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Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis.
Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene–Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0–11 years), and late (12–17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use.
The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord.
Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.
While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis.
We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case–control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.
We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case–control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case–control status.
Controls (86.1%) and FEPp (75.63%) were most likely to report ‘because of friends’ as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: ‘to feel better’ as their RFUC (χ2 = 50.97; p < 0.001). RFUC ‘to feel better’ was associated with being a FEPp (OR 1.74; 95% CI 1.03–2.95) while RFUC ‘with friends’ was associated with being a control (OR 0.56; 95% CI 0.37–0.83). The path model indicated an association between RFUC ‘to feel better’ with heavy cannabis use and with FEPp-control status.
Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use ‘to feel better’. People who reported their reason for first using cannabis to ‘feel better’ were more likely to progress to heavy use and develop a psychotic disorder than those reporting ‘because of friends’.
Schizophrenia (SZ), bipolar disorder (BD) and depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode case–control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD).
Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons.
In case–control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case–case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54–0.92] and PRS-D (OR = 1.31, 95% CI 1.06–1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23–3.74).
Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.
Dr Nick Martin has made enormous contributions to the field of behavior genetics over the past 50 years. Of his many seminal papers that have had a profound impact, we focus on his early work on the power of twin studies. He was among the first to recognize the importance of sample size calculation before conducting a study to ensure sufficient power to detect the effects of interest. The elegant approach he developed, based on the noncentral chi-squared distribution, has been adopted by subsequent researchers for other genetic study designs, and today remains a standard tool for power calculations in structural equation modeling and other areas of statistical analysis. The present brief article discusses the main aspects of his seminal paper, and how it led to subsequent developments, by him and others, as the field of behavior genetics evolved into the present era.
The ‘jumping to conclusions’ (JTC) bias is associated with both psychosis and general cognition but their relationship is unclear. In this study, we set out to clarify the relationship between the JTC bias, IQ, psychosis and polygenic liability to schizophrenia and IQ.
A total of 817 first episode psychosis patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC, and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia.
The estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia polygenic risk score was non-significantly associated with a higher number of beads drawn (B = 0.47, 95% CI −0.21 to 1.16, p = 0.17); whereas IQ PRS (B = 0.51, 95% CI 0.25–0.76, p < 0.001) significantly predicted the number of beads drawn, and was thus associated with reduced JTC bias. The JTC was more strongly associated with the higher level of psychotic-like experiences (PLEs) in controls, including after controlling for IQ (B = −1.7, 95% CI −2.8 to −0.5, p = 0.006), but did not relate to delusions in patients.
Our findings suggest that the JTC reasoning bias in psychosis might not be a specific cognitive deficit but rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to PLEs, independent of IQ. The work has the potential to inform interventions targeting cognitive biases in early psychosis.
The etiology of depression remains poorly understood. Changes in blood lipid levels were reported to be associated with depression and suicide, however study findings were mixed.
We performed a two-sample Mendelian randomisation (MR) analysis to investigate the causal relationship between blood lipids and depression phenotypes, based on large-scale GWAS summary statistics (N = 188 577/480 359 for lipid/depression traits respectively). Five depression-related phenotypes were included, namely major depression (MD; from PGC), depressive symptoms (DS; from SSGAC), longest duration and number of episodes of low mood, and history of deliberate self-harm (DSH)/suicide (from UK Biobank). MR was conducted with inverse-variance weighted (MR-IVW), Egger and Generalised Summary-data-based MR (GSMR) methods.
There was consistent evidence that triglyceride (TG) is causally associated with DS (MR-IVW β for one-s.d. increase in TG = 0.0346, 95% CI 0.0114–0.0578), supported by MR-IVW and GSMR and multiple r2 clumping thresholds. We also observed relatively consistent associations of TG with DSH/suicide (MR-Egger OR = 2.514, CI 1.579–4.003). There was moderate evidence for positive associations of TG with MD and the number of episodes of low mood. For HDL-c, we observed moderate evidence for causal associations with DS and MD. LDL-c and TC did not show robust causal relationships with depression phenotypes, except for weak evidence that LDL-c is inversely related to DSH/suicide. We did not detect significant associations when depression phenotypes were treated as exposures.
This study provides evidence to a causal relationship between TG, and to a lesser extent, altered cholesterol levels with depression phenotypes. Further studies on its mechanistic basis and the effects of lipid-lowering therapies are warranted.
Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients.
We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses.
In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14–0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = −0.22; 95% CI −0.37 to −0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use.
Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.
The value of the nosological distinction between non-affective and affective psychosis has frequently been challenged. We aimed to investigate the transdiagnostic dimensional structure and associated characteristics of psychopathology at First Episode Psychosis (FEP). Regardless of diagnostic categories, we expected that positive symptoms occurred more frequently in ethnic minority groups and in more densely populated environments, and that negative symptoms were associated with indices of neurodevelopmental impairment.
This study included 2182 FEP individuals recruited across six countries, as part of the EUropean network of national schizophrenia networks studying Gene–Environment Interactions (EU-GEI) study. Symptom ratings were analysed using multidimensional item response modelling in Mplus to estimate five theory-based models of psychosis. We used multiple regression models to examine demographic and context factors associated with symptom dimensions.
A bifactor model, composed of one general factor and five specific dimensions of positive, negative, disorganization, manic and depressive symptoms, best-represented associations among ratings of psychotic symptoms. Positive symptoms were more common in ethnic minority groups. Urbanicity was associated with a higher score on the general factor. Men presented with more negative and less depressive symptoms than women. Early age-at-first-contact with psychiatric services was associated with higher scores on negative, disorganized, and manic symptom dimensions.
Our results suggest that the bifactor model of psychopathology holds across diagnostic categories of non-affective and affective psychosis at FEP, and demographic and context determinants map onto general and specific symptom dimensions. These findings have implications for tailoring symptom-specific treatments and inform research into the mood-psychosis spectrum.
The propensity to take risk underpins a wide variety of decision-making behavior, ranging from common ones such as asking for directions and trying out a new restaurant to more substantial economic decisions involving, for instance, one's investment or career. Despite the fundamental role of risk attitude in the economy, its genetic basis remains unknown. Using an experimental economics protocol combined with a classical twin strategy, we provide the first direct evidence of the heritability of economic risk attitude, at 57%. We do not find a significant role for shared environmental effects, a common observation in behavioral genetics that is contrary to commonly held views in economics. Our findings complement recent neuroeconomic studies in enhancing the understanding of the neurobiological basis of risk taking.
Anecdotal and biographical reports suggest that bipolar disorder may be
associated with high IQ or creativity, but evidence for any such
connection is weak.
To investigate possible associations between scholastic achievement and
later bipolar disorder, using prospective data, in a whole-population
Using individual school grades from all individuals finishing compulsory
schooling in Sweden between 1988 and 1997, we tested associations between
scholastic achievement at age 15–16 and hospital admission for psychosis
between ages 17 and 31, adjusting for potential confounders.
Individuals with excellent school performance had a nearly fourfold
increased risk of later bipolar disorder compared with those with average
grades (hazard ratio HR = 3.79, 95% CI 2.11–6.82). This association
appeared to be confined to males. Students with the poorest grades were
also at moderately increased risk of bipolar disorder (HR = 1.86, 95% CI
These findings provide support for the hypothesis that exceptional
intellectual ability is associated with bipolar disorder.
A number of studies with conflicting results have examined the
familiality of schizophrenia syndromes in Western populations.
The objective of this study was to determine, using clinical data from
concordant sibling pairs, whether symptom dimensions and other clinical
characteristics of schizophrenia show familial aggregation and are
therefore potentially useful traits in genetic studies.
We measured clinical and demographic features, and symptom dimensions of
schizophrenia in 137 families from China who had two or more affected
members with schizophrenia. Within-sibling pair correlation was assessed
with intraclass correlation coefficient and kappa statistics.
Global functioning, positive, disorganisation and dysphoric symptoms,
premorbid schizotypal and schizoid traits, premorbid social adjustment,
type and age at illness onset all showed significant evidence of familial
aggregation. DSM–IV schizophrenia subtypes were also found to be
This is the first study in a large non-European population to confirm
that schizophrenia dimensions and clinical characteristics show
significant familiality, implying possible heritability. This supports
their use in the delineation of homogeneous subsets for future genetic
Genetic epidemiology explores the interrelationship of genetic and environmental risk factors in which genes are measured indirectly in ways that reflect aggregate effects "averaged" across the entire genome. This chapter describes the principles and methodology of psychiatric genetics using four-paradigm framework: basic genetic epidemiology, advanced genetic epidemiology, gene finding, and molecular genetics. Each of these paradigms has strengths and limitations, and they are in a process of dynamic interaction with each other. Genetic epidemiology has proved a reliable method to answer basic questions about the overall importance of genetic risk factors for psychiatric illness. The advanced genetic epidemiology paradigm has been used to study the relationships between neuroticism and depression. Molecular genetics is an entirely laboratory-based discipline applying a range of modern methods from genomics to neuroscience to try to identify and then trace pathophysiological pathways.
Reaction time (RT) variability is one of the strongest findings to emerge in cognitive-experimental research of attention deficit hyperactivity disorder (ADHD). We set out to confirm the association between ADHD and slow and variable RTs and investigate the degree to which RT performance improves under fast event rate and incentives. Using a group familial correlation approach, we tested the hypothesis that there are shared familial effects on RT performance and ADHD.
A total of 144 ADHD combined-type probands, 125 siblings of the ADHD probands and 60 control participants, ages 6–18, performed a four-choice RT task with baseline and fast-incentive conditions.
ADHD was associated with slow and variable RTs, and with greater improvement in speed and RT variability from baseline to fast-incentive condition. RT performance showed shared familial influences with ADHD. Under the assumption that the familial effects represent genetic influences, the proportion of the phenotypic correlation due to shared familial influences was estimated as 60–70%.
The data are inconsistent with models that consider RT variability as reflecting a stable cognitive deficit in ADHD, but instead emphasize the extent to which energetic or motivational factors can have a greater effect on RT performance in ADHD. The findings support the role of RT variability as an endophenotype mediating the link between genes and ADHD.
Dimensional structures are established for many psychiatric diagnoses, but dimensions have not been compared between diagnostic groups.
To examine the structure of dimensions in psychosis, to analyse their correlations with disease characteristics and to assess the relative contribution of dimensions v. diagnosis in explaining these characteristics.
Factor analysis of the OPCRIT items of 191 Maudsley Family Study patients with schizophrenia, mood disorders with psychosis, schizoaffective disorder, and other psychotic illnesses, followed by regression of disease characteristics from factor scores and diagnosis.
Five factors were identified (mania, reality distortion, depression, disorganisation, negative); all were more variable in schizophrenia than in affective psychosis. Mania was the best discriminator between schizophrenia and affective psychosis; the negative factor was strongly correlated with poor premorbid functioning, insidious onset and worse course. Dimensions explained more of the disease characteristics than did diagnosis, but the explanatory power of the latter was also high.
Kraepelinian diagnostic categories suffice for understanding illness characteristics, but the use of dimensions adds substantial information.
Schneider's first-rank symptoms are given particular weight when making a diagnosis of schizophrenia, but the nuclear syndrome, characterised by one or more first-rank symptoms, has been found previously to have no heritability.
To estimate the heritability of the nuclear syndrome.
A total of 224 twin pairs (106 monozygotic, 118 same-gender dizygotic) were ascertained from the Maudsley Twin Register in London via probands with any psychosis. Lifetime-ever first-rank symptoms were rated using the OPCRIT checklist. Probandwise concordance rates were calculated for the nuclear syndrome and a heritability estimate was derived from biometric model fitting.
Probandwise concordance rates were 13/49 (26.5%) for monozygotic and 0/45 to 2/46 (0.0–4.3%) for dizygotic pairs. The heritability estimate for the best-fitting model was 71% (95% CI 57–82).
These results indicate that the nuclear syndrome shows substantial heritability, although this is slightly lower than that for schizophrenia as defined by the DSM and ICD systems.
Symptomatology in psychoses can be summarised as quantitative symptom dimensions, but their genetic basis is unknown.
To investigate whether genes make an important contribution to symptom dimensions.
A total of 224 probandwise twin pairs (106 monozygotic, 118 same-gender dizygotic) where probands had psychosis were ascertained from the Maudsley Twin Register in London. Factor analysis was performed on lifetime symptoms rated on the Operational Checklist for Psychotic Disorders (OPCRIT). Correlations of dimension scores within monozygotic and dizygotic pairs concordant for Research Diagnostic Criteria psychoses were performed. Relationships between dimension scores and genetic loading for psychoses were assessed using logistic regression.
Patterns of familial aggregation consistent with a genetic effect were found for the disorganised dimension and for some measures of the negative, manic and general psychotic dimensions. Disorganised dimension scores were related significantly to genetic loading for psychoses.
The disorganised dimension, and possibly other symptom dimensions, may be useful phenotypes for molecular genetic studies of psychoses.
Studies examining a possible decline in the incidence of schizophrenia over the last two to three decades have paid little attention to the possible role of birth cohort effects. We collected data on a Scottish national sample of all schizophrenic patients, admitted for the first time between 1966 and 1990 (N = 11348; male = 6301). In an Age–Period–Cohort analysis, a full model, incorporating three factors, had a substantially better fit to the data than other models (especially, an Age–Period model), providing clear evidence of the presence of a cohort effect. After adjustment for the effects of age and period, there was a 55% reduction in the rate of schizophrenia in men and a 39% fall in the number of women over the 50-year birth period from 1923 to 1973. The marked decline in the first admission rates observed in Scotland cannot, however, be attributed entirely to this cohort effect. Rather, a greater proportion of the declining first admission rates (88%) is ascribed to the period effect (i.e. artefactual or causally related cross-sectional effects). Nevertheless, the fact that a birth-cohort effect accounts for part of the declining incidence, suggests that causal environmental factors operating early in life have been diminishing in intensity.
It has been suggested that in schizophrenia an association exists between family history of schizophrenia and poor outcome on the one hand, and family history of affective disorders and good outcome on the other.
We tested for associations between four-year outcome and familial loading for psychotic disorders in a mixed sample of 150 consecutively admitted patients with functional psychosis (schizophrenia, psychotic affective disorders, other psychotic disorders) of recent onset. For each proband, a familial loading score for (i) broadly defined psychotic disorder, (ii) schizophrenia, and (iii) affective disorder was calculated using information on relatives obtained through the Family History Research Diagnostic Criteria method and direct interviews of relatives with the Schedule for Affective Disorders and Schizophrenia.
In our sample of psychotic patients, familial loading for psychotic disorder predicted persistent negative symptoms over the follow-up period (OR 1.5; 95% CI 1–2.2), especially in schizophrenia, and was also associated with more time hospitalised (P > 0.05), and more social disability at follow-up (P < 0.05). Greater familial loading for schizophrenia predicted a greater likelihood of non-recovery (OR 2.2; 95% CI 1.1–4.4) and a greater likelihood to have had persistent negative symptoms over the follow-up period (OR 1.7; 95% CI 0.9–3.1). No association was found between outcome and familial loading for affective disorder.
We conclude that familial loading may be a continuous risk factor for some dimensions of clinical outcome in the functional psychoses. This suggests that there is a continuum of genetic liability not only to the emergence of psychotic illness, but also the subsequent chronicity of the disorder.
Recent reports that some influenza epidemics may be followed by a transient increase in the births of schizophrenic patients have led to the hypothesis that maternal viral infections contribute to the aetiology of schizophrenia. It is well known that respiratory viral infections are frequently brought into the home by young children. We tested the predictions that the risk of schizophrenia is decreased in first-born children, and increased in individuals who had siblings of a young age while in utero, using data from a Swedish family study. Our results are consistent with these predictions. In particular, having siblings three to four years older was associated with a significantly increased risk of schizophrenia, even after allowing for birth order, sibship size, and other potential confounders. If replicated, these results provide indirect support for the maternal viral infection hypothesis, although there are alternative explanations.