Mitochondrial Genome‐Wide Association Study Investigating Indices of Mitochondrial Dysfunction in Mexican Americans Compared to non‐Hispanic Whites
Danielle M Reid, Megan Rowe, Mohammad Housini, Kumudu Subasinghe, Isabelle Garlotte, Robert Barber, Harlan P Jones, Roland J. Thorpe, Jie Sun, Zhengyang Zhou, Nicole Phillips- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Mexican Americans (MAs) endure racial/ethnic disparities in Alzheimer’s Disease (AD) risk, such as late‐stage diagnosis, earlier onset, and more severe forms of cognitive impairment (CI) compared to non‐Hispanic Whites (NHWs), despite low propensity for the genetic predisposition (e.g., APOE e4 has limited effect on MA AD risk). These complexities have challenged our understanding of AD etiology in this population. MAs are the fastest growing subpopulation within the Hispanic/Latinx population, and as they age, AD will disproportionately affect MAs. Common risk factors for developing CI in MAs include stroke, diabetes, obesity, and depression; however, the reason for the association remains unknown. Diabetes is three times more prevalent among MAs relative to NHWs, and mitochondrial dysfunction is implicated in both AD and diabetes. As a result, mtDNA can accumulate reactive oxygen species damage and elicit pro‐inflammatory processes upon release. Previously, we determined MAs exhibited elevated oxidative mtDNA damage and associated with AD, sex, tobacco abuse, and education compared to NHWs. Here, we hypothesize that mtSNPs will be associated with indices of mitochondrial dysfunction (e.g., mtDNA copy number [mtDNA CN] and 8oxoG variants) in MAs, particularly those with AD and/or diabetes, compared to NHWs.
Method
Whole mtDNA was amplified from extracted buffy coat PBMCs and plasma from 559 TARCC participants using REPLI‐g® Human Mitochondrial DNA Kit and sequenced via Illumina NextSeq. We performed a mitochondrial genome‐wide association study to identify variants associated with 8oxoG mutational load and altered mtDNA CN in MAs compared to NHWs. Analyses control for covariates like age, sex, education, diabetes, tobacco abuse, and depression.
Result
We will report haplogroup effects and determine if specific variants are associated with elevated oxidative burden and/or altered mtDNA CN to better understand population‐specific risks for mitochondrial dysfunction in connection to complex age‐related disease.
Conclusion
This study will establish if mtDNA‐based genetics is relevant to mitochondrial dysfunction (i.e., oxidative damage and/or altered mtDNA CN), which we have shown to be associated with cognitive decline. These results will be evaluated for population‐ and sex‐specific effects taking into consideration key comorbidities (e.g., diabetes). This data could help identify targets for precise approaches to help assess and reduce disease risk.