Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms

Tissue-specific regulatory regions harbor substantial genetic risk for disease. Because brain development is a critical epoch for neuropsychiatric disease susceptibility, we characterized the genetic control of the transcriptome in 201 mid-gestational human brains, identifying 7,962 expression quantitative trait loci (eQTL) and 4,635 spliceQTL (sQTL), including several thousand prenatal-specific regulatory regions. We show that significant genetic liability for neuropsychiatric disease lies within prenatal eQTL and sQTL. Integration of eQTL and sQTL with genome-wide association studies (GWAS) via transcriptome-wide association identified dozens of novel candidate risk genes, highlighting shared and stage-specific mechanisms in schizophrenia (SCZ). Gene network analysis revealed that SCZ and autism spectrum disorder (ASD) affect distinct developmental gene co-expression modules. Yet, in each disorder, common and rare genetic variation converges within modules, which in ASD implicates superficial cortical neurons. More broadly, these data, available as a web browser and our analyses, demonstrate the genetic mechanisms by which developmental events have a widespread influence on adult anatomical and behavioral phenotypes. [Display omitted] •We identify eQTLs and sQTLs specific to human prenatal brain development•Regulation of expression and splicing differs substantially across development•Distinct relationships exist between expression, splicing, and disease risk•Variation in splicing carries as much, if not more, disease risk than expression An atlas of expression and splice quantitative trait loci from mid-gestational human brain is integrated with genetic risk for schizophrenia, suggesting additional causal genes and highlighting the importance of QTL datasets derived from developmental stages most relevant to disease initiation.