title: Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder.
abstract: Schizophrenia (SCZ) and bipolar disorder (BPD) are severe mental disorders with high heritability. Clinicians have long noticed the similarities of clinic symptoms between these disorders. In recent years, accumulating evidence indicates some shared genetic liabilities. However, what is shared remains elusive. In this study, we conducted whole transcriptome analysis of post-mortem brain tissues (cingulate cortex) from SCZ, BPD and control subjects, and identified differentially expressed genes in these disorders. We found 105 and 153 genes differentially expressed in SCZ and BPD, respectively. By comparing the t-test scores, we found that many of the genes differentially expressed in SCZ and BPD are concordant in their expression level (q⩽0.01, 53 genes; q⩽0.05, 213 genes; q⩽0.1, 885 genes). Using genome-wide association data from the Psychiatric Genomics Consortium, we found that these differentially and concordantly expressed genes were enriched in association signals for both SCZ (P<10(-7)) and BPD (P=0.029). To our knowledge, this is the first time that a substantially large number of genes show concordant expression and association for both SCZ and BPD. Pathway analyses of these genes indicated that they are involved in the lysosome, Fc gamma receptor-mediated phagocytosis, regulation of actin cytoskeleton pathways, along with several cancer pathways. Functional analyses of these genes revealed an interconnected pathway network centered on lysosomal function and the regulation of actin cytoskeleton. These pathways and their interacting network were principally confirmed by an independent transcriptome sequencing data set of the hippocampus. Dysregulation of lysosomal function and cytoskeleton remodeling has direct impacts on endocytosis, phagocytosis, exocytosis, vesicle trafficking, neuronal maturation and migration, neurite outgrowth and synaptic density and plasticity, and different aspects of these processes have been implicated in SCZ and BPD.
authors.affiliation: Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Beijing Genomics Institute (BGI), Shenzhen, Guangdong, 518083, China.
authors.forename: Jiabao
authors.initials: J
authors.lastname: Xu
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Stanley Laboratory of Brain Research, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Sanghyeon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Reimers
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Silviu-Alin
authors.initials: SA
authors.lastname: Bacanu
authors.affiliation: Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60637, USA.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Sun
authors.affiliation: Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Peilin
authors.initials: P
authors.lastname: Jia
authors.affiliation: Beijing Genomics Institute (BGI), Shenzhen, Guangdong, 518083, China.
authors.forename: Fengping
authors.initials: F
authors.lastname: Xu
authors.affiliation: Beijing Genomics Institute (BGI), Shenzhen, Guangdong, 518083, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.affiliation: Beijing Genomics Institute (BGI), Shenzhen, Guangdong, 518083, China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Chen
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics* / Q000378:metabolism; D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008247:Lysosomes / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D015999:Multivariate Analysis; D017510:Protein Folding; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D013223:Statistics as Topic
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