Validation of a microRNA target site polymorphism in H3F3B that is potentially associated with a broad schizophrenia phenotype
| Autor: | Stephen K. Siecinski, Michael P. Moreau, Linda M. Brzustowicz, Veronica J. Vieland, Marco A. Azaro, William Manley, Steven Buyske, Gillian Davis, Anne S. Bassett |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Linkage disequilibrium Heredity Gene Expression lcsh:Medicine Biochemistry Linkage Disequilibrium Histones 0302 clinical medicine Genes Reporter Untranslated Regions Genotype Medicine and Health Sciences lcsh:Science 3' Untranslated Regions Genetics Multidisciplinary Messenger RNA Luciferase Assay Genomics Enzymes Nucleic acids Phenotype Bioassays and Physiological Analysis RNA Interference Oxidoreductases Luciferase Research Article 3' Utr Single-nucleotide polymorphism Biology Research and Analysis Methods Transfection Polymorphism Single Nucleotide 03 medical and health sciences Genetic linkage Mental Health and Psychiatry Genome-Wide Association Studies SNP Humans Epigenetics RNA Messenger Allele Non-coding RNA Molecular Biology Techniques Gene Molecular Biology Alleles Genetic Association Studies Enzyme Assays Binding Sites Biology and life sciences lcsh:R Proteins Computational Biology Human Genetics Genome Analysis Gene regulation MicroRNAs 030104 developmental biology Schizophrenia Enzymology RNA lcsh:Q Biochemical Analysis 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE, Vol 13, Iss 3, p e0194233 (2018) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Despite much progress, few genetic findings for schizophrenia have been assessed by functional validation experiments at the molecular level. We previously reported evidence for genetic linkage of broadly defined schizophrenia to chromosome 17q25 in a sample of 24 multiplex families. 2,002 SNPs under this linkage peak were analyzed for evidence of linkage disequilibrium using the posterior probability of linkage (PPL) framework. SNP rs1060120 produced the strongest evidence for association, with a PPLD|L score of 0.21. This SNP is located within the 3'UTR of the histone gene H3F3B and colocalizes with potential gene target miR-616. A custom miRNA target prediction program predicted that the binding of miR-616 to H3F3B transcripts would be altered by the allelic variants of rs1060120. We used dual luciferase assays to experimentally validate this interaction. The rs1060120 A allele significantly reduced luciferase expression, indicating a stronger interaction with miR-616 than the G allele (p = 0.000412). These results provide functional validation that this SNP could alter schizophrenia epigenetic mechanisms thereby contributing to schizophrenia-related disease risk. |
| Databáze: | OpenAIRE |
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