Role of methylation in risk for cognitive impairment in Mexican Americans

Purpose: Mexican Americans (MAs) are the largest aging (›65 years old) and growing US ethnic minority group, with a unique risk for cognitive impairment (CI) in comparison to non-Hispanic whites (NHWs). MAs have an earlier age of onset and a risk for CI that is largely metabolism related in contrast to NHWs who have a more inflammation-based risk for CI. CI is defined in this study as individuals diagnosed with either Alzheimer’s disease (AD), or mild cognitive impairment (MCI) (a likely precursor to AD). Risk for CI is multifactorial and involves an epigenetic form of gene regulation called DNA methylation, which involves the addition of a methyl group to the cytosine base of DNA. DNA methylation patterns can be altered or possibly reversed through changes in environmental factors such as diet and lifestyle. Our aim was to identify differentially methylated sites of the genome associated with CI and determine DNA methylation profiles that are specific to MAs and NHWs. Methods: Peripheral blood was drawn from 551 Texas Alzheimer's Research and Care Consortium participants (299 MAs and 252 NHWs) and DNA was typed on the Illumina Infinium MethylationEPIC chip array, assessing >850,000 CpG genomic sites. Participants were compared according to cognitive status (control versus CI(AD/MCI)) among each ethnic group. Beta values that represent relative degree of methylation were normalized using the Beta MIxture Quantile dilation (BMIQ) method. Differential methylation between control and CI was assessed using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages within R studio. Results: Two significant differentially methylated sites were associated with CI at an FDR-adjusted p-value threshold <0.05: cg13135255 in MAs and cg27002303 in NHWs. Three differentially methylated sites were suggestively associated with CI at an FDR-adjusted p-value threshold <0.1: cg01887506 and cg10607142 in MAs, and cg13529380 in NHWs. Four of the five significant and suggestively differentially methylated sites were hypermethylated in CI compared to normal controls, except for hypomethylated site cg13529380. The site most significantly associated with CI was cg13135255 within the CREBBP gene in MAs (FDR-adjusted p-value = 0.029). The CREBBP protein is a histone acetyltransferase, involved in epigenetic regulation, and plays a role in memory formation. Conclusion: This is the first study to report these specific CpG sites as either significantly or suggestively associated with CI among MAs and NHWs. These sites may be used in addition to other methylated sites to develop risk assessments that are ethnicity specific for CI. Following further validation and replication in other cohorts these sites may aid development of ethnic specific therapeutics that could deter or delay CI in the future.