GENOME-WIDE ASSOCIATION STUDY USING ALZHEIMER-RELATED PATHOLOGICAL BIOMARKERS

Abstract

Genome-wide association study (GWAS) is a powerful technique to identify polymorphisms associated with a particular disease. However, standard case-control study can often be disappointing because no SNPs reach genome-wide significance. Another way to highlight potential disease-modifying SNPs is to perform the study with pathology-specific biomarkers. This method was applied for late-onset Alzheimer's disease (LOAD). GWAS was performed with Illumina 550-Quad BeadChip using DNA samples from Quebec Founder Population (QFP). A total of 629 French Canadians (384 LOAD patients and 245 age-matched control subjects) were recruited for the study. DNA was extracted either from blood samples or directly from available brain tissues (from the Douglas - Bell Canada Brain Bank). For a subset of post-mortem samples, the density of senile plaques (SP) and neurofibrillary tangles (NFT) were evaluated by a neuropathologist. Single nucleotide polymorphisms (SNPs) significantly associated with the disease, the age of onset or with neuropathological data will be assessed for replication in the population from the Alzheimer's Disease Neuroimaging Initiative (ADNI). With the standard case-control analysis, only four SNPs reached genome-wide significance (p< 5 x 10 -8). These four SNPs (rs429358, rs2075650, rs405509 and rs8106922) were all located on chromosome 19 near APOE gene. The strongest SNP (rs429358, p= 4.1 x 10 -24) also correlated with the age of onset (p= 2.4 x 10 -4), the density of SP in the frontal cortex (p= 6.5 x 10 -8) and in the CA1 region of the hippocampus (p= 3.6 x 10 -3), and the density of NFT in the frontal cortex (p= 7.3 x 10 -7) and in the CA1 region of the hippocampus (p= 4.6 x 10 -3). A second analysis is currently being performed in an effort to find other SNPs that correlate with pathology-related biomarkers. SNPs will be selected based on P values and the number of significant correlations with different biomarkers from our study and the ADNI database. The contribution of APOE to late-onset Alzheimer's disease has already been well established. The present study will help to identify genes never before associated with the disease.