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

Abstract

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