Heritability of Individual Psychotic Experiences Captured by Common Genetic Variants in a Community Sample of Adolescents.

Occurrence of psychotic experiences is common amongst adolescents in the general population. Twin studies suggest that a third to a half of variance in adolescent psychotic experiences is explained by genetic influences. Here we test the extent to which common genetic variants account for some of the twin-based heritability. Psychotic experiences were assessed with the Specific Psychotic Experiences Questionnaire in a community sample of 2152 16-year-olds. Self-reported measures of Paranoia, Hallucinations, Cognitive Disorganization, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms were obtained. Estimates of SNP heritability were derived and compared to the twin heritability estimates from the same sample. Three approaches to genome-wide restricted maximum likelihood (GREML) analyses were compared: (1) standard GREML performed on full genome-wide data; (2) GREML stratified by minor allele frequency (MAF); and (3) GREML performed on pruned data. The standard GREML revealed a significant SNP heritability of 20 % for Anhedonia (SE = 0.12; p < 0.046) and an estimate of 19 % for Cognitive Disorganization, which was close to significant (SE = 0.13; p < 0.059). Grandiosity and Paranoia showed modest SNP heritability estimates (17 %; SE = 0.13 and 14 %; SE = 0.13, respectively, both n.s.), and zero estimates were found for Hallucinations and Negative Symptoms. The estimates for Anhedonia, Cognitive Disorganization and Grandiosity accounted for approximately half the previously reported twin heritability. SNP heritability estimates from the MAF-stratified approach were mostly consistent with the standard estimates and offered additional information about the distribution of heritability across the MAF range of the SNPs. In contrast, the estimates derived from the pruned data were for the most part not consistent with the other two approaches. It is likely that the difference seen in the pruned estimates was driven by the loss of tagged causal variants, an issue fundamental to this approach. The current results suggest that common genetic variants play a role in the etiology of some adolescent psychotic experiences, however further research on larger samples is desired and the use of MAF-stratified approach recommended

Characterization of psychotic experiences in adolescence using the Specific Psychotic Experiences Questionnaire (SPEQ): findings from a study of 5000 16-year-old twins

We aimed to characterize multiple psychotic experiences, each assessed on a spectrum of severity (ie, quantitatively), in a general population sample of adolescents. Over five thousand 16-year-old twins and their parents completed the newly devised Specific Psychotic Experiences Questionnaire (SPEQ); a subsample repeated it approximately 9 months later. SPEQ was investigated in terms of factor structure, intersubscale correlations, frequency of endorsement and reported distress, reliability and validity, associations with traits of anxiety, depression and personality, and sex differences. Principal component analysis revealed a 6-component solution: paranoia, hallucinations, cognitive disorganization, grandiosity, anhedonia, and parent-rated negative symptoms. These components formed the basis of 6 subscales. Correlations between different experiences were low to moderate. All SPEQ subscales, except Grandiosity, correlated significantly with traits of anxiety, depression, and neuroticism. Scales showed good internal consistency, test-retest reliability, and convergent validity. Girls endorsed more paranoia, hallucinations, and cognitive disorganization; boys reported more grandiosity and anhedonia and had more parent-rated negative symptoms. As in adults at high risk for psychosis and with psychotic disorders, psychotic experiences in adolescents are characterized by multiple components. The study of psychotic experiences as distinct dimensional quantitative traits is likely to prove an important strategy for future research, and the SPEQ is a self- and parent-report questionnaire battery that embodies this approach

Are genetic risk factors for psychosis also associated with dimension-specific psychotic experiences in adolescence?

Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value=2.57x10-4) and rs9960767 (p-value=6.23x10-4). Replication in an independent sample of 16-year-olds (N=3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed

Investigation into the contribution of common genetic variants to the aetiology of dimension-specific psychotic experiences in the general population of adolescents and the association with schizophrenia

There is a substantial body of research on characterisation of psychotic experiences (PEs), however much remains to be learnt about the contribution of common genetic variants to the aetiology of dimension-specific PEs in adolescence and their association with schizophrenia. In this thesis, Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Negative Symptoms were assessed in a community sample of 2,175 16-year-olds. The findings presented here make a number of contributions to the existing body of literature on adolescent PEs. First, estimates of heritability of dimension-specific PEs captured by common single nucleotide polymorphisms (SNPs) are provided and suggest that SNPs account for variation in Anhedonia, Cognitive Disorganisation, Grandiosity, and possibly Paranoia and explain approximately 50% of twin-based heritability estimates. Second, findings from an investigation using polygenic risk score (PRS), single SNP and composite SNP score analyses, which tested whether genetic variants previously associated with either schizophrenia or bipolar disorder are also associated with specific PEs, revealed no significant positive associations between the phenotypes under investigation. In addition, one SNP in TCF4 previously associated with schizophrenia liability was also associated with Paranoia in adolescence. Revised analyses using updated schizophrenia PRS yielded a consistent pattern of results and some negative associations were observed. Third, there was limited evidence that cumulative effects of common SNPs associated with schizophrenia interact with substance use or family history of psychotic disorders to increase risk of specific PEs. Finally, evidence for modest negative SNP-genetic correlations between schizophrenia and some specific PEs was given. Despite multiple negative results, the findings presented here provide evidence for the contribution of common genetic variants to the aetiology of adolescent dimension-specific PEs and are suggestive of a degree of SNP genetic overlap with schizophrenia. The findings are discussed and critically evaluated to inform future work

Investigation into the contribution of common genetic variants to the aetiology of dimension-specific psychotic experiences in the general population of adolescents and the association with schizophrenia

There is a substantial body of research on characterisation of psychotic experiences (PEs), however much remains to be learnt about the contribution of common genetic variants to the aetiology of dimension-specific PEs in adolescence and their association with schizophrenia. In this thesis, Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Negative Symptoms were assessed in a community sample of 2,175 16-year-olds. The findings presented here make a number of contributions to the existing body of literature on adolescent PEs. First, estimates of heritability of dimension-specific PEs captured by common single nucleotide polymorphisms (SNPs) are provided and suggest that SNPs account for variation in Anhedonia, Cognitive Disorganisation, Grandiosity, and possibly Paranoia and explain approximately 50% of twin-based heritability estimates. Second, findings from an investigation using polygenic risk score (PRS), single SNP and composite SNP score analyses, which tested whether genetic variants previously associated with either schizophrenia or bipolar disorder are also associated with specific PEs, revealed no significant positive associations between the phenotypes under investigation. In addition, one SNP in TCF4 previously associated with schizophrenia liability was also associated with Paranoia in adolescence. Revised analyses using updated schizophrenia PRS yielded a consistent pattern of results and some negative associations were observed. Third, there was limited evidence that cumulative effects of common SNPs associated with schizophrenia interact with substance use or family history of psychotic disorders to increase risk of specific PEs. Finally, evidence for modest negative SNP-genetic correlations between schizophrenia and some specific PEs was given. Despite multiple negative results, the findings presented here provide evidence for the contribution of common genetic variants to the aetiology of adolescent dimension-specific PEs and are suggestive of a degree of SNP genetic overlap with schizophrenia. The findings are discussed and critically evaluated to inform future work

Mean sex differences on psychotic experiences.

<p>Note. M = Mean; SD = standard deviations; df = degrees of freedom. Raw scores provided. Paranoia, Hallucinations, Grandiosity and Parent-rated Negative Symptoms were transformed prior to statistical testing.</p

Results of Allelic & Genotypic Association Analyses for PLIKS-Q Transformed Data (adjusted for sex and age)

<p>Note: Chr, chromosome; Allele, risk allele; Beta, regression coefficient; ADD, additive linear regression model; GENO_2DF, two degrees of freedom joint test of additivity and dominance deviation (it does not assume a linear relationship); * proxies for rs17512836.</p

Descriptive statistics for the six dimensions of psychotic experiences as measured by SPEQ and PLIKS-Q.

<p>Note. SD, standard deviation.</p

Summary of results for bipolar disorder PRS as a predictor of SPEQ subscales at p_T = 0.5.

<p>Note. β, unstandardized beta value; C.I., confidence intervals; t, t-statistic; N, sample size; df, degrees of freedom; 8 PCs were included as covariates.</p