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Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder
BACKGROUND: Bipolar disorder (BD) is a complex psychiatric phenotype with a high heritability and a multifactorial etiology. Multisite collaborative efforts using genome-wide association studies (GWAS) have identified only a portion of DNA sequence-based risk factors in BD. In addition to predisposi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215812/ https://www.ncbi.nlm.nih.gov/pubmed/25505691 http://dx.doi.org/10.1186/2194-7511-1-28 |
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author | Strauss, John S Khare, Tarang De Luca, Vincenzo Jeremian, Richie Kennedy, James L Vincent, John B Petronis, Arturas |
author_facet | Strauss, John S Khare, Tarang De Luca, Vincenzo Jeremian, Richie Kennedy, James L Vincent, John B Petronis, Arturas |
author_sort | Strauss, John S |
collection | PubMed |
description | BACKGROUND: Bipolar disorder (BD) is a complex psychiatric phenotype with a high heritability and a multifactorial etiology. Multisite collaborative efforts using genome-wide association studies (GWAS) have identified only a portion of DNA sequence-based risk factors in BD. In addition to predisposing DNA sequence variants, epigenetic misregulation may play an etiological role in BD and account for monozygotic twin discordance, parental origin effects, and fluctuating course of BD. In this study, we investigated DNA methylation of the brain-derived neurotrophic factor (BDNF) gene in BD. METHODS: Fifty participants with BD were compared to the same number of age- and sex-matched controls for DNA methylation differences at BDNF promoters 3 and 5. DNA methylation reads were obtained using a mass spectrophotometer for 64 cytosine-guanine (CpG) sites in 36 CpG ‘units’ across three amplicons of BDNF promoters 3 and 5. RESULTS AND DISCUSSION: Methylation fractions differed between BD participants and controls for 11 of 36 CpG units. Five CpG units, mostly in promoter 5, remained significant after false discovery rate correction (FDR) (p values ≤ 0.004) with medium to large effect sizes (Cohen's d ≥ 0.61). Several of the significant CpGs overlapped with or were immediately adjacent to transcription factor binding sites (TFBSs) - including two of the FDR-significant CpG units in promoter 5. For the CpGs in promoter 3, there was a positive and significant correlation between age at sample collection and DNA methylation fraction (rho = 0.56, p = 2.8 ×10(−5)) in BD cases, but not in controls. Statistically significant differences in mean methylation fraction at 5/36 CpG units (after FDR), some at or immediately adjacent to TFBSs, suggest possible relevance for the current findings to BD etiopathogenesis. The positive correlation between age and methylation seen in promoter 3 is consistent with age-related decline in BDNF expression previously reported. Future studies should provide more exhaustive epigenetic study of the BDNF locus to better characterize the relationship between BDNF methylation differences and BD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2194-7511-1-28) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4215812 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-42158122014-12-10 Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder Strauss, John S Khare, Tarang De Luca, Vincenzo Jeremian, Richie Kennedy, James L Vincent, John B Petronis, Arturas Int J Bipolar Disord Research BACKGROUND: Bipolar disorder (BD) is a complex psychiatric phenotype with a high heritability and a multifactorial etiology. Multisite collaborative efforts using genome-wide association studies (GWAS) have identified only a portion of DNA sequence-based risk factors in BD. In addition to predisposing DNA sequence variants, epigenetic misregulation may play an etiological role in BD and account for monozygotic twin discordance, parental origin effects, and fluctuating course of BD. In this study, we investigated DNA methylation of the brain-derived neurotrophic factor (BDNF) gene in BD. METHODS: Fifty participants with BD were compared to the same number of age- and sex-matched controls for DNA methylation differences at BDNF promoters 3 and 5. DNA methylation reads were obtained using a mass spectrophotometer for 64 cytosine-guanine (CpG) sites in 36 CpG ‘units’ across three amplicons of BDNF promoters 3 and 5. RESULTS AND DISCUSSION: Methylation fractions differed between BD participants and controls for 11 of 36 CpG units. Five CpG units, mostly in promoter 5, remained significant after false discovery rate correction (FDR) (p values ≤ 0.004) with medium to large effect sizes (Cohen's d ≥ 0.61). Several of the significant CpGs overlapped with or were immediately adjacent to transcription factor binding sites (TFBSs) - including two of the FDR-significant CpG units in promoter 5. For the CpGs in promoter 3, there was a positive and significant correlation between age at sample collection and DNA methylation fraction (rho = 0.56, p = 2.8 ×10(−5)) in BD cases, but not in controls. Statistically significant differences in mean methylation fraction at 5/36 CpG units (after FDR), some at or immediately adjacent to TFBSs, suggest possible relevance for the current findings to BD etiopathogenesis. The positive correlation between age and methylation seen in promoter 3 is consistent with age-related decline in BDNF expression previously reported. Future studies should provide more exhaustive epigenetic study of the BDNF locus to better characterize the relationship between BDNF methylation differences and BD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2194-7511-1-28) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2013-12-30 /pmc/articles/PMC4215812/ /pubmed/25505691 http://dx.doi.org/10.1186/2194-7511-1-28 Text en © Strauss et al.; licensee Springer. 2013 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Strauss, John S Khare, Tarang De Luca, Vincenzo Jeremian, Richie Kennedy, James L Vincent, John B Petronis, Arturas Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder |
title | Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder |
title_full | Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder |
title_fullStr | Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder |
title_full_unstemmed | Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder |
title_short | Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder |
title_sort | quantitative leukocyte bdnf promoter methylation analysis in bipolar disorder |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215812/ https://www.ncbi.nlm.nih.gov/pubmed/25505691 http://dx.doi.org/10.1186/2194-7511-1-28 |
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