Genetic Variants Regulating MicroRNA Expression in the Developing Human Neocortex

Genome-wide association studies (GWAS) have revealed several genomic loci associated with risk for neuropsychiatric disorders and brain-related traits, but for many of these loci, the causal mechanisms are unknown. Using expression quantitative trait loci (eQTL) data, many of the risk loci can be linked to protein-coding genes or long non-coding RNAs. However, the mechanism underlying a significant proportion of loci remain unexplained. MicroRNAs (miRNAs) are poorly measured in standard eQTL studies yet have important influences on neurogenesis and have been found to be differentially expressed in brain tissue from patients with neuropsychiatric disorders. By linking miRNA-eQTLs to previously defined mRNA-eQTLs and genome-wide significant loci for brain traits, I aimed to reveal causal mechanisms by which common genetic variation influences gene regulation and inter-individual differences in brain-related traits. Additionally, I sought to find evidence for novel early brain-expressed miRNAs and define an expanded set of miRNAs associated with human neocortical neurogenesis and neuron maturity. Here, in 212 mid-gestation neocortical tissue samples, I profiled expression of 907 miRNAs, discovering 111 novel miRNAs and identified 85 local-miRNA-eQTLs. Colocalization of miRNA-eQTLs with GWAS summary statistics yielded one robust colocalization of miR-4707-3p expression with educational attainment and head size phenotypes, where the miRNA expression increasing allele was associated with decreased head size. After increasing expression of miR-4707-3p in primary human neural progenitor cultures and their differentiated progeny, I detected an increase in both proliferative and neurogenic gene markers by qPCR and ICC assays, implying an early cell-cycle exit and an increase in neurogenic divisions. Using 17 neocortical tissue samples micro-dissected into progenitor rich germinal zone and neuron rich cortical plate, I identified 504 miRNAs associated with neurogenesis or neuron maturity. Finally, I was able to prioritize these neurogenesis associated miRNAs by looking at the differential expression of their predicted mRNA targets. In summary, this work shows how miRNA-eQTLs and neurogenesis associated miRNAs in developing neocortical tissue yielded insight into the causal mechanisms by which genetic variants influence brain traits.Doctor of Philosoph