Title: Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex
Legend: Common Variant cis-eQTLs – (A) Prenatal (x axis) and postnatal (y axis) effects for the eQTLs with the smallest p value for 8,421 eGenes (points). The eQTLs are split into five categories based on temporal predominance using effect size and statistical thresholds; categories are represented by color. (B-D) Characteristics of non-eGenes, temporal-predominant eGenes, and disorder-associated genes are shown by plotting the (E) proportion of coding and noncoding genes, (F) proportion of genes with pLI scores in different bins, and (G) BioGRID protein-protein interactions (permuted Z scores from Ripley’s K-net function; Cornish and Markowetz, 2014; the black line is the non-eGene median). (E) Density plot of the distance of top eQTLs per eGene from the transcription start site by eGene temporal category. TSS, transcription start site; Statistical analysis: (D) and (E), two-sided WRST test for constant versus other eGenes; (E) and (F), two-sided FET for constant versus other eGenes;
Citation: Werling DM, Pochareddy S, Choi J, An JY, Sheppard B, Peng M, Li Z, Dastmalchi C, Santpere G, Sousa AMM, et al. (2020). Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex. Cell Reports, 31(1):107489. doi: 10.1016/j.celrep.2020.03.053.
Abstract: Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and post-natal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both “constant” and “temporal-predominant” eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology.
About the Lab: Donna Werling is interested in characterizing sex-differential risk mechanisms in autism spectrum disorder (ASD). During her doctoral work in the laboratory of Dan Geschwind at the University of California, Los Angeles, Werling used functional genomics, human genetics and bioinformatics approaches to understand the relationship between sex and genetic risk in ASD.