Wang, Baihan; (2022) Endophenotypes for Psychosis: Genetic Basis and Mechanistic Insights. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Despite breakthroughs made by genome-wide association studies (GWAS) in our understanding of psychosis, further research is still needed to characterise the effects of the genetic variants identified and clarify the neurobiological mechanisms underlying these associations. In this thesis, I aim to bridge these knowledge gaps by studying endophenotypes for psychosis, which are intermediate phenotypes associated with the genetics of psychosis that pinpoint abnormalities in a specific neurobiological domain. In Chapter 1, I conducted a meta-analysis on the N100 event-related potential, combining the results of a local family study and previous literature. I found reduced N100 amplitudes and prolonged N100 latencies in both patients with psychosis and their unaffected relatives compared to controls, suggesting that the N100 is a promising endophenotype. Further analysis of the local family study revealed that the N100 was associated with the CHRNA4 gene, indicating the potential involvement of nicotinic acetylcholine receptors in the N100. In Chapter 2, I computed gene-set specific polygenic risk scores for psychosis by stratifying polygenic risk scores into specific biological domains and tested their associations with established endophenotypes. I found that reduced P300 amplitudes were associated with abnormalities in early brain development in psychosis, supporting the neurodevelopmental hypothesis of schizophrenia. Finally, Chapter 3 involves a mixed-model GWAS on adolescent verbal memory as a psychosis endophenotype in a sample of diverse genetic ancestry. I found new evidence of a significant genetic correlation between schizophrenia and verbal memory in adolescents, consistent with previous observations in family studies. Furthermore, I discovered two genome-wide significant loci that influence verbal memory performance. In particular, the NSF gene identified by my GWAS is involved in synaptic neurotransmission and membrane fusion, and thus my data suggest it plays a role in verbal memory deficits in psychosis. This thesis integrates multiple research methods covering neurophysiology, cognition, and genomics to show how endophenotypes for psychosis can inform our understanding of its aetiology.

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