RT Journal Article
SR Electronic
T1 Gene expression imputation across multiple brain regions reveals schizophrenia risk throughout development
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 222596
DO 10.1101/222596
A1 Laura M. Huckins
A1 Amanda Dobbyn
A1 Douglas M. Ruderfer
A1 Gabriel Hoffman
A1 Weiqing Wang
A1 Antonio Pardinas
A1 Veera M Rajagopal
A1 Thomas D. Als
A1 Hoang Nguyen
A1 Kiran Girdhar
A1 James Boocock
A1 Panos Roussos
A1 Menachem Fromer
A1 Robin Kramer
A1 Enrico Domencini
A1 Eric Gamazon
A1 Shaun Purcell
A1 CommonMind Consortium, the Schizophrenia Working Group of the Psychiatric Genomics Consortium, iPSYCH-GEMS Schizophrenia Working Group, Ditte Demontis
A1 Anders D. Børglum
A1 James Walters
A1 Michael O’Donovan
A1 Patrick Sullivan
A1 Michael Owen
A1 Bernie Devlin
A1 Solveig K. Sieberts
A1 Nancy Cox
A1 Hae Kyung Im
A1 Pamela Sklar
A1 Eli A. Stahl
YR 2017
UL http://biorxiv.org/content/early/2017/11/21/222596.abstract
AB Transcriptomic imputation approaches offer an opportunity to test associations between disease and gene expression in otherwise inaccessible tissues, such as brain, by combining eQTL reference panels with large-scale genotype data. These genic associations could elucidate signals in complex GWAS loci and may disentangle the role of different tissues in disease development. Here, we use the largest eQTL reference panel for the dorso-lateral pre-frontal cortex (DLPFC), collected by the CommonMind Consortium, to create a set of gene expression predictors and demonstrate their utility. We applied these predictors to 40,299 schizophrenia cases and 65,264 matched controls, constituting the largest transcriptomic imputation study of schizophrenia to date. We also computed predicted gene expression levels for 12 additional brain regions, using publicly available predictor models from GTEx. We identified 413 genic associations across 13 brain regions. Stepwise conditioning across the genes and tissues identified 71 associated genes (67 outside the MHC), with the majority of associations found in the DLPFC, and of which 14/67 genes did not fall within previously genome-wide significant loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple pathways associated with porphyric disorders. We investigated developmental expression patterns for all 67 non-MHC associated genes using BRAINSPAN, and identified groups of genes expressed specifically pre-natally or post-natally.