Genome-wide association studies have identified 108 schizophrenia risk loci, but biological mechanisms for individual loci are largely unknown. Using developmental, genetic and illness-based RNA sequencing expression analysis in human brain, 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 postnatal life. We found widespread expression quantitative trait loci (eQTLs), including many with transcript specificity and previously unannotated sequence that were independently replicated. We leveraged this general eQTL database to show that 48.1% of risk variants for schizophrenia associate with nearby expression. We lastly found 237 genes significantly differentially expressed between patients and controls, which replicated in an independent dataset, implicated synaptic processes, and were strongly regulated in early development. These findings together offer genetics- and diagnosis-related targets for better modeling of schizophrenia risk. This resource is publicly available at http://eqtl.brainseq.org/phase1.
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We thank R. Zielke, R. D. Vigorito and R. M. Johnson of the National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland for providing fetal, child and adolescent brain specimens. This work was supported by the funding from Lieber Institute for Brain Development and the Maltz Research Laboratories and partially supported by NIH R21MH109956 (A.E.J.) and Consejo Nacional de Ciencia y Tecnología México 351535 (L.C.-T.). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI/SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171) and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to the Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grants DA006227 and DA033684 and to contract N01MH000028. Statistical methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina - Chapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810) and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from dbGaP accession number phs000424.v6.p1 on October 6, 2015. Data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, R01-MH-075916, P50M096891, P50MH084053S1, R37MH057881, R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC leadership: Pamela Sklar and Joseph Buxbaum (Icahn School of Medicine at Mount Sinai), Bernie Devlin and David Lewis (University of Pittsburgh), Raquel Gur and Chang-Gyu Hahn (University of Pennsylvania), Keisuke Hirai and Hiroyoshi Toyoshiba (Takeda Pharmaceuticals Company Limited), Enrico Domenici and Laurent Essioux (F. Hoffman-La Roche Ltd), Lara Mangravite and Mette Peters (Sage Bionetworks), and Thomas Lehner and Barbara Lipska (NIMH).
Members of the BrainSeq consortium include: Christian R. Schubert, Patricio O’Donnell, Jie Quan, Jens R. Wendland, Hualin S. Xi, Ashley R. Winslow, Enrico Domenici, Dheeraj Malhotra, Laurent Essioux, Tony Kam-Thong, David C. Airey, John N. Calley, David A. Collier, Hong Wang, Brian Eastwood, Philip Ebert, Yushi Liu, Laura Nisenbaum, Cara Ruble, James Scherschel, Ryan Matthew Smith, Hui-Rong Qian, Kalpana Merchant, Michael Didriksen, Mitsuyuki Matsumoto, Takeshi Saito, Nicholas J. Brandon, Alan J. Cross, Qi Wang, Husseini Manji, Hartmuth Kolb, Maura Furey, Wayne C. Drevets, Joo Heon Shin, Andrew E. Jaffe, Rujuta Narurkar, Yankai Jia, Richard E. Straub, Amy Deep-Soboslay, Thomas M. Hyde, Joel E. Kleinman and Daniel R. Weinberger.
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