Genome-wide SNP analysis finds executive-prominent late-onset Alzheimer's disease is highly heritable

Abstract

Background:Mitochondrial dysfunction may play a key role in the pathogenesis of Alzheimer’s disease (AD) with progressive mitochondrial dysfunction reported in post-mortem AD brains (Devi et al. 2006). Genetic defects in the mitochondrial genome may result in mitochondrial dysfunction and increase AD susceptibility. Several studies have reported the association of specific mitochondrial DNA (mtDNA) single nucleotide polymorphisms (SNPs) with AD, with concordant and conflicting results. Also, investigation at the sub-haplogroup level has shown a positive association between AD and sub-haplogroup H5 (Santoro et al. 2010). Recently, we sort to replicate the mtDNA SNP associations reported with AD utilising a powerful cohort of 4,133 AD cases and 1,602 matched controls (the Genetic and Environmental Risk in AD1 (GERAD1) sample). However, no SNP showed consistent association (Hudson et al. 2012). This study investigates the role of mtDNA SNPs and sub-haplogroups in AD using a two stage analysis. Stage one analysed mitochondrial SNPs represented on the Illumina 610-quad chip in the GERAD1 sample. Stage 2 genotyped 123 mitochondrial variants in an additional 8,042 cases and 9,387 controls as part of the International Genomics of Alzheimer’s Project (IGAP). Methods: This study comprised a total sample of 12175 Alzheimer’s disease cases and 10989 controls. Stage 1 genotyping was performed on the Illumina 610-quad chip at the Sanger Institute, UK. Stage 2 genotyping was performed using a custom Illumina iSelect array at the Centre National de G enotypage (CNG), France. Variant frequencies were compared in case patients and controls: 1) on an individual SNP-by-SNP basis using Pearson’s test (p) and 2) across the entire data set by permuting the disease status (p*), an approach that partially accounts for the phylogenetic structure of the data. All statistical analysis was carried out in PLINK (v2.050) using a single allele-based model. Results: Will be presented at AAIC 2013. Conclusions: A large body of evidence suggests that intervention at the mitochondrial level could ameliorate As triggered dysfunction and degeneration, and reduce or alleviate defects in glucose utilization and oxidative phosphorylation in the brains of AD patients. This study uses a powerful design to investigate mitochondrial genetic variation in a large AD case-control dataset.