Transcriptome study of differential expression in schizophrenia

Alan R. Sanders, Harald H H Göring, Jubao Duan, Eugene I. Drigalenko, Winton Moy, Jessica Freda, Deli He, Jianxin Shi, Pablo V. Gejman

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Schizophrenia genome-wide association studies (GWAS) have identified common SNPs, rare copy number variants (CNVs) and a large polygenic contribution to illness risk, but biological mechanisms remain unclear. Bioinformatic analyses of significantly associated genetic variants point to a large role for regulatory variants. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines (LCLs) from 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate (FDR) of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, microRNA (miRNA) processing and immunity. This functional diversity is consistent with schizophrenia's likely significant pathophysiological heterogeneity. The overall enrichment of immune-related genes among those differentially expressed by affection status is consistent with hypothesized immune contributions to schizophrenia risk. The observed differential expression of extended major histocompatibility complex (xMHC) region histones (HIST1H2BD, HIST1H2BC, HIST1H2BH, HIST1H2BG and HIST1H4K) converges with the genetic evidence from GWAS, which find the xMHC to be the most significant susceptibility locus. Among the differentially expressed immune-related genes, B3GNT2 is implicated in autoimmune disorders previously tied to schizophrenia risk (rheumatoid arthritis and Graves' disease), and DICER1 is pivotal in miRNA processing potentially linking to miRNA alterations in schizophrenia (e.g. MIR137, the second strongest GWAS finding). Our analysis provides novel candidate genes for further study to assess their potential contribution to schizophrenia.

Original languageEnglish (US)
Article numberddt350
Pages (from-to)5001-5014
Number of pages14
JournalHuman Molecular Genetics
Volume22
Issue number24
DOIs
StatePublished - Dec 2013
Externally publishedYes

Fingerprint

Transcriptome
Schizophrenia
Genome-Wide Association Study
MicroRNAs
Genes
Genome
cdc Genes
Graves Disease
Computational Biology
Major Histocompatibility Complex
Synaptic Transmission
Histones
Single Nucleotide Polymorphism
Immunity
Rheumatoid Arthritis
Regression Analysis
Apoptosis
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Sanders, A. R., Göring, H. H. H., Duan, J., Drigalenko, E. I., Moy, W., Freda, J., ... Gejman, P. V. (2013). Transcriptome study of differential expression in schizophrenia. Human Molecular Genetics, 22(24), 5001-5014. [ddt350]. https://doi.org/10.1093/hmg/ddt350

Transcriptome study of differential expression in schizophrenia. / Sanders, Alan R.; Göring, Harald H H; Duan, Jubao; Drigalenko, Eugene I.; Moy, Winton; Freda, Jessica; He, Deli; Shi, Jianxin; Gejman, Pablo V.

In: Human Molecular Genetics, Vol. 22, No. 24, ddt350, 12.2013, p. 5001-5014.

Research output: Contribution to journalArticle

Sanders, AR, Göring, HHH, Duan, J, Drigalenko, EI, Moy, W, Freda, J, He, D, Shi, J & Gejman, PV 2013, 'Transcriptome study of differential expression in schizophrenia', Human Molecular Genetics, vol. 22, no. 24, ddt350, pp. 5001-5014. https://doi.org/10.1093/hmg/ddt350
Sanders AR, Göring HHH, Duan J, Drigalenko EI, Moy W, Freda J et al. Transcriptome study of differential expression in schizophrenia. Human Molecular Genetics. 2013 Dec;22(24):5001-5014. ddt350. https://doi.org/10.1093/hmg/ddt350
Sanders, Alan R. ; Göring, Harald H H ; Duan, Jubao ; Drigalenko, Eugene I. ; Moy, Winton ; Freda, Jessica ; He, Deli ; Shi, Jianxin ; Gejman, Pablo V. / Transcriptome study of differential expression in schizophrenia. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 24. pp. 5001-5014.
@article{480de24e434c45a083a5f3756ed96caf,
title = "Transcriptome study of differential expression in schizophrenia",
abstract = "Schizophrenia genome-wide association studies (GWAS) have identified common SNPs, rare copy number variants (CNVs) and a large polygenic contribution to illness risk, but biological mechanisms remain unclear. Bioinformatic analyses of significantly associated genetic variants point to a large role for regulatory variants. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines (LCLs) from 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate (FDR) of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, microRNA (miRNA) processing and immunity. This functional diversity is consistent with schizophrenia's likely significant pathophysiological heterogeneity. The overall enrichment of immune-related genes among those differentially expressed by affection status is consistent with hypothesized immune contributions to schizophrenia risk. The observed differential expression of extended major histocompatibility complex (xMHC) region histones (HIST1H2BD, HIST1H2BC, HIST1H2BH, HIST1H2BG and HIST1H4K) converges with the genetic evidence from GWAS, which find the xMHC to be the most significant susceptibility locus. Among the differentially expressed immune-related genes, B3GNT2 is implicated in autoimmune disorders previously tied to schizophrenia risk (rheumatoid arthritis and Graves' disease), and DICER1 is pivotal in miRNA processing potentially linking to miRNA alterations in schizophrenia (e.g. MIR137, the second strongest GWAS finding). Our analysis provides novel candidate genes for further study to assess their potential contribution to schizophrenia.",
author = "Sanders, {Alan R.} and G{\"o}ring, {Harald H H} and Jubao Duan and Drigalenko, {Eugene I.} and Winton Moy and Jessica Freda and Deli He and Jianxin Shi and Gejman, {Pablo V.}",
year = "2013",
month = "12",
doi = "10.1093/hmg/ddt350",
language = "English (US)",
volume = "22",
pages = "5001--5014",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "24",

}

TY - JOUR

T1 - Transcriptome study of differential expression in schizophrenia

AU - Sanders, Alan R.

AU - Göring, Harald H H

AU - Duan, Jubao

AU - Drigalenko, Eugene I.

AU - Moy, Winton

AU - Freda, Jessica

AU - He, Deli

AU - Shi, Jianxin

AU - Gejman, Pablo V.

PY - 2013/12

Y1 - 2013/12

N2 - Schizophrenia genome-wide association studies (GWAS) have identified common SNPs, rare copy number variants (CNVs) and a large polygenic contribution to illness risk, but biological mechanisms remain unclear. Bioinformatic analyses of significantly associated genetic variants point to a large role for regulatory variants. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines (LCLs) from 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate (FDR) of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, microRNA (miRNA) processing and immunity. This functional diversity is consistent with schizophrenia's likely significant pathophysiological heterogeneity. The overall enrichment of immune-related genes among those differentially expressed by affection status is consistent with hypothesized immune contributions to schizophrenia risk. The observed differential expression of extended major histocompatibility complex (xMHC) region histones (HIST1H2BD, HIST1H2BC, HIST1H2BH, HIST1H2BG and HIST1H4K) converges with the genetic evidence from GWAS, which find the xMHC to be the most significant susceptibility locus. Among the differentially expressed immune-related genes, B3GNT2 is implicated in autoimmune disorders previously tied to schizophrenia risk (rheumatoid arthritis and Graves' disease), and DICER1 is pivotal in miRNA processing potentially linking to miRNA alterations in schizophrenia (e.g. MIR137, the second strongest GWAS finding). Our analysis provides novel candidate genes for further study to assess their potential contribution to schizophrenia.

AB - Schizophrenia genome-wide association studies (GWAS) have identified common SNPs, rare copy number variants (CNVs) and a large polygenic contribution to illness risk, but biological mechanisms remain unclear. Bioinformatic analyses of significantly associated genetic variants point to a large role for regulatory variants. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines (LCLs) from 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate (FDR) of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, microRNA (miRNA) processing and immunity. This functional diversity is consistent with schizophrenia's likely significant pathophysiological heterogeneity. The overall enrichment of immune-related genes among those differentially expressed by affection status is consistent with hypothesized immune contributions to schizophrenia risk. The observed differential expression of extended major histocompatibility complex (xMHC) region histones (HIST1H2BD, HIST1H2BC, HIST1H2BH, HIST1H2BG and HIST1H4K) converges with the genetic evidence from GWAS, which find the xMHC to be the most significant susceptibility locus. Among the differentially expressed immune-related genes, B3GNT2 is implicated in autoimmune disorders previously tied to schizophrenia risk (rheumatoid arthritis and Graves' disease), and DICER1 is pivotal in miRNA processing potentially linking to miRNA alterations in schizophrenia (e.g. MIR137, the second strongest GWAS finding). Our analysis provides novel candidate genes for further study to assess their potential contribution to schizophrenia.

UR - http://www.scopus.com/inward/record.url?scp=84888155351&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888155351&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddt350

DO - 10.1093/hmg/ddt350

M3 - Article

C2 - 23904455

AN - SCOPUS:84888155351

VL - 22

SP - 5001

EP - 5014

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 24

M1 - ddt350

ER -