Mitochondrial Genetics Reinforces Multiple Layers of Interaction in Alzheimer's Disease

Abstract

Nuclear DNA has been the main source of genome-wide loci association in neurodegenerative diseases, only partially accounting for the heritability of Alzheimer's Disease (AD). In this context, mitochondrial DNA (mtDNA) is gaining more attention. Here, we investigated mitochondrial genes and genetic variants that may influence mild cognitive impairment and AD, through an integrative analysis including differential gene expression and mitochondrial genome-wide epistasis. We assessed the expression of mitochondrial genes in different brain tissues from two public RNA-Seq databases (GEO and GTEx). Then, we analyzed mtDNA from the ADNI Cohort and investigated epistasis regarding mitochondrial variants and levels of Aβ1-42, TAU, and Phosphorylated TAU (PTAU) from cognitively healthy controls, and both mild cognitive impairment (MCI) and AD cases. We identified multiple differentially expressed mitochondrial genes in the comparisons between cognitively healthy individuals and AD patients. We also found increased protein levels in MCI and AD patients when compared to healthy controls, as well as novel candidate networks of mtDNA epistasis, which included variants in all mitochondrially-encoded oxidative phosphorylation complexes, 12S rRNA and MT-DLOOP. Our results highlight layers of potential interactions involving mitochondrial genetics and suggest specific molecular alterations as potential biomarkers for AD.

Keywords: Alzheimer’s Disease; PTAU; TAU; cerebrospinal fluid; differential expression; epistasis; mtDNA.

Figure 1

Analyses of the GEO and GTEx samples. (A) Volcano plot of DE analysis for Alzheimer’s disease; the marked dots are differentially expressed mitochondrial DNA genes, while all others are nuclear genes; (B) GTEx biclustering for mtDNA genes in 13 brain tissues; (C) gene–gene interaction network of MTRNR2L1.

Figure 2

Analyses of the CSF PTAU levels and mtDNA variants. On the top left, we show the CSF PTAU levels at baseline for the ADNI cohort. On the top right, we show the epistasis network with statistical significance between mtDNA variants and PTAU CSF levels. The network was made from linear model analysis (p-value ≤ 1.0 $\times {10}^{-9}$). Wilcoxon test results and distribution of mtDNA genotype pairs in relation to PTAU levels.

Figure 3

Analyses of the CSF TAU levels and mtDNA variants. On the top left, we show the CSF TAU levels at baseline for the ADNI Cohort. On the top right, we show the epistasis interactions between mtDNA variants and TAU levels that reached a linear model (p-value ≤ 1.0 $\times {10}^{-5}$). Wilcoxon test results and distribution of mtDNA genotype pairs in relation to TAU levels.