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DNA methylation in the APOE genomic region is associated with cognitive function in African Americans

BACKGROUND: Genetic variations in apolipoprotein E (APOE) and proximal genes (PVRL2, TOMM40, and APOC1) are associated with cognitive function and dementia, particularly Alzheimer’s disease. Epigenetic mechanisms such as DNA methylation play a central role in the regulation of gene expression. Recen...

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Autores principales: Liu, Jiaxuan, Zhao, Wei, Ware, Erin B., Turner, Stephen T., Mosley, Thomas H., Smith, Jennifer A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941603/
https://www.ncbi.nlm.nih.gov/pubmed/29739406
http://dx.doi.org/10.1186/s12920-018-0363-9
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author Liu, Jiaxuan
Zhao, Wei
Ware, Erin B.
Turner, Stephen T.
Mosley, Thomas H.
Smith, Jennifer A.
author_facet Liu, Jiaxuan
Zhao, Wei
Ware, Erin B.
Turner, Stephen T.
Mosley, Thomas H.
Smith, Jennifer A.
author_sort Liu, Jiaxuan
collection PubMed
description BACKGROUND: Genetic variations in apolipoprotein E (APOE) and proximal genes (PVRL2, TOMM40, and APOC1) are associated with cognitive function and dementia, particularly Alzheimer’s disease. Epigenetic mechanisms such as DNA methylation play a central role in the regulation of gene expression. Recent studies have found evidence that DNA methylation may contribute to the pathogenesis of dementia, but its association with cognitive function in populations without dementia remains unclear. METHODS: We assessed DNA methylation levels of 48 CpG sites in the APOE genomic region in peripheral blood leukocytes collected from 289 African Americans (mean age = 67 years) from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Using linear regression, we examined the relationship between methylation in the APOE genomic region and multiple cognitive measures including learning, memory, processing speed, concentration, language and global cognitive function. RESULTS: We identified eight CpG sites in three genes (PVRL2, TOMM40, and APOE) that showed an inverse association between methylation level and delayed recall, a measure of memory, after adjusting for age and sex (False Discovery Rate q-value < 0.1). All eight CpGs are located in either CpG islands (CGIs) or CGI shelves, and six of them are in promoter regions. Education and APOE ε4 carrier status significantly modified the effect of methylation in cg08583001 (PVRL2) and cg22024783 (TOMM40), respectively. Together, methylation of the eight CpGs explained an additional 8.7% of the variance in delayed recall, after adjustment for age, sex, education, and APOE ε4 carrier status. Methylation was not significantly associated with any other cognitive measures. CONCLUSIONS: Our results suggest that methylation levels at multiple CpGs in the APOE genomic region are inversely associated with delayed recall during normal cognitive aging, even after accounting for known genetic predictors for cognition. Our findings highlight the important role of epigenetic mechanisms in influencing cognitive performance, and suggest that changes in blood methylation may be an early indicator of individuals at risk for dementia as well as potential targets for intervention in asymptomatic populations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12920-018-0363-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-59416032018-05-14 DNA methylation in the APOE genomic region is associated with cognitive function in African Americans Liu, Jiaxuan Zhao, Wei Ware, Erin B. Turner, Stephen T. Mosley, Thomas H. Smith, Jennifer A. BMC Med Genomics Research Article BACKGROUND: Genetic variations in apolipoprotein E (APOE) and proximal genes (PVRL2, TOMM40, and APOC1) are associated with cognitive function and dementia, particularly Alzheimer’s disease. Epigenetic mechanisms such as DNA methylation play a central role in the regulation of gene expression. Recent studies have found evidence that DNA methylation may contribute to the pathogenesis of dementia, but its association with cognitive function in populations without dementia remains unclear. METHODS: We assessed DNA methylation levels of 48 CpG sites in the APOE genomic region in peripheral blood leukocytes collected from 289 African Americans (mean age = 67 years) from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Using linear regression, we examined the relationship between methylation in the APOE genomic region and multiple cognitive measures including learning, memory, processing speed, concentration, language and global cognitive function. RESULTS: We identified eight CpG sites in three genes (PVRL2, TOMM40, and APOE) that showed an inverse association between methylation level and delayed recall, a measure of memory, after adjusting for age and sex (False Discovery Rate q-value < 0.1). All eight CpGs are located in either CpG islands (CGIs) or CGI shelves, and six of them are in promoter regions. Education and APOE ε4 carrier status significantly modified the effect of methylation in cg08583001 (PVRL2) and cg22024783 (TOMM40), respectively. Together, methylation of the eight CpGs explained an additional 8.7% of the variance in delayed recall, after adjustment for age, sex, education, and APOE ε4 carrier status. Methylation was not significantly associated with any other cognitive measures. CONCLUSIONS: Our results suggest that methylation levels at multiple CpGs in the APOE genomic region are inversely associated with delayed recall during normal cognitive aging, even after accounting for known genetic predictors for cognition. Our findings highlight the important role of epigenetic mechanisms in influencing cognitive performance, and suggest that changes in blood methylation may be an early indicator of individuals at risk for dementia as well as potential targets for intervention in asymptomatic populations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12920-018-0363-9) contains supplementary material, which is available to authorized users. BioMed Central 2018-05-08 /pmc/articles/PMC5941603/ /pubmed/29739406 http://dx.doi.org/10.1186/s12920-018-0363-9 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Liu, Jiaxuan
Zhao, Wei
Ware, Erin B.
Turner, Stephen T.
Mosley, Thomas H.
Smith, Jennifer A.
DNA methylation in the APOE genomic region is associated with cognitive function in African Americans
title DNA methylation in the APOE genomic region is associated with cognitive function in African Americans
title_full DNA methylation in the APOE genomic region is associated with cognitive function in African Americans
title_fullStr DNA methylation in the APOE genomic region is associated with cognitive function in African Americans
title_full_unstemmed DNA methylation in the APOE genomic region is associated with cognitive function in African Americans
title_short DNA methylation in the APOE genomic region is associated with cognitive function in African Americans
title_sort dna methylation in the apoe genomic region is associated with cognitive function in african americans
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941603/
https://www.ncbi.nlm.nih.gov/pubmed/29739406
http://dx.doi.org/10.1186/s12920-018-0363-9
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