or ADHD and that are shared by ASD and ADHD, including two novel genes INSM1 and PAX1. Our bidirectional Mendelian randomization analyses indicated that the risk of ASD was associated with an increased risk of ADHD and vice versa. CONCLUSIONS: Using multivariate genomic analyses, the present study uncovers shared and specific genetic variants associated with ASD and ADHD. Further functional investigation of genes mapped to those shared variants may help identify pathophysiological pathways and new targets for treatment

Association Between Continued Cannabis Use and Risk of Relapse in First-Episode Psychosis: A Quasi-Experimental Investigation Within an Observational Study

IMPORTANCE: Cannabis use after first-episode psychosis is associated with poor outcomes, but the causal nature of this association is unclear. OBJECTIVE: To examine the precise nature of the association between continued cannabis use after the onset of psychosis and risk of relapse of psychosis. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study followed up for at least 2 years after the onset of psychosis 220 patients who presented to psychiatric services in South London, England, from April 12, 2002, to July 26, 2013, with first-episode psychosis. Longitudinal modeling (fixed-effects analysis, cross-lagged path analysis) was used to examine whether the association between changes in cannabis use and risk of relapse over time is the result of shared vulnerability between psychosis and cannabis use, psychosis increasing the risk of cannabis use (reverse causation), or a causal effect of cannabis use on psychosis relapse. INTERVENTIONS: Exposure to cannabis within the first and second years after onset of psychosis. MAIN OUTCOMES AND MEASURES: The main outcome measure was relapse of psychosis, defined as subsequent hospitalization for psychosis. Effect of cannabis use status in the first year (Ct1) and second year (Ct2) and pattern of cannabis use continuation in the first year and second year were modeled for risk of relapse in the first year (Rt1) and risk of relapse in the second year (Rt2) after psychosis onset. RESULTS: A total of 220 patients with first-episode psychosis were included in the analysis (mean [SD] age, 28.62 [8.58] years; age range, 18-65 years; 90 women [40.9%] and 130 men [59.1%]). Fixed-effects models that adjusted for time-variant (other illicit drug use, antipsychotic medication adherence) and time-invariant (eg, genetic or premorbid environment) unobserved confounders revealed that there was an increase in the odds of experiencing a relapse of psychosis during periods of cannabis use relative to periods of no use (odds ratio, 1.13; 95% CI, 1.03-1.24). Change in the pattern of continuation significantly increased the risk (odds ratio, 1.07; 95% CI, 1.02-1.13), suggesting a dose-dependent association. Cross-lagged analysis confirmed that this association reflected an effect of cannabis use on subsequent risk of relapse (Ct1→Rt2: β = 0.44, P = .04) rather than an effect of relapse on subsequent cannabis use (Rt1→Ct2: β = -0.29, P = .59). CONCLUSIONS AND RELEVANCE: These results reveal a dose-dependent association between change in cannabis use and relapse of psychosis that is unlikely to be a result of self-medication or genetic and environmental confounding

Quasi-experimental evidence on short and long-term consequences of bullying victimization: A meta-analysis

Exposure to bullying victimization is associated with a wide-range of short and long-term adverse outcomes. However, the extent to which these associations reflect a causal influence of bullying victimization remains disputed. Here, we aimed to provide the most stringent evidence regarding the consequences of bullying victimization by meta-analysing all relevant Quasi-Experimental (QE) studies. Multilevel random effects models and meta-regression were employed to (i) estimate the pooled QE-adjusted effect size (Cohen d) for bullying victimization on outcomes and to (ii) evaluate potential sources of heterogeneity. A total of 16 studies were included. We derived 101 QE-estimates from three different methods (twin design, fixed effects analysis, and propensity score matching) for three pools of outcomes (internalizing symptoms, externalizing symptoms, academic difficulties). QE-adjusted effects were small for internalizing symptoms (dadjusted=0.27, 95%CI 0.05;0.49), and smaller for externalizing symptoms (dadjusted=0.15, 95%CI 0.10;0.21) and academic difficulties (dadjusted=0.10, 95%CI 0.06; 0.13). Accounting for a shared rater effect between the exposure and the outcome further reduced the effect for internalizing (dnon-shared rater=0.14, 95%CI 0.05;0.23) and externalizing symptoms (dnon-shared rater=0.06, 95%CI 0.01;0.11). Finally, the adverse effects declined in the long-term, most markedly for internalizing symptoms (dlong-term=0.06, 95%CI -0.01;0.13). Based on the most stringent evidence available to date, findings indicate that bullying victimization may causally impact children’s wellbeing in the short-term, especially anxiety and depression levels. The reduction of adverse effects over time highlights the potential for resilience in individuals who have experienced bullying. Secondary preventive interventions in bullied children should therefore focus on resilience and address children's pre-existing vulnerabilities

Development of wide range photon detection system for muonic X-ray spectroscopy

We have developed a photon detection system for muonic X-ray spectroscopy. The detector system consists of high-purity germanium detectors with BGO Compton suppressors. The signals from the detectors are readout with a digital acquisition system. The absolute energy accuracy, energy and timing resolutions, photo-peak efficiency, the performance of the Compton suppressor, and high count rate durability are studied with standard $\gamma$-ray sources and in-beam experiment using $^{27}\mathrm{Al}(p, \gamma){}^{28}\mathrm{Si}$ resonance reaction. The detection system was demonstrated at Paul Scherrer Institute. A calibration method for a photon detector at a muon facility using muonic X-rays of $^{197}$Au and $^{209}$Bi is proposed