Genome-Wide Methylation of Mild Cognitive Impairment in Mexican Americans Highlights Genes Involved in Synaptic Transport, Alzheimer’s Disease-Precursor Phenotypes, and Metabolic Morbidities

Article type: Research Article

Authors: Pathak, Gita A.^a | Silzer, Talisa K.^a | Sun, Jie^a | Zhou, Zhengyang^b | Daniel, Ann A.^a | Johnson, Leigh^{c; d} | O’Bryant, Sid^{c; d} | Phillips, Nicole R.^a | Barber, Robert C.^{d; *}

Affiliations: [a] Department of Microbiology, Immunology and Genetics, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA | [b] Department of Biostatistics and Epidemiology, School of Public Health, University of North Texas Health Science Center, Fort Worth, TX, USA | [c] Institute of Translational Medicine, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA | [d] Department of Pharmacology and Neuroscience, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA

Correspondence: [*] Correspondence to: Dr. Robert Barber, Associate Professor, CBH – 312, Department of Pharmacology and Neuroscience, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. Tel.: +1 817 735 2506; E-mail: [email protected].

Abstract: The Mexican American population is among the fastest growing aging population and has a younger onset of cognitive decline. This group is also heavily burdened with metabolic conditions such as hypertension, diabetes, and obesity. Unfortunately, limited research has been conducted in this group. Understanding methylation alterations, which are influenced by both genetic and lifestyle factors, is key to identifying and addressing the root cause for mild cognitive impairment, a clinical precursor for dementia. We conducted an epigenome-wide association study on a community-based Mexican American population using the Illumina EPIC array. Following rigorous quality control measures, we identified 10 CpG sites to be differentially methylated between normal controls and individuals with mild cognitive impairment annotated to PKIB, KLHL29, SEPT9, OR2C3, CPLX3, BCL2L2-PABPN1, and CCNY. We found four regions to be differentially methylated in TMEM232, SLC17A8, ALOX12, and SEPT8. Functional gene-set analysis identified four gene-sets, RIN3, SPEG, CTSG, and UBE2L3, as significant. The gene ontology and pathway analyses point to neuronal cell death, metabolic dysfunction, and inflammatory processes. We found 1,450 processes to be enriched using empirical Bayes gene-set enrichment. In conclusion, the functional overlap of differentially methylated genes associated with cognitive impairment in Mexican Americans implies cross-talk between metabolically-instigated systemic inflammation and disruption of synaptic vesicular transport.

Keywords: Alzheimer’s disease, cognitive dysfunction, epigenetics, Mexican Americans, SEPT8 protein

DOI: 10.3233/JAD-190634

Journal: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 733-749, 2019