Regional Heterogeneity in Gene Expression, Regulation, and Coherence in the Frontal Cortex and Hippocampus across Development and Schizophrenia

Leonardo Collado-Torres; Emily E Burke; Amy Peterson; JooHeon Shin; Richard E Straub; Anandita Rajpurohit; Stephen A Semick; William S Ulrich; BrainSeq Consortium; Amanda J Price; Cristian Valencia; Ran Tao; Amy Deep-Soboslay; Thomas M Hyde; Joel E Kleinman; Daniel R Weinberger; Andrew E Jaffe

doi:10.1016/j.neuron.2019.05.013

Regional Heterogeneity in Gene Expression, Regulation, and Coherence in the Frontal Cortex and Hippocampus across Development and Schizophrenia

Neuron. 2019 Jul 17;103(2):203-216.e8. doi: 10.1016/j.neuron.2019.05.013. Epub 2019 Jun 4.

Authors

Leonardo Collado-Torres¹, Emily E Burke², Amy Peterson³, JooHeon Shin², Richard E Straub², Anandita Rajpurohit², Stephen A Semick², William S Ulrich²; BrainSeq Consortium; Amanda J Price⁴, Cristian Valencia³, Ran Tao², Amy Deep-Soboslay², Thomas M Hyde⁵, Joel E Kleinman⁶, Daniel R Weinberger⁷, Andrew E Jaffe⁸

Affiliations

¹ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; Center for Computational Biology, Johns Hopkins University, Baltimore, MD 21205, USA.
² Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA.
³ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
⁴ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
⁶ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
⁷ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address: drweinberger@libd.org.
⁸ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; Center for Computational Biology, Johns Hopkins University, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Electronic address: andrew.jaffe@libd.org.

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.

Keywords: RNA-seq; TWAS; brain; development; eQTL; human; regional coherence; schizophrenia.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Female
Frontal Lobe* / embryology
Frontal Lobe* / growth & development
Frontal Lobe* / metabolism
Gene Expression Regulation, Developmental / physiology*
Gene Ontology
Genetic Predisposition to Disease
Genome-Wide Association Study
Hippocampus* / embryology
Hippocampus* / growth & development
Hippocampus* / metabolism
Humans
Male
Middle Aged
Schizophrenia / genetics*
Schizophrenia / pathology*
Young Adult

Grants and funding

R21 MH109956/MH/NIMH NIH HHS/United States