Liability For Schizophrenia Research Articles

Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment

BackgroundTreatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively.ResultsWe identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10−7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10−6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively.ConclusionsWe report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.

Associations Between Genetic Risk, Physical Activities, and Distressing Psychotic-like Experiences.

Persistent distressing psychotic-like experiences (PLE) are associated with impaired functioning and future psychopathology. Prior research suggests that physical activities may be protective against psychopathology. However, it is unclear whether physical activities may interact with genetics in the development of psychosis. This study included 4679 participants of European ancestry from the Adolescent Brain Cognitive Development Study. Persistent distressing PLE was derived from the Prodromal-Questionnaire-Brief Child Version using four years of data. Generalized linear mixed models tested the association between polygenic risk score for schizophrenia (PRS-SCZ), physical activities, and PLE. The models adjusted for age, sex, parental education, income-to-needs ratio, family history of psychosis, body mass index, puberty status, principal components for PRS-SCZ, study site, and family. PRS-SCZ was associated with a greater risk for persistent distressing PLE (adjusted relative risk ratio (RRR) = 1.14, 95% CI [1.04, 1.24], P = .003). Physical activity was associated with less risk for persistent distressing PLE (adjusted RRR = 0.87, 95% CI [0.79, 0.96], P = .008). Moreover, physical activities moderated the association between PRS-SCZ and persistent distressing PLE (adjusted RRR = 0.89, 95% CI [0.81, 0.98], P = .015), such that the association was weaker as participants had greater participation in physical activities. These findings demonstrate that the interaction between genetic liability and physical activities is associated with trajectories of distressing PLE. Further research is needed to understand the mechanisms of physical activities and genetic liability for schizophrenia in the development of psychosis.

Genetically Informed Study Highlights Income-Independent Effect of Schizophrenia Liability on Mental and Physical Health

Genetically Informed Study Highlights Income-Independent Effect of Schizophrenia Liability on Mental and Physical Health

Key subphenotypes of bipolar disorder are differentially associated with polygenic liabilities for bipolar disorder, schizophrenia, and major depressive disorder.

Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment.

Polygenic liability for antipsychotic dosage and polypharmacy - a real-world registry and biobank study.

Genomic prediction of antipsychotic dose and polypharmacy has been difficult, mainly due to limited access to large cohorts with genetic and drug prescription data. In this proof of principle study, we investigated if genetic liability for schizophrenia is associated with high dose requirements of antipsychotics and antipsychotic polypharmacy, using real-world registry and biobank data from five independent Nordic cohorts of a total of N = 21,572 individuals with psychotic disorders (schizophrenia, bipolar disorder, and other psychosis). Within regression models, a polygenic risk score (PRS) for schizophrenia was studied in relation to standardized antipsychotic dose as well as antipsychotic polypharmacy, defined based on longitudinal prescription registry data as well as health records and self-reported data. Meta-analyses across the five cohorts showed that PRS for schizophrenia was significantly positively associated with prescribed (standardized) antipsychotic dose (beta(SE) = 0.0435(0.009), p = 0.0006) and antipsychotic polypharmacy defined as taking ≥2 antipsychotics (OR = 1.10, CI = 1.05-1.21, p = 0.0073). The direction of effect was similar in all five independent cohorts. These findings indicate that genotypes may aid clinically relevant decisions on individual patients´ antipsychotic treatment. Further, the findings illustrate how real-world data have the potential to generate results needed for future precision medicine approaches in psychiatry.

Assessing the association between global structural brain age and polygenic risk for schizophrenia in early adulthood: A recall-by-genotype study

Neuroimaging studies consistently show advanced brain age in schizophrenia, suggesting that brain structure is often ‘older’ than expected at a given chronological age. Whether advanced brain age is linked to genetic liability for schizophrenia remains unclear. In this pre-registered secondary data analysis, we utilised a recall-by-genotype approach applied to a population-based subsample from the Avon Longitudinal Study of Parents and Children to assess brain age differences between young adults aged 21–24 years with relatively high (n = 96) and low (n = 93) polygenic risk for schizophrenia (SCZ-PRS). A global index of brain age (or brain-predicted age) was estimated using a publicly available machine learning model previously trained on a combination of region-wise gray-matter measures, including cortical thickness, surface area and subcortical volumes derived from T1-weighted magnetic resonance imaging (MRI) scans. We found no difference in mean brain-PAD (the difference between brain-predicted age and chronological age) between the high- and low-SCZ-PRS groups, controlling for the effects of sex and age at time of scanning (b = −.21; 95% CI −2.00, 1.58; p = .82; Cohen's d = −.034; partial R2 = .00029). These findings do not support an association between SCZ-PRS and brain-PAD based on global age-related structural brain patterns, suggesting that brain age may not be a vulnerability marker of common genetic risk for SCZ. Future studies with larger samples and multimodal brain age measures could further investigate global or localised effects of SCZ-PRS.

Measurement invariance of brief forms of the Schizotypal Personality Questionnaire across convenience versus random samples

Schizotypy, a multifaceted personality construct that represents liability for schizophrenia, is generally measured with self-report questionnaires that have been developed and validated in samples of undergraduate students. Given that understanding schizotypy in non-clinical samples is essential for furthering our understanding of schizophrenia-spectrum psychopathologies, it is critical to test whether non-clinically identified undergraduate and other convenience samples respond to schizotypy scales in the same way as random samples of the general population. Here, 651 undergraduates, 350 MTurk workers, and two randomly selected high school samples (n = 177, n = 551) completed brief versions of the Schizotypal Personality Questionnaire (SPQ-BR or SPQ-BRU). Multigroup confirmatory factor analysis was used to test whether measurement invariance was present across samples. Tests were made for all samples together and for each pair of samples. Results showed that a first-order nine-factor model fit the data well, and this factor structure displayed configural and metric invariance across the four samples. This suggests that schizotypy has the same factor structure, and the SPQ-BR/BRU is measuring the same construct across the different groups. However, when all groups were compared, results indicated a lack of scalar invariance across these samples, suggesting mean comparisons may be inappropriate across different sample types. However, when randomly selected high school students were compared with undergraduate students, scalar invariance was present. This suggests that factors such as culture and form type may be driving invariance, rather than sampling method (convenience vs general population).

Copy Number Variations in Neuropsychiatric Disorders.

Neuropsychiatric disorders are complex conditions that represent a significant global health burden with complex and multifactorial etiologies. Technological advances in recent years have improved our understanding of the genetic architecture of the major neuropsychiatric disorders and the genetic loci involved. Previous studies mainly investigated genome-wide significant SNPs to elucidate the cross-disorder and disorder-specific genetic basis of neuropsychiatric disorders. Although copy number variations represent a major source of genetic variations, they are known risk factors in developing a variety of human disorders, including certain neuropsychiatric diseases. In this review, we demonstrate the current understanding of CNVs contributing to liability for schizophrenia, bipolar disorder, and major depressive disorder.

Specificity of polygenic signatures across symptom dimensions in bipolar disorder: an analysis of UK Bipolar Disorder Research Network data

Current definitions and clinical heterogeneity in bipolar disorder are major concerns as they obstruct aetiological research and impede drug development. Therefore, stratification of bipolar disorder is a high priority. To inform stratification, our analysis aimed to examine the patterns and relationships between polygenic liability for bipolar disorder, major depressive disorder (MDD), and schizophrenia with multidimensional symptom representations of bipolar disorder. In this analysis, data from the UK Bipolar Disorder Research Network (BDRN) were assessed with the Operational Checklist for Psychotic Disorders. Individuals with bipolar disorder as defined in DSM-IV, of European ancestry (self-reported), aged 18 years or older at time of interview, living in the UK, and registered with the BDRN were eligible for inclusion. Psychopathological variables obtained via interview by trained research psychologists or psychiatrists and psychiatric case notes were used to identify statistically distinct symptom dimensions, calibrated with exploratory factor analysis and validated with confirmatory factor analysis (CFA). CFA was extended to include three polygenic risk scores (PRSs) indexing liability for bipolar disorder, MDD, and schizophrenia in a multiple indicator multiple cause (MIMIC) structural equation model to estimate PRS relationships with symptom dimensions. Of 4198 individuals potentially eligible for inclusion, 4148 (2804 [67·6%] female individuals and 1344 [32·4%] male individuals) with a mean age at interview of 45 years (SD 12·03) were available for analysis. Three reliable dimensions (mania, depression, and psychosis) were identified. The MIMIC model fitted the data well (root mean square error of approximation 0·021, 90% CI 0·019-0·023; comparative fit index 0·99) and suggests statistically distinct symptom dimensions also have distinct polygenic profiles. The PRS for MDD was strongly associated with the depression dimension (standardised β 0·125, 95% CI 0·080-0·171) and the PRS for schizophrenia was strongly associated with the psychosis dimension (0·108, 0·082-0·175). For the mania dimension, the PRS for bipolar disorder was weakly associated (0·050, 0·002-0·097). Our findings support the hypothesis that genetic heterogeneity underpins clinical heterogeneity, suggesting that different symptom dimensions within bipolar disorder have partly distinct causes. Furthermore, our results suggest that a specific symptom dimension has a similar cause regardless of the primary psychiatric diagnosis, supporting the use of symptom dimensions in precision psychiatry. Wellcome Trust and UK Medical Research Council.

Relational memory function in schizophrenia: Electrophysiological evidence for early perceptual and late associative abnormalities.

We used event-related potentials (ERPs) to examine encoding and retrieval during episodic memory in people with schizophrenia (SZ) and biological relatives of SZ (SZr). To isolate contextual from item-specific aspects of memory, we employed the Relational and Item-Specific Encoding (RISE) task. Twenty two healthy controls (HCs), 22 SZ, and 19 SZr, encoded visual depictions of objects when displayed alone (item-specific) or in pairs (relational encoding), and were later tested on recognition of specific objects and whether pairs of objects had appeared together. An early posterior component (P2) during encoding predicted later recognition and was diminished in SZ. A late negative potential (LNP) over left frontal brain regions during recognition was larger for relationally encoded objects than new and item-specific encoded objects in HCs. This pattern was absent for SZ and SZr. Smaller P2 and LNP components were associated with greater self-reported cognitive-perceptual abnormalities. Early posterior brain responses likely relevant to perceptual functions supporting memory formation were diminished in schizophrenia. Late frontal electrophysiological responses associated with relational aspects of memory appear diminished in SZ and SZr, potentially reflecting the influence of genetic liability for schizophrenia on brain functions supporting episodic memory.

The association between exposome score for schizophrenia and metabolic parameters in individuals with schizophrenia and healthy controls: Findings from the EUGEI study

IntroductionExposome is all nongenetic exposures from the prenatal period to death. Exposome score for schizophrenia (ES-SCZ) is a cumulative measure of environmental liability for schizophrenia. Our previous studies showed that the ES-SCZ is associated with mental and physical health outcome.ObjectivesThe aim of the study is to investigate the association of the ES-SCZ with metabolic parameters in individuals with schizophrenia and healthy controls.MethodsThis study obtained 124 individuals with schizophrenia and 440 healthy controls from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions, Work Package 6 (Vulnerability and Severity) Turkey dataset. The ES-SCZ was calculated by summing log-odds weighted environmental exposures (childhood adversities, winter birth, hearing impairment and cannabis use). Linear regression analysis was used to investigate the association between ES-SCZ and metabolic parameters. After that analysis age and sex were added as covariates.ResultsThere was an association between ES-SCZ and diastolic blood pressure (B = -2.69 [95% CI -4.74; -.65], P-value = 0.010) in schizophrenia. ES-SCZ was associated with the fasting glucose level (B = -6.23 [95% CI -11.59; -.87], P-value = 0.023); high density lipid level (B = 1.77 [95% CI .27; 3.27], P-value = 0.021) in control and these results remained significant after adjusting for age and sex.ConclusionsES-SCZ was associated with important metabolic parameters. These findings show that ES-SCZ is not only related to increasing the risk for psychosis development but may also influence comorbidities. This result is important since it may increase our knowledge of ES-SCZ and contribute to the importance and framework of its clinical implementation.Disclosure of InterestNone Declared

A pilot randomized controlled trial comparing a novel compassion and metacognition approach for schizotypal personality disorder with a combination of cognitive therapy and psychopharmacological treatment

BackgroundSchizotypal personality disorder is characterized by a pervasive pattern of maladaptive behavior that has been associated with the liability for schizophrenia. Little is known about effective psychosocial interventions. This pilot non-inferiority randomized controlled trial aimed to compare a novel form of psychotherapy tailored for this disorder and a combination of cognitive therapy and psychopharmacological treatment. The former treatment – namely, Evolutionary Systems Therapy for Schizotypy—integrated evolutionary, metacognitively oriented, and compassion focused approaches.MethodsThirty-three participants were assessed for eligibility, twenty-four randomized on a 1:1 ratio, nineteen included in the final analysis. The treatments lasted 6 months (24 sessions). The primary outcome was change across nine measurements in personality pathology, the secondary outcomes were remission from diagnosis and pre-post changes in general symptomatology and metacognition.ResultsPrimary outcome suggested a non-inferiority of the experimental treatment in respect to control condition. Secondary outcomes reported mixed results. There was no significant difference in terms of remission, but experimental treatment showed a larger reduction of general symptomatology (η2 = 0.558) and a larger increase in metacognition (η2 = 0.734).ConclusionsThis pilot study reported promising results about the effectiveness of the proposed novel approach. A confirmatory trial on large sample size is needed to provide evidence about relative effectiveness of the two treatment conditions.Trial registrationClinicalTrials.gov; NCT04764708; Registration day 21/02/2021.

Polygenic Risk and Episode Polarity Among Individuals With Bipolar Disorder.

The authors investigated associations between polygenic liabilities for bipolar disorder, major depression, and schizophrenia and episode polarity among individuals with bipolar disorder. The sample consisted of 2,705 individuals diagnosed with bipolar disorder at Danish psychiatric hospitals between January 1995 and March 2017. DNA was obtained from dried blood spots collected at birth as part of routine screening. Polygenic risk scores (PRSs) for bipolar disorder, major depression, and schizophrenia were generated using a meta-PRS method combining internally and externally trained components. Associations between PRS and polarity at first episode, polarity at any episode, and number of episodes with a given polarity were evaluated for each disorder-specific PRS using logistic and negative binominal regressions adjusted for the other two PRSs, age, sex, genotype platform, and five ancestral principal components. PRS for bipolar disorder was positively associated with any manic episodes (odds ratio=1.23, 95% CI=1.09-1.38). PRS for depression was positively associated with any depressive (odds ratio=1.11, 95% CI=1.01-1.23) and mixed (odds ratio=1.15, 95% CI=1.03-1.28) episodes and negatively associated with any manic episodes (odds ratio=0.76, 95% CI=0.69-0.84). PRS for schizophrenia was positively associated with any manic episodes (odds ratio=1.13, 95% CI=1.01-1.27), but only when psychotic symptoms were present (odds ratio for psychotic mania: 1.27, 95% CI=1.05-1.54; odds ratio for nonpsychotic mania: 1.06, 95% CI=0.93-1.20). These patterns were similar for first-episode polarity and for the number of episodes within each pole. PRSs for bipolar disorder, major depression, and schizophrenia are associated with episode polarity and psychotic symptoms in a congruent manner among individuals with bipolar disorder.

Associations Between Cannabis Use, Polygenic Liability for Schizophrenia, and Cannabis-related Experiences in a Sample of Cannabis Users.

Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs. We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD). Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e-7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample. Among individuals who regularly use cannabis, genetic liability for schizophrenia-even in those without clinical features-may increase the likelihood of reporting unusual experiences related to cannabis use.

Is there a causal relationship between executive function and liability to mental health and substance use? A Mendelian randomization approach.

Poorer performance in tasks testing executive function (EF) is associated with a range of psychopathologies such as schizophrenia, major depressive disorder (MDD) and anxiety, as well as smoking and alcohol consumption. We used two-sample bidirectional Mendelian randomization to examine whether these may reflect causal relationships and the direction of causation. We used genome-wide association study summary data (N = 17 310 to 848 460) for a common EF factor score (cEF), schizophrenia, MDD, anxiety, smoking initiation, alcohol consumption, alcohol dependence and cannabis use disorder (CUD). We found evidence of increased cEF on reduced schizophrenia liability (OR = 0.10; CI: 0.05 to 0.19; p-value = 3.43 × 10-12), MDD liability (OR = 0.52; CI: 0.38 to 0.72; p-value = 5.23 × 10-05), drinks per week (β = -0.06; CI: -0.10 to -0.02; p-value = 0.003) and CUD liability (OR = 0.27; CI: 0.12 to 0.61; p-value = 1.58 × 10-03). We also found evidence of increased schizophrenia liability (β = -0.04; CI: -0.04 to -0.03; p-value = 3.25 × 10-27) and smoking initiation on decreased cEF (β = -0.06; CI: -0.09 to -0.03; p-value = 6.11 × 10-05). Our results indicate potential causal relationships between cEF and mental health and substance use. Further studies are required to improve our understanding of the underlying mechanisms of these effects, but our results suggest that EF may be a promising intervention target for mental health and substance use.

Association Between Polygenic Risk Scores and Outcome of ECT.

Identifying biomarkers associated with response to electroconvulsive therapy (ECT) may aid clinical decisions. The authors examined whether greater polygenic liabilities for major depressive disorder, bipolar disorder, and schizophrenia are associated with improvement following ECT for a major depressive episode. Between 2013 and 2017, patients who had at least one treatment series recorded in the Swedish National Quality Register for ECT were invited to provide a blood sample for genotyping. The present study included 2,320 participants (median age, 51 years; 62.8% women) who had received an ECT series for a major depressive episode (77.1% unipolar depression), who had a registered treatment outcome, and whose polygenic risk scores (PRSs) could be calculated. Ordinal logistic regression was used to estimate the effect of PRS on Clinical Global Impressions improvement scale (CGI-I) score after each ECT series. Greater PRS for major depressive disorder was significantly associated with less improvement on the CGI-I (odds ratio per standard deviation, 0.89, 95% CI=0.82, 0.96; R2=0.004), and greater PRS for bipolar disorder was associated with greater improvement on the CGI-I (odds ratio per standard deviation, 1.14, 95% CI=1.05, 1.23; R2=0.005) after ECT. PRS for schizophrenia was not associated with improvement. In an overlapping sample (N=1,207) with data on response and remission derived from the self-rated version of the Montgomery-Åsberg Depression Rating Scale, results were similar except that schizophrenia PRS was also associated with remission. Improvement after ECT is associated with polygenic liability for major depressive disorder and bipolar disorder, providing evidence of a genetic component for ECT clinical response. These liabilities may be considered along with clinical predictors in future prediction models of ECT outcomes.

Genomic Stratification of Clozapine Prescription Patterns Using Schizophrenia Polygenic Scores

BackgroundTreatment-resistant schizophrenia affects approximately 30% of individuals with the disorder. Clozapine is the medication of choice in treatment-resistant schizophrenia, but optimizing administration and dose titration is complex. The identification of factors influencing clozapine prescription and response, including genetics, is of interest in a precision psychiatry framework. MethodsWe used linear regression models accounting for demographic, pharmacological, and clinical covariates to determine whether a polygenic risk score (PRS) for schizophrenia would be associated with the highest dose recorded during clozapine treatment. Analyses were performed across 2 independent multiancestry samples of individuals from a UK patient monitoring system, CLOZUK2 (n = 3133) and CLOZUK3 (n = 909), and a European sample from a Norwegian therapeutic drug monitoring service (n = 417). In a secondary analysis merging both UK cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRSs and clozapine doses classified as low, standard, or high. ResultsAfter controlling for relevant covariates, the schizophrenia PRS was correlated with the highest clozapine dose on record for each individual across all samples: CLOZUK2 (β = 12.22, SE = 3.78, p = .001), CLOZUK3 (β = 12.73, SE = 5.99, p = .034), and the Norwegian cohort (β = 46.45, SE = 18.83, p = .014). In a secondary analysis, the schizophrenia PRS was associated with taking clozapine doses >600 mg/day (odds ratio = 1.279, p = .006). ConclusionsThe schizophrenia PRS was associated with the highest clozapine dose prescribed for an individual in records from 3 independent samples, suggesting that the genetic liability for schizophrenia might index factors associated with therapeutic decisions in cohorts of patients with treatment-resistant schizophrenia.

Influences on the Genetic Relationship Between Cannabis Use and Schizophrenia: The Role of the Externalizing Spectrum.

The nature of the robust association between cannabis use and schizophrenia remains undetermined. Plausible hypotheses explaining this relationship include the premise that cannabis use causes schizophrenia, increased liability for schizophrenia increases the risk of cannabis use initiation (eg, self-medication), or the bidirectional causal hypothesis where both factors play a role in the development of the other. Alternatively, factors that confound the relationship between schizophrenia and cannabis use may explain their association. Externalizing behaviors are related to both schizophrenia and cannabis use and may influence their relationship. This study aimed to evaluate whether externalizing behaviors influence the genetic relationship between cannabis use and schizophrenia. We conducted a multivariate genome-wide association analysis of 6 externalizing behaviors in order to construct a genetic latent factor of the externalizing spectrum. Genomic structural equation modeling was used to evaluate the influence of externalizing behaviors on the genetic relationship between cannabis use and schizophrenia. We found that externalizing behaviors partially explained the association between cannabis use and schizophrenia by up to 42%. This partial explanation of the association by externalizing behaviors suggests that there may be other unidentified confounding factors, alongside a possible direct association between schizophrenia and cannabis use. Future studies should aim to identify further confounding factors to accurately explain the relationship between cannabis use and schizophrenia.

Early manifestations of genetic liability for ADHD, autism and schizophrenia at ages 18 and 24 months.

ADHD and autism are neurodevelopmental conditions, for which non-specific precursors or early signs include difficulties with language and motor skills, and differences in temperament in the first and second year of life. These early features have also been linked to later diagnosis of schizophrenia which is widely considered to have neurodevelopmental origins. Given that ADHD, autism and schizophrenia are all highly heritable, we tested the hypothesis that in the general population, measures of toddler language development, motor development and temperament are associated with genetic liability to ADHD, autism and/or schizophrenia. Data were analysed from the Avon Longitudinal Study of Parents and Children (ALSPAC) which included motor development scores at age 18 months and language development and temperament scores at age 24 months (N=7498). Genetic liability was indexed by polygenic risk scores (PGS) for ADHD, autism and schizophrenia. ADHD PGS were associated with specific temperament scales (higher activity β=0.07, 95% CI=0.04, 0.09 and lower withdrawal β=-0.05, 95% CI=-0.07, -0.02) as well as better gross motor scores (β=0.04, 95% CI=0.01, 0.06). Schizophrenia PGS were associated with one specific temperament scale (negative mood β=0.04, 95% CI=0.02, 0.07). We did not find strong evidence of association of autism PGS with any of the toddler measures; there was also not strong evidence of association with motor or language delays for any of the PGS. This study suggests that some specific aspects of early temperament and gross motor differences in the general population could represent part of the early manifestation of genetic liability to neurodevelopmental conditions.

Premorbid screening of healthy students may carry latent liability for schizophrenia or bipolar affective disorder with neurocognitive and neurophenomenological methods

IntroductionThis study was carried out to map psychosis spectrum disorder risk factors.ObjectivesOur goal was to find what kind of instrumental methods may help to detect latent liabilities for schizophrenia and bipolar affective disorderMethodsUsing online questionnaires n=710 students were screened. Groups were formed based on the inclusion criteria: N = 25 people prone to mood swings, N = 30 people prone to odd experiences and delusive thinking, and a normal control group with N = 30 people. Personality, temperament, self-experiences, affectivity scales, and cognitive screening were conducted in addition to actigraphy coupled with a mobile application for detecting subjective experiences (EMA). Furthermore, instrumental examination of self-agency, testing time interval discrimination and (re)production, eye-tracking, EEG-microstates, and laboratory testing of inflammatory, immunologic and cardio-metabolic measures of allostatic load were applied.ResultsSelf-experience disorders: both risk groups showed significantly higher scores than the control group (CG). Self-agency: based on incorrectly attributed responses, the positive schizotypy risk factor (PSF) group differed from the CG (p = 0.003). Antisaccade study: the PSF group showed a difference from the CG (p = 0.002). Actigraphy: based on the distributions of diurnal cumulative activities, it distinguished those with a cyclothymic risk factor (CTF) from the CG (67% probability in the k-means clustering procedure).ConclusionsHealthy students with a latent liability for schizotypy or bipolarity could be distinguished by some targeted laboratory methods. Susceptibility for bipolarity was indicated by actigraphic analyzes, and the risk for schizotypal development was indicated by deficiencies in the self-agency experience and by anti-saccadic eye movement disorders.DisclosureNo significant relationships.