Evaluating disorders of cognition using integrative genomics

Abstract

Integrative genomics embodies a collaborative approach that brings together various disciplines, merging genomic and computational methodologies to achieve a comprehensive understanding of complex biological systems. By integrating and analysing various omics datasets, researchers can uncover novel insights into biological processes, disease mechanisms, and molecular interactions.

This thesis applies integrative genomic approaches to study the biological mechanisms of cognitive disorders resulting from neurodegenerative and neurodevelopmental impairments. It includes three studies utilising transcriptomic profiling to identify and assess these mechanisms. The final discussion chapter summarises the main findings, including shared and distinct mechanisms across different cognitive disorders, addressing technical limitations, and outlining future research directions.

The first study focuses on Lewy body diseases, utilising single-nucleus transcriptomics. Differential expression analysis reveals widespread dysregulation in neurons and glial cell types, with similar gene expression profiles observed in Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB), while Parkinson’s Disease (PD) shows distinct transcriptional profiles. Heritability enrichment analysis highlights a genetic association between glial cell dysregulation and PD age of onset. A unique population of neurons associated with DLB, resembling medium spiny neurons, is also identified. The second study investigates early-stage abnormal tau species-related gene expression changes in Alzheimer’s Disease (AD). Analysis of gene expression at the single-cell level demonstrates distinct patterns between Tau-proximity Ligation Assay (tauPLA) positive and tauPLA negative brain tissues. Dysregulation of genes in various cell-types in tauPLA positive samples is observed in the absence of neurofibrillary tangles. Reactive astrocyte activation, even in the absence of neurofibrillary tangles, is also reported for the first time in a transcriptomic-based study, suggesting their role in AD progression.

The third study examines the neurodevelopmental outcomes of valproate exposure. Transcriptomic analysis reveals significant gene expression changes in the brains of gestationally exposed pups, affecting synaptic function, neurodevelopment, and genes associated with schizophrenia, bipolar disorder, and IQ heritability. Differential splicing analysis suggests enduring effects on brain function through epigenetic encoding.

Convergent and divergent mechanisms underlying various neurodegenerative disorders are identified across the studies, including pathways related to axonal degeneration, mRNA splicing, synaptic organisation, autophagy, neuron death, phosphorylation, memory, mitochondrial function, and vesicle-mediated transport regulation.

This thesis contributes to understanding the biological basis of cognitive disorders through integrative genomic approaches, providing insights into shared and distinct mechanisms across different disorders. The findings have implications for the development of therapeutic interventions and underscore the importance of rigorous experimental design in transcriptomic investigations. Future research directions are outlined to further unravel the complex molecular mechanisms underlying cognitive disorders.