Brain Expressed microRNAs Implicated in Schizophrenia Etiology

Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Inde...

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Published inPloS one Vol. 2; no. 9; p. e873
Main Authors Hansen, Thomas, Olsen, Line, Lindow, Morten, Jakobsen, Klaus D., Ullum, Henrik, Jonsson, Erik, Andreassen, Ole A., Djurovic, Srdjan, Melle, Ingrid, Agartz, Ingrid, Hall, Håkan, Timm, Sally, Wang, August G., Werge, Thomas
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 12.09.2007
Public Library of Science (PLoS)
Subjects
Adult
Analysis
Bioinformatics
Brain
Brain - metabolism
Brain research
Case-Control Studies
Denmark
Development and progression
Diagnostic tests
DNA binding proteins
Etiology
Female
Gene expression
Genes
Genetic aspects
Genetic diversity
Genetic factors
Genetic variance
Genetics
Genetics and Genomics/Genetics of Disease
Genetics and Genomics/Medical Genetics
Genomes
Genotype
Haplotypes
Humans
Informatics
Male
Mental disorders
Metabolism
MicroRNA
MicroRNAs
MicroRNAs - genetics
Middle Aged
miRNA
Neurosciences
Norway
Oxidative stress
Phenotypic variations
Population
Psychiatry
Schizophrenia
Schizophrenia - genetics
Single-nucleotide polymorphism
Studies
Sweden
Transcription factors
Denmark
Norway
Sweden
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Abstract Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia. We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.
AbstractList BACKGROUND: Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. METHODOLOGY/PRINCIPAL FINDINGS: We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia. CONCLUSIONS/SIGNIFICANCE: We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.
Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia. We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.
Background Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. Methodology/Principal Findings We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia. Conclusions/Significance We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.
Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation.BACKGROUNDProtein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation.We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia.METHODOLOGY/PRINCIPAL FINDINGSWe have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia.We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.CONCLUSIONS/SIGNIFICANCEWe found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.
Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia. We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.
Audience Academic
Author Agartz, Ingrid
Djurovic, Srdjan
Lindow, Morten
Jakobsen, Klaus D.
Hansen, Thomas
Olsen, Line
Andreassen, Ole A.
Melle, Ingrid
Wang, August G.
Timm, Sally
Ullum, Henrik
Jonsson, Erik
Werge, Thomas
Hall, Håkan
AuthorAffiliation 8 Centre for Pharmacogenomics, University of Copenhagen, Copenhagen, Denmark
4 Human Brain Informatics, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet and Hospital, Stockholm, Sweden
1 Research Institute of Biological Psychiatry, Sct. Hans Hospital, Roskilde, Denmark
7 University Department of Psychiatry, Psychiatric Centre Amager, Copenhagen, Denmark
Innsbruck Medical University, Austria
3 Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark
5 TOP-project, Department of Psychiatry, Ullevål University Hospital, Oslo, Norway
6 University Department of Psychiatry, Psychiatric Centre Frederiksberg, Frederiksberg, Denmark
2 Bioinformatics Centre, Institute of Molecular Biology, University of Copenhagen, Copenhagen, Denmark
AuthorAffiliation_xml – name: 1 Research Institute of Biological Psychiatry, Sct. Hans Hospital, Roskilde, Denmark
– name: Innsbruck Medical University, Austria
– name: 2 Bioinformatics Centre, Institute of Molecular Biology, University of Copenhagen, Copenhagen, Denmark
– name: 3 Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark
– name: 4 Human Brain Informatics, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet and Hospital, Stockholm, Sweden
– name: 8 Centre for Pharmacogenomics, University of Copenhagen, Copenhagen, Denmark
– name: 5 TOP-project, Department of Psychiatry, Ullevål University Hospital, Oslo, Norway
– name: 6 University Department of Psychiatry, Psychiatric Centre Frederiksberg, Frederiksberg, Denmark
– name: 7 University Department of Psychiatry, Psychiatric Centre Amager, Copenhagen, Denmark
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  fullname: Melle, Ingrid
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  surname: Wang
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  surname: Werge
  fullname: Werge, Thomas
BackLink https://www.ncbi.nlm.nih.gov/pubmed/17849003$$D View this record in MEDLINE/PubMed
http://kipublications.ki.se/Default.aspx?queryparsed=id:119879545$$DView record from Swedish Publication Index
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Conceived and designed the experiments: TH TW LO ML. Performed the experiments: TH LO. Analyzed the data: TH LO. Contributed reagents/materials/analysis tools: KJ HU EJ OA SD IM IA HH ST AW. Wrote the paper: TH LO.
Current address: Santaris Pharma A/S, Hørsholm, Denmark
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Snippet Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs...
Background Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory...
BACKGROUND: Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory...
Background Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory...
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SubjectTerms Adult
Analysis
Bioinformatics
Brain
Brain - metabolism
Brain research
Case-Control Studies
Denmark
Development and progression
Diagnostic tests
DNA binding proteins
Etiology
Female
Gene expression
Genes
Genetic aspects
Genetic diversity
Genetic factors
Genetic variance
Genetics
Genetics and Genomics/Genetics of Disease
Genetics and Genomics/Medical Genetics
Genomes
Genotype
Haplotypes
Humans
Informatics
Male
Mental disorders
Metabolism
MicroRNA
MicroRNAs
MicroRNAs - genetics
Middle Aged
miRNA
Neurosciences
Norway
Oxidative stress
Phenotypic variations
Population
Psychiatry
Schizophrenia
Schizophrenia - genetics
Single-nucleotide polymorphism
Studies
Sweden
Transcription factors
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Title Brain Expressed microRNAs Implicated in Schizophrenia Etiology
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