Abstract
BackgroundWith the exception of APOE ε4 allele, the common genetic risk factors for sporadic Alzheimer's Disease (AD) are unknown.Methods and FindingsWe completed a genome-wide association study on 381 participants in the ADNI (Alzheimer's Disease Neuroimaging Initiative) study. Samples were genotyped using the Illumina Human610-Quad BeadChip. 516,645 unique Single Nucleotide Polymorphisms (SNPs) were included in the analysis following quality control measures. The genotype data and raw genetic data are freely available for download (LONI, http://www.loni.ucla.edu/ADNI/Data/). Two analyses were completed: a standard case-control analysis, and a novel approach using hippocampal atrophy measured on MRI as an objectively defined, quantitative phenotype. A General Linear Model was applied to identify SNPs for which there was an interaction between the genotype and diagnosis on the quantitative trait. The case-control analysis identified APOE and a new risk gene, TOMM40 (translocase of outer mitochondrial membrane 40), at a genome-wide significance level of≤10−6 (10−11 for a haplotype). TOMM40 risk alleles were approximately twice as frequent in AD subjects as controls. The quantitative trait analysis identified 21 genes or chromosomal areas with at least one SNP with a p-value≤10−6, which can be considered potential “new” candidate loci to explore in the etiology of sporadic AD. These candidates included EFNA5, CAND1, MAGI2, ARSB, and PRUNE2, genes involved in the regulation of protein degradation, apoptosis, neuronal loss and neurodevelopment. Thus, we identified common genetic variants associated with the increased risk of developing AD in the ADNI cohort, and present publicly available genome-wide data. Supportive evidence based on case-control studies and biological plausibility by gene annotation is provided. Currently no available sample with both imaging and genetic data is available for replication.ConclusionsUsing hippocampal atrophy as a quantitative phenotype in a genome-wide scan, we have identified candidate risk genes for sporadic Alzheimer's disease that merit further investigation.
Highlights
Age is a major risk factor for Alzheimer’s disease (AD), and with both life expectancy and population increases, its incidence is expected to double in the two decades [1]
Risk factors have been identified for the sporadic cases, which are the majority of AD patients, these factors collectively explain a relatively modest amount of the genetic risk for AD [2]
We present the results of a genome-wide association studies (GWAS) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, a longitudinal multi-site observational study including AD, mild cognitive impairment (MCI), and elderly individuals with normal cognition [5] assessing clinical and cognitive measures, magnetic resonance imaging (MRI) and positron emission tomography (PET) scans (FDG and 11C PIB) and blood and CNS biomarkers
Summary
Age is a major risk factor for Alzheimer’s disease (AD), and with both life expectancy and population increases, its incidence is expected to double in the two decades [1]. The high incidence of dementia in Down’s syndrome and analysis of the amino acid sequence of beta-amyloid has led to identification of a series of mutations associated with increased amyloid production. Such mutations only account for a very small percentage of Alzheimer cases. The late onset of Alzheimer’s disease and the sporadic nature of most cases complicate family studies, more than a dozen have been performed [2]. These family studies and the case-control studies strongly implicate multiple genetic loci in susceptibility to AD [2]. With the exception of APOE e4 allele, the common genetic risk factors for sporadic Alzheimer’s Disease (AD) are unknown
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