Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease

Abstract

Introduction: Findings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer's disease (AD) are inconsistent.

Methods: We developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer's Disease Sequencing Project (ADSP). Association of AD risk was evaluated with each mtDNA variant and variants located in 1158 nuclear genes related to mitochondrial function using the SCORE test. Gene-based tests were performed using SKAT-O.

Results: Analysis of 4220 mtDNA variants revealed study-wide significant association of AD with a rare MT-ND4L variant (rs28709356 C>T; minor allele frequency = 0.002; P = 7.3 × 10^-5 ) as well as with MT-ND4L in a gene-based test (P = 6.71 × 10^-5 ). Significant association was also observed with a MT-related nuclear gene, TAMM41, in a gene-based test (P = 2.7 × 10^-5 ). The expression of TAMM41 was lower in AD cases than controls (P = .00046) or mild cognitive impairment cases (P = .03).

Discussion: Significant findings in MT-ND4L and TAMM41 provide evidence for a role of mitochondria in AD.

Keywords: Alzheimer's disease; genetic association; mitochondrial haplogroup; mitochondrial variant calling; whole exome sequencing.

FIGURE 1

Heatmap of module‐trait relationships depicting correlations between module eigengenes and clinical/pathological Alzheimer's disease (AD) status and AD‐related endophenotypes traits. Numbers in the table correspond to the coefficient and P‐value (in parentheses) for the pairwise correlations. The degree of correlation is illustrated with the color legend. Note that increasing Mini‐Mental State Examination (MMSE) and plaque scores, and decreasing values for Braak stage and AD status, are in the direction of normal