1/2 Identification and Validation of Expression Quantitative Trait Loci (eQTLs) in discrete cell types across human brain development

ABSTRACT Functional genomic analyses of the developing human brain have revealed highly dynamic spatiotemporal patterns of gene expression and epigenetic changes during prenatal and early postnatal development and across brain regions. Disruptions of these developmentally dynamic processes have been implicated by numerous

complementary analyses in the etiology of multiple neurodevelopmental and neuropsychiatric disorders. Expression quantitative trait loci (eQTLs), along with splicing quantitative trait loci (sQTLs) and structural variant quantitative trait loci (svQTLs), are genomic variants that differ between individuals, with these differences

correlating with functional changes to gene expression or splicing behavior. Many of these QTLs show specificity to tissues, brain regions, developmental stages, or cell types, and a proportion overlap with known genetic risk factors of human disorders. Here, we propose to pursue three integrated Aims, including whole-genome

sequencing and both bulk tissue and single-nuclei RNA sequencing, to identify genomic variants, eQTL/sQTL/svQTLs, and patterns of gene expression and co-expression in two regions of the human brain across mid-fetal development through to adolescence. In addition, we will apply novel and newly developed

computational tools to associate these QTLs with specific cell types and loci or genes implicated in neuropsychiatric disorders. By so doing we will augment, and dramatically expand upon, earlier efforts to understand QTLs and their roles in neural development, function, and neuropsychiatric disorders.