Identification of risk genes and their molecular mechanism on the development of Alzheimer disease based on the personal genome analysis

Ryozo Kuwano,Department of Molecular Genetics,Brain Research Institute,Niigata University

Akiyoshi Kakita,Department of Pathological Neuroscience,Brain Research Institute,Niigata University

Akinori Miyashita,Department of Molecular Genetics,Brain Research Institute,Niigata University

The goal of this personal genome analyses is to identify genetic risk factor(s) associated with Alzheimer disease (AD) and to elucidate molecular mechanism on the development of AD. Twin study demonstrated higher concordance of AD in monozygotic compared with dizygotic twins with hereditability of 58~79%. Genetic factors are thought to play an important role in the onset and progress of AD. Many genetic association studies have been performed to identify the susceptibility genes. Meta analysis shows that odds ratios are calculated as small as around 1.5 except that of apolipoprotein E (APOE) gene. APOE is associated with not only familial but also sporadic cases of late-onset AD (LOAD),and contribute to both risk and age at disease onset of LOAD beyond ethnicity. A half of patients carries the APOE e 4 allele and the remaining half of AD patients has APOE e 3*3 genotype. AD has an overall ls of 5,with a ls of only 2 for APOE. These data suggest that there are additional unknown risk genes,and then the identification of additional factors to APOE are essential for further understanding of the molecular mechanism for development of AD.

Recently a large-scale genome-wide association study (GWAS) demonstrated several risk genes by genotyping 500,000 ~ 1,000,000 SNPs with relatively high allele frequency. Beyond the GWAS we are going to identify rare variants,insertions and deletions known as copy number variants associated with AD based on the personal genome sequencing of subjects with family history. These rare variants might be stronger effect on individual development of AD than the genes obtained by the common disease common variant hypothesis. An identified risk gene will be verified on a large number of sporadic AD patients that are collected on the cross-sectional and prospective cohort studies. In the second half of this study,we are planning the gene expression and DNA methylation analyses of the autopsy confirmed AD brain tissues.