TY - JOUR
T1 - Genome-Wide Methylation of Mild Cognitive Impairment in Mexican Americans Highlights Genes Involved in Synaptic Transport, Alzheimer's Disease-Precursor Phenotypes, and Metabolic Morbidities
AU - Pathak, Gita A.
AU - Silzer, Talisa K.
AU - Sun, Jie
AU - Zhou, Zhengyang
AU - Daniel, Ann A.
AU - Johnson, Leigh
AU - O'Bryant, Sid
AU - Phillips, Nicole R.
AU - Barber, Robert C.
N1 - Funding Information:
Despite the limitations, we have strengthened our study design by implementing a very rigorous and The research team thanks the local Fort Worth community and participants of the Health & Aging Brain Study. Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG054073 and R56AG054073. We would also like to acknowledge the NIH – Neurobiology of Aging T32 grant AG020494 for supporting this research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2019-IOS Press and the authors. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Mexican Americans
KW - SEPT8 protein
KW - cognitive dysfunction
KW - epigenetics
UR - http://www.scopus.com/inward/record.url?scp=85075871009&partnerID=8YFLogxK
U2 - 10.3233/JAD-190634
DO - 10.3233/JAD-190634
M3 - Article
C2 - 31640099
AN - SCOPUS:85075871009
SN - 1387-2877
VL - 72
SP - 733
EP - 749
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 3
ER -