O3‐03‐03: Epigenome‐wide Association Studies Implicate Genes Involved in Glial Cell Function and Viral Response in Cerebral White Matter Hyperintensities
Year: 2018
Type: article
Abstract: Cerebral white matter hyperintensities (WMH) detected on MRI are strong radiological correlates of age-related cognitive decline and represent an early marker of Alzheimer's disease (AD), independent of AD pathology. Despite a recognized high heritability, the molecular basis of WMH susceptibility has not been fully characterized. In particular, the contribution of epigenetic modifications, such as DNA methylation, has not been explored. We conducted a meta-analysis of epigenome-wide association studies of WMH burden in up to 5679 elderly participants of European and African ancestry from 9 population-based cohorts using blood-derived DNA methylation measured on the Infinium HumanMethylation450 BeadChip. Cohort-specific associations between burden of WMH and DNA methylation beta values were estimated using linear mixed-effect models and combined in a sample-size weighted fixed-effect meta-analysis. In addition, we used two different approaches to identify differentially methylated regions (DMRs), which may be more informative than individual loci. Bonferroni correction and False Discovery Rates were used to account for the multiple tests. Single-site analyses identified a CpG site on chromosome 11 significantly associated with WMH (cg24202936, P= 1.2x10). Region-based analyses, which leverage the correlations between nearby CpG sites identified 3 DMRs across 3 genes significantly associated with WMH burden: PRMT1, BTBD17, and IFITM10 (P= 1.4x10, 2.3x10, and 3.6x10, respectively). PRMT1 encodes the Protein Arginine N-methylase 1, which methylates histones in genes involved in glioblastomagenesis. Mice lacking this gene are characterized by severe defects in oligodendrocyte maturation processes. The function of BTBD17 and IFITM10 is not characterized but both are expressed in the brain and exhibit changes in expression in response to viral infection. Consistent with our previously reported genetic association studies, this genome-wide DNA methylation analysis supports a role of genes involved in glial cell function in WMH etiology. It also suggests a novel role of genes involved in viral response. Analyses are in progress to examine whether these changes in DNA methylation are under genetic control and are associated with cognitive outcomes.
Source: Alzheimer s & Dementia
Institutions: The University of Texas Health Science Center at Houston, Erasmus MC, University of Washington, University of Edinburgh, Universitätsmedizin Greifswald, Northwestern University, University of Michigan, National Institutes of Health, National Institute on Aging, The University of Texas at San Antonio Health Science Center, German Centre for Cardiovascular Research, Boston University
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2896543447