Genetic control of gene expression and splicing in the developing human brain

Summary Most genetic risk for human diseases lies within non-coding regions of the genome, which is predicted to regulate gene expression, often in a tissue and stage specific manner. This has motivated building of extensive eQTL resources to understand how human allelic variation affects gene expression and splicing throughout the body, focusing primarily on adult tissue. Given the importance of regulatory pathways during brain development, we characterize the genetic control of the developing human cerebral cortical transcriptome, including expression and splicing, in 201 mid-gestational human brains, to understand how common allelic variation affects gene regulation during development. We leverage expression and splice quantitative trait loci to identify genes and isoforms relevant to neuropsychiatric disorders and brain volume. These findings demonstrate genetic mechanisms by which early developmental events have a striking and widespread influence on adult anatomical and behavioral phenotypes, as well as the evolution of the human cerebral cortex. Highlights Genome wide map of human fetal brain eQTLs and sQTLs provides a new view of genetic control of expression and splicing. There is substantial contrast between genetic control of transcript regulation in mature versus developing brain. We identify novel regulatory regions specific to fetal brain development. Integration of eQTLs and GWAS reveals specific relationships between expression and disease risk for neuropsychiatric diseases and relevant human brain phenotypes.