RT Journal Article
SR Electronic
T1 Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 585430
DO 10.1101/585430
A1 Donna M. Werling
A1 Sirisha Pochareddy
A1 Jinmyung Choi
A1 Joon-Yong An
A1 Brooke Sheppard
A1 Minshi Peng
A1 Zhen Li
A1 Claudia Dastmalchi
A1 Gabriel Santpere
A1 Andre M. M. Sousa
A1 Andrew T. N. Tebbenkamp
A1 Navjot Kaur
A1 Forrest O. Gulden
A1 Michael S. Breen
A1 Lindsay Liang
A1 Michael C. Gilson
A1 Xuefang Zhao
A1 Shan Dong
A1 Lambertus Klei
A1 A. Ercument Cicek
A1 Joseph D. Buxbaum
A1 Homa Adle-Biassette
A1 Jean-Leon Thomas
A1 Kimberly A. Aldinger
A1 Diana R. O’Day
A1 Ian A. Glass
A1 Noah A. Zaitlen
A1 Michael E. Talkowski
A1 Kathryn Roeder
A1 Matthew W. State
A1 Bernie Devlin
A1 Stephan J. Sanders
A1 Nenad Sestan
YR 2019
UL http://biorxiv.org/content/early/2019/03/22/585430.abstract
AB Variation in gene expression underlies neurotypical development, while genomic variants contribute to neuropsychiatric disorders. BrainVar is a unique resource of paired whole-genome sequencing and bulk-tissue RNA-sequencing from the human dorsolateral prefrontal cortex of 176 neurotypical individuals across prenatal and postnatal development, providing the opportunity to assay genomic and transcriptomic variation in tandem. Leveraging this resource, we identified rare premature stop codons with commensurate reduced and allele-specific expression of corresponding genes, and common variants that alter gene expression (expression quantitative trait loci, eQTLs). Categorizing eQTLs by prenatal and postnatal effect, genes affected by temporally-specific eQTLs, compared to constitutive eQTLs, are enriched for haploinsufficiency, protein-protein interactions, and neuropsychiatric disorder risk loci. Expression levels of over 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell type specific genes and neuropsychiatric disorder loci, underscoring the importance of cataloguing developmental trajectories in understanding cortical physiology and pathology.HighlightsWhole-genome and RNA-sequencing across human prefrontal cortex development in BrainVarGene-specific developmental trajectories characterize the late-fetal transitionIdentification of constitutive, prenatal-specific, postnatal-specific, and rare eQTLsIntegrated analysis reveals genetic and developmental influences on CNS traits and disorders