Role of DNA Methylation in Risk for Cognitive Impairment in Mexican Americans

Mexican Americans (MA) are the largest growing aging ethnic minority group in the US and have a unique risk for cognitive impairment (CI). The risk for Alzheimer's disease (AD) and mild cognitive impairment (MCI) in MAs is largely metabolism-based compared to non-Hispanic whites (NHW). This risk for CI is multifactorial involving both genetic and epigenetic factors. During DNA methylation (an epigenetic process influenced by environment and lifestyle), a methyl group is added to the cytosine base of DNA; typically, at cytosine-phosphate-guanine (CpG) sites. The aim of this study was to identify differentially methylated regions of the genome associated with CI and determine ethnicity-specific DNA methylation profiles in MAs and NHWs. A total of 551 participants (299 MAs and 252 NHWs) from the Texas Alzheimer's Research and Care Consortium were selected and stratified by cognitive status (control vs CI). DNA from participants' peripheral blood was typed on the Illumina Infinium® MethylationEPIC chip array assessing >850,000 CpG sites. Beta values representing degree of methylation at CpG sites were normalized using the Beta MIxture Quantile dilation method. The Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R were used to assess differential methylation. Two differentially methylated sites at a false discovery rate (FDR) p-value <0.05 were significant: cg13135255 in MAs and cg27002303 in NHWs. Three suggestive hits at additional sites cg01887506 (MAs) and cg10607142 and cg13529380 (NHWs) based on an FDR p-value <0.1 were also obtained. Most significant sites were hypermethylated in CI versus controls, except for hypomethylated cg13529380. Strongest CI association (FDR-adjusted p-value = 0.029) was at cg13135255 within the CREBBP gene in MAs. Ingenuity Pathway Analysis was used to identify CI associated disease pathways and upstream regulators from the significant CpG hits obtained using a nominal p-value <0.0005. Metabolic diseases for MAs and inflammatory diseases for NHWs were among the top five pathways. Upstream regulators in MAs, PHLPP1 and PHLPP2, have been associated with AD. The results display a more metabolism-related methylation-based risk for CI in MAs compared to NHWs in this cohort. Identifying additional ethnicity-specific methylation sites could help develop CI risk assessments for MAs in the future.