Neurocognitive effects of risk factors for psychosis: Neuropsychological and neuroimaging studies of immune-related genetic and environmental factors

Abstract

Schizophrenia (SZ) is a debilitating psychiatric disorder that afflicts approximately 1% of people worldwide. It is often characterized by hallucinations, sometimes by emotional blunting, and in a majority of cases by a decline in cognitive functioning.. In understanding the aetiology of SZ (which is likely to involve both genetic and environmental factors), immune dysfunction has recently become an area of significant attention. This is in part because many recently identified genetic variants found to be associated with SZ have biological roles that are associated with immune function. This thesis sought to characterize the effects of immune-related genetic variants and immune-related environmental factors on neurocognitive outcomes associated with SZ. My first study focused on Early Life Adversity (ELA) and immune markers, which have been associated with SZ. Immune processes, when perturbed, are thought to contribute to SZ pathophysiology, and some research suggests ELA could trigger this dysregulation. I investigated the association between ELA and cognitive deficits common in SZ, as well as the relationship between ELA and immune function, using data from the Avon Longitudinal Study of Parents And Children (ALSPAC). I created 4 ELA variables up to age 5, which were tested for association with a later measure of cognitive performance at ages 9 and 13. Counter to the hypothesis, I found no association between ELA measures and social cognition. However, ‘Harsh Parenting’, an ELA measure of physical discipline from mother to child was found to be associated with decreased IQ scores at age 9. Finally, although I found that lower IQ scores were associated with increased immune marker scores, these did not account for the relationship between ELA and IQ. Following from this, I focused on genetic variants known to impact immune response (aside from the targeted immune markers in study 1), to further investigate how the immune system can affect cognitive deficits associated with SZ. Of various immune genes identified in recent research, the gene family associated with complement expression was chosen for further analysis. Recent studies have suggested that structural variation within one complement gene, C4, may account for a large proportion of SZ risk implicated in many GWAS to date. Aside from C4, I wanted to investigate how other complement genes contributed to variation in IQ and cognitive domains associated with SZ risk. For my second study I created a ‘complement’ gene set using various online databases, informed by recent research. This ‘complement’ gene set was tested for enrichment using the largest available GWAS dataset for SZ (36,989 cases, 113,075 controls). Based on the genetic overlap between SZ and cognition, gene-sets were also investigated for a genetic contribution to IQ using the largest available IQ GWAS dataset (N=269,867). Interestingly, this complement gene-set was enriched for the phenotype of IQ, but not enriched for the phenotype of SZ. Thus, a polygenic score (PGS) was created using the same ‘complement’ gene-set, for genes associated with IQ. This PGS was tested for an association with cognition in a dataset of ~1000 patients with SZ and healthy controls. The ‘complement’ PGS created was found to be positively associated with general cognitive ability, specifically premorbid IQ, whereby higher expression of complement PGS was associated with higher IQ. At a gene-set level, this may suggest that the wider complement pathway is more strongly associated with neurodevelopmental processes important to global cognitive development. Given recent studies of complement genes and cognition in SZ (G Donohoe et al., 2018; G Donohoe, Walters, et al., 2013; C. Zhang, Lv, Fan, Tang, & Yi, 2017) a question remained about the possible relationship between SZ risk genes associated with complement and cognitive function. Complement genes have historically been related to synapse formation (Veerhuis, Nielsen, & Tenner, 2011), and more recently synaptic pruning in SZ (Sekar et al., 2016; Sellgren et al., 2019) thus brain development could be differentially impacted by complement expression. In order to further investigate this, the third study of this thesis examined the differential impact of C4 expression and a polygenic risk score (PRS) for ‘complement’ (using SZ GWAS data) on neurocognitive outcomes. Firstly, this ‘complement’ PRS created using SZ GWAS data was seen to predict memory scores similar to a recent publication on C4 expression by our group (Donohoe, 2018). Thus, we wished to test for a differential relationship between the ‘complement’ PRS and C4 expression levels on brain volume in Irish participants. C4 was not found to be associated with any brain volume measure included. However, the ‘complement’ PRS was found to impact on hippocampal volume measures, albeit nominally. The association between complement genes and brain volume warrants further exploration in SZ patients only. On the whole, the role of the complement system aside from C4 may be relevant to the study of cognitive development as well as SZ pathology. Aspects of the immune system related to SZ incidence may be a joining point between genetics and environment, and both gene and environment influences are seen to impact cognition as well as diagnosis.