2/2 - 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.
