@article{791f061713e64dc39cd8a10a69036388,
title = "Regional Heterogeneity in Gene Expression, Regulation, and Coherence in the Frontal Cortex and Hippocampus across Development and Schizophrenia",
abstract = "The hippocampus formation, although prominently implicated in schizophrenia pathogenesis, has been overlooked in large-scale genomics efforts in the schizophrenic brain. We performed RNA-seq in hippocampi and dorsolateral prefrontal cortices (DLPFCs) from 551 individuals (286 with schizophrenia). We identified substantial regional differences in gene expression and found widespread developmental differences that were independent of cellular composition. We identified 48 and 245 differentially expressed genes (DEGs) associated with schizophrenia within the hippocampus and DLPFC, with little overlap between the brain regions. 124 of 163 (76.6%) of schizophrenia GWAS risk loci contained eQTLs in any region. Transcriptome-wide association studies in each region identified many novel schizophrenia risk features that were brain region-specific. Last, we identified potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia and offer new insights into potentially causative biology. Collado-Torres et al. describe the BrainSeq Phase II gene expression resource encompassing two brain regions from 551 genotyped individuals spanning the entire human lifespan (286 with schizophrenia). This resource can answer region-specific questions about development and schizophrenia and its genetic risk.",
keywords = "RNA-seq, TWAS, brain, development, eQTL, human, regional coherence, schizophrenia",
author = "{BrainSeq Consortium} and Leonardo Collado-Torres and Burke, {Emily E.} and Amy Peterson and Shin, {Joo Heon} and Straub, {Richard E.} and Anandita Rajpurohit and Semick, {Stephen A.} and Ulrich, {William S.} and Price, {Amanda J.} and Cristian Valencia and Ran Tao and Amy Deep-Soboslay and Hyde, {Thomas M.} and Kleinman, {Joel E.} and Weinberger, {Daniel R.} and Jaffe, {Andrew E.}",
note = "Funding Information: The authors would like to express their gratitude to our colleagues whose tireless efforts have led to the donation of postmortem tissue to advance these studies: the Office of the Chief Medical Examiner of the District of Columbia; the Office of the Chief Medical Examiner for Northern Virginia, Fairfax Virginia; and the Office of the Chief Medical Examiner of the State of Maryland, Baltimore, Maryland. We would also like to acknowledge Llewellyn B. Bigelow, MD, for his diagnostic expertise. We also 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. Finally, we are indebted to the generosity of the families of the decedents, who donated the brain tissue used in these studies. This project was supported by the Lieber Institute for Brain Development, the BrainSeq Consortium, and partially by NIH R21-MH109956-01 (to A.E.J.). We would like to thank the GTEx consortium. The data used for the analyses described in this manuscript were obtained from dbGaP accession number phs000424.v6.p1 on October 6, 2015. Conceptualization, L.C.-T. R.E.S. BrainSeq Consortium, T.M.H. J.E.K. D.R.W. and A.E.J.; Methodology, L.C.-T. R.E.S. D.R.W. and A.E.J.; Software, L.C.-T. and E.E.B.; Formal Analysis, L.C.-T. E.E.B. A.P. S.A.S. C.V. and A.E.J.; Investigation, J.H.S. R.A. A.J.P. R.T. and T.M.H.; Data Curation, A.D.-S. and J.E.K.; Writing – Original Draft, L.C.-T. E.E.B. and A.E.J.; Writing – Review & Editing, L.C.-T. D.R.W. and A.E.J.; Visualization, L.C.-T. E.E.B. S.A.S. and W.S.U.; Supervision, L.C.-T. J.H.S. R.E.S. T.M.H. J.E.K. D.R.W. and A.E.J.; Project Administration, BrainSeq Consortium; Funding Acquisition, BrainSeq Consortium, D.R.W. and A.E.J. The following BrainSeq Consortium members have competing interests. M.M. T.S. K.T. and D.J.H. are employees of Astellas Pharma. N.J.B. and A.J.C. are employees of AstraZeneca. D.A.C. J.N.C. C.L.A.R. B.J.E. P.J.E. D.C.A. Y. Li, Y. Liu, K.M. B.B.M. J.E.S. and H.W. are employees of Eli Lilly and Company. M.F. D.H. and H.K. are employees of Janssen Research & Development LLC and Johnson and Johnson. M.D. and L.F. are employees of H. Lundbeck A/S. T.K.-T. and D.M. are employees of F. Hoffmann-La Roche. P.O. S.X. and J.Q. are former employees of Pfizer. Funding Information: The authors would like to express their gratitude to our colleagues whose tireless efforts have led to the donation of postmortem tissue to advance these studies: the Office of the Chief Medical Examiner of the District of Columbia; the Office of the Chief Medical Examiner for Northern Virginia, Fairfax Virginia; and the Office of the Chief Medical Examiner of the State of Maryland, Baltimore, Maryland. We would also like to acknowledge Llewellyn B. Bigelow, MD, for his diagnostic expertise. We also 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. Finally, we are indebted to the generosity of the families of the decedents, who donated the brain tissue used in these studies. This project was supported by the Lieber Institute for Brain Development , the BrainSeq Consortium , and partially by NIH R21-MH109956-01 (to A.E.J.). We would like to thank the GTEx consortium. The data used for the analyses described in this manuscript were obtained from dbGaP accession number phs000424.v6.p1 on October 6, 2015. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = jul,
day = "17",
doi = "10.1016/j.neuron.2019.05.013",
language = "English (US)",
volume = "103",
pages = "203--216.e8",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "2",
}