At the intersection of autism and psychosis

: an investigation of causal pathways and shared risk factors

Abstract

There is increasing evidence suggesting that autism and psychosis co-occur at higher rates than would be expected by chance. Little is known on the reasons underlying this, and several aetiological models have been proposed. In this thesis I assessed evidence on two aetiological models of the autism-psychosis co-occurrence, proposing that the two conditions are causally linked and/or share immunological pathways. I applied a combination of study designs, utilising phenotype and genotype data, to triangulate evidence and strengthen causal inference.

Towards assessing the autism-psychosis causal links, I investigated the associations between autism polygenic risk (PRS), autistic traits in childhood and psychotic experiences in adulthood using data from a population-based birth cohort (Chapter 3). I triangulated the study findings, by applying two-sample Mendelian randomization (MR) and multivariable MR to examine the causal effects of genetic liability to autism and autistic traits on psychotic experiences and schizophrenia (Chapter 4).

Towards investigating whether shared immunological pathways underly autism and psychosis, I firstly interrogated the causal role of immune response in autism. I utilised four distinct methodological approaches, including a nationwide cohort study, Linkage disequilibrium score regression, PRS and two-sample MR, to investigate the causal links between a parental inflammatory bowel disease and offspring autism (Chapter 5). I used information from this study to identify causal immunological markers for autism and assess their causal effects on schizophrenia, within a two-sample MR and genetic colocalisation framework (Chapter 6).

There was evidence to suggest that the autism-psychosis co-occurrence might be explained by causal links, driven by autism common variation, social communication difficulties and trauma in childhood. Causal immunological pathways were identified in both autism and schizophrenia, but they were unique for each condition. Overall the findings suggest that beyond underlying biological processes, phenotypic and environmental factors are central in the autism-psychosis co-occurrence.

Date of Award	27 Sept 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	Dheeraj Rai (Supervisor), Stan Zammit (Supervisor), Sarah A Sullivan (Supervisor) & Hannah J Jones (Supervisor)