Trabzuni, D; (2013) The role of genetic variations on gene expression and splicing in control human brain: dissection of the aetiology of complex neurological diseases. Doctoral thesis , UCL (University College London).

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Abstract

Over the past two decades there has been a realization of the importance of understanding the underlying molecular mechanism of complex neurological diseases. GWAS studies confirmed a significant association between SNPs and complex neurologic and psychiatric diseases such as Parkinson’s disease and Alzheimer’s disease. In this project, the impact of genetic variations on gene expression and alternative splicing in control post-mortem human brain tissues from twelve different regions were assessed. These are disease associated regions and support different functional roles. They are: frontal cortex, temporal cortex, occipital cortex, white matter, hippocampus, thalamus, hypothalamus, putamen, substantia nigra, medulla, cerebellum and spinal cord. Based on 1231 RNA human exon arrays, genotyped and imputed DNA samples from 137 control human brain, brain transcriptome profiles, gene and exon expression quantitative trait loci (QTL) were identified in multiple brain regions. Significant region-specific exon and gene expression QTLs were reported. Cerebellum and white matter show more unique expression profiles and expression QTLs in comparison with other brain regions. Furthermore, alternative splicing patterns were in a specific group of regions such as the cortical regions. In addition, two neurodegenerative disease related genes were investigated in detail, namely LRRK2 and MAPT. Significant regional differences in expression at mRNA and protein levels were shown. Moreover, exon QTLs correlated with the expression of specific exons located in functional protein domains of LRRK2. Also, an exon QTL has been found that shows a protective effect against Parkinson’s disease with an increase in the inclusion of exon 3 in grey matter for MAPT. This study has yielded novel regional specific expression QTLs and novel insights into the expression, regulation and function of specific genes in different regions of control human brain that are related to neurological diseases. This reference dataset is a valuable resource to complement other datasets for research into the complex genetics of neurological diseases.

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