Mito-nuclear compatibility in risk for cognitive decline in admixed populations
Background. The issue of missing heritability has vexed the study of many complex diseases, Alzheimer’s disease (AD) not excluded. Only ~35% of the heritability of AD has been accounted for, the majority of which lies in APOE allele e4, which has a less-pronounced effect in certain admixed populations. There are few genetic and/or mitochondrial studies of admixed populations, and our understanding of mitochondrially-related cognitive decline has largely been based on studies of highly homogenous populations (by design). The concept of mito-nuclear compatibility states that optimization of mitochondrial DNA (mtDNA) with nuclear genetic background is a source of significant selective evolutionary pressure. Evidence for this phenomenon in human populations is emerging (Zaidi and Makova, 2019), and opens the door for studies in the context of human disease. Purpose. The purpose of this study is to determine whether divergent nuclear and mitochondrial genomes confer risk for cognitive impairment and decline in admixed populations. Methods. Participants in the Texas Alzheimer’s Research and Care Consortium (TARCC) were used for this study. DNA extracts from peripheral blood buffy coat were genotyped on the Multi-Ethnic Genotyping Array (Illumina) which types 1.7 million SNPs and includes ancestry specific genetic variation. The top 10 eigenvectors (smartpca via Eigensoft) were generated via principle component analysis of nuclear DNA (nDNA) and used to cluster subjects with the 1000 Genomes population data in order to ascertain global, ancestral nDNA background. Mitochondrial DNA variants from the array were analyzed using HaploGrep/MitoTool for mtDNA haplotype assignment. Non-concordance of mtDNA:nDNA ancestry will be identified and scored as in Zaidi and Makova, 2019 and tested for association with cognitive state (normal, mild cognitive impairment, or Alzheimer’s disease) as well as cognitive decline between time points. Results. Preliminary studies indicate that cognitive decline is associated with mitochondrial phenotypes in Caucasian subjects; these results were dependent on sex. Mitochondrial copy number was a main driver in the predictive model in both males and females, but to a differing degree. Conclusion. Discrepancy between mtDNA and nDNA genomic backgrounds has been previously correlated with mtDNA copy number (Zaidi and Makova, 2019); similar discrepancy may explain health disparities in complex diseases that are more prevalent in particular admixed populations.