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MicroRNA expression in the developing human brain and its role in neuropsychiatric disorders

Toste, Carolina 2022. MicroRNA expression in the developing human brain and its role in neuropsychiatric disorders. PhD Thesis, Cardiff University.
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Foetal brain development is a critical period for future brain function where highly dynamic gene expression patterns give rise to the cellular diversity and complexity of the human brain. As a consequence, this is also likely to be an important period of vulnerability for neurodevelopmental and neuropsychiatric disorders. microRNAs (miRNAs) are a class of small noncoding RNA molecules with a prominent role in shaping and fine-tuning gene expression. In this thesis, I have used small-RNA sequencing to evaluate how variation in miRNA expression in 2nd trimester foetal brain might contribute to risk for neuropsychiatric disorders. I detected 1449 miRNAs in 2nd trimester foetal brain (corresponding to 55% of all known miRNAs) and assessed the effects of sex and gestational age on miRNA expression. Combining these data with genome-wide genotyping, I performed an eQTL analysis and identified 30 miRNAs where expression is associated with common genetic variation (miR-eQTLs) at FDR < 0.05. Finally, I related the identified miR-eQTLs to neuropsychiatric disorders and other brain traits using summary data-based Mendelian randomization. I identified 3 miRNAs for which eQTL are pleiotropically, and potentially causally associated with psychiatric traits. The A-allele of rs112622797 and the A-allele of rs12880925 were associated with higher miR-6840- 5p and miR-4707-3p expression respectively, and both alleles were associated with decreased adult brain volume. The C-allele of rs174561 was associated with increased miR-1908-5p expression and increased risk for bipolar disorder, increased irritability, and increased sleep duration. Predicted gene targets of miR-1908-5p were also found to be enriched for genetic association with bipolar disorder. Further dissecting this association may translate to more effective treatments and a better quality of life for affected individuals.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 13 April 2023
Last Modified: 13 Apr 2024 01:30

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