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O3‐03‐05: INTEGRATIVE NETWORK ANALYSIS IDENTIFIES RELATIONSHIPS BETWEEN METABOLOMICS, GENOMICS, AND RISK FACTORS FOR AD
Author(s) -
Darst Burcu F.,
Lu Qiongshi,
Koscik Rebecca L.,
Jonaitis Erin,
Clark Lindsay R.,
Hogan Kirk J.,
Johnson Sterling C.,
Engelman Corinne D.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.2786
Subject(s) - genomics , metabolomics , heritability , missing heritability problem , biology , genotyping , disease , computational biology , trait , sibling , genome wide association study , genetic association , genetics , bioinformatics , psychology , medicine , gene , genome , computer science , developmental psychology , genotype , single nucleotide polymorphism , programming language
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. Results: Singlesite analyses identified a CpG site on chromosome 11 significantly associated with WMH (cg24202936, P1⁄4 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 (P1⁄4 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. Conclusions:Consistent with our previously reported genetic association studies, this genome-wide DNAmethylation 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.