RT Journal Article
SR Electronic
T1 Developmental and genetic regulation of the human cortex transcriptome in schizophrenia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 124321
DO 10.1101/124321
A1 Andrew E Jaffe
A1 Richard E Straub
A1 Joo Heon Shin
A1 Ran Tao
A1 Yuan Gao
A1 Leonardo Collado Torres
A1 Tony Kam-Thong
A1 Hualin S Xi
A1 Jie Quan
A1 Qiang Chen
A1 Carlo Colantuoni
A1 Bill Ulrich
A1 Brady J. Maher
A1 Amy Deep-Soboslay
A1 The BrainSeq Consortium
A1 Alan Cross
A1 Nicholas J. Brandon
A1 Jeffrey T Leek
A1 Thomas M. Hyde
A1 Joel E. Kleinman
A1 Daniel R Weinberger
YR 2017
UL http://biorxiv.org/content/early/2017/04/05/124321.abstract
AB GWAS have identified over 108 loci that confer risk for schizophrenia, but risk mechanisms for individual loci are largely unknown. Using developmental, genetic, and illness-based RNA sequencing expression analysis, we characterized the human brain transcriptome around these loci and found enrichment for developmentally regulated genes with novel examples of shifting isoform usage across pre- and post-natal life. Within patients and controls, we implemented a novel algorithm for RNA quality adjustment, and identified 237 genes significantly associated with diagnosis that replicated in an independent case-control dataset. These genes implicated synaptic processes and were strongly regulated in early development (p < 10−20). Lastly, we found 42.5% of risk variants associate with nearby genes and diverse transcript features that converge on developmental regulation and subsequent dysregulation in illness and 34 loci show convergent directionality with illness association implicating specific causative transcripts. These data offer new targets for modeling schizophrenia risk in cellular systems.