Genome-wide analyses to investigate the genetic factors underlying specific psychotic experiences in adolescence and their overlap with psychiatric disorders

Pain, Oliver (2018) Genome-wide analyses to investigate the genetic factors underlying specific psychotic experiences in adolescence and their overlap with psychiatric disorders. Doctoral thesis, Birkbeck, University of London.

Abstract

Psychotic experiences (PEs) are non-clinical traits, which at the extreme resemble symptoms of psychotic disorders, such as schizophrenia. PEs during adolescence have been associated with a range of psychiatric disorders, including schizophrenia, bipolar disorder, and major depression. Adolescent PEs are moderately heritable, however no genetic variant has been associated with adolescent PEs at genome-wide significance. There are limited and mixed findings regarding a common genetic overlap between adolescent PEs and psychiatric disorders. Following a systematic review of previous studies using genome-wide genetic data to investigate adolescent PEs, this thesis sets out to improve upon previous research through two main approaches: 1) the use of specific and quantitative measures of adolescent PEs, and 2) the combined analysis of multiple samples. In Chapter 2, a GWAS (genome-wide association study) is performed using specific and quantitative measures of adolescent PEs using the TEDS (Twins Early Development Study) sample. In Chapter 3, the procedure in which phenotypic data is normalised and controlled for covariates is investigated. The remainder of the thesis is based on the combined analysis of three European adolescent samples (TEDS and two others) with available PE data. In Chapter 4, the phenotypic data relating to PEs within each sample are harmonised to create four measures assessing specific PE traits that are comparable across samples. These four traits are Paranoia and Hallucinations, Cognitive Disorganisation, Anhedonia, and Parent-rated Negative Symptoms. In Chapter 5, mega-GWASs of the four specific PE traits (N = 6,297-10,098) are performed across the three samples to highlight associated genetic variation. Chapter 6 then estimates the variance in specific PEs, and the covariance between PEs, that is attributable to common genetic variation. Chapter 4 7 uses both polygenic risk scoring and LD-score regression to test for common genetic overlap between specific adolescent PEs and schizophrenia, bipolar disorder, and major depression. This thesis provides evidence that specific PEs during adolescence show common genetic effects, and have a common genetic overlap with psychiatric disorders, specifically schizophrenia and major depression. The findings of this thesis are placed in the context of previous research, with a discussion of the limitations and future directions

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