Genetics of cell-type-specific gene regulation and drug-sensitive cellular phenotypes during human neurogenesis

To interpret the function of genetic variants associated with neuropsychiatric disorders and inter-individual variation in other brain-relevant traits, expression quantitative trait loci (eQTL) analysis is commonly performed in adult brain bulk tissue. However, genetic variants associated with brain-relevant traits detected in genome-wide association studies (GWASs) are enriched in regulatory regions which are functional during development. Moreover, the heterogeneity of bulk tissue may mask the regulatory effect of these loci. Furthermore, not all GWAS loci are explained by eQTLs, which led to the coining of the term “missing regulation”. To this end, studying QTLs for other gene regulatory phenotypes including alternative splicing, RNA-editing and alternative polyadenylation can be useful. In my dissertation research, I utilized a cell-type-specific system including two major cell-types of the developing human brain as progenitors (n = 85) and neurons (n = 74). I performed eQTL, splicing QTL (sQTL), RNA-editing (edQTL) and alternative polyadenylation QTL (apaQTL) analyses for each cell-type. Leveraging these molecular QTLs with brain-relevant trait GWASs via colocalization and transcriptome-wide association study approaches, I proposed cell-type-specific mechanisms driving the brain-relevant traits during development. Furthermore, integrating eQTLs with caQTLs derived from the same cell-type-specific system, I identified regulatory regions mediating the expression of the genes. Finally, applying recent pharmacogenomics in a dish approach allowing performing a cellular trait GWAS, I identified genetic variants associated with drug-sensitive cellular phenotypes in progenitors. Taken together, these findings will improve understanding of the risk for neuropsychiatric disorders and inter-individual variation in other brain-relevant traits by proposing essential genetically altered cell-type- and temporal-specific molecular and cellular mechanisms.