S2-02-03: Identification of new genetic risk factors

Abstract

Background: The Japanese Genetic Study Consortium for AD (JGSCAD) was organized in 2000 to discover strategies to delay onset and progression of dementia. The apolipoprotein E (APOE) gene has been consistently shown to be a major genetic risk factor, however, all of Alzheimer’s disease (AD) cannot be attributed to the e4 variant of APOE, because about half of AD patients have the APOE-e3*3 genotype. Chromosomes 1, 9, 10, 12, 21 and X have linkage peaks that have also been observed in APOE-e4 negative sib pairs. Objective: To identify an additional gene(s) causing susceptibility to APOE-e4 negative late-onset AD (LOAD). Methods: We performed single nucleotide polymorphisms (SNP)-based association analysis on chromosomes 10, 19 and whole genome. The DNA samples collected by JGSCAD were stratified with APOE genotype or gender. Two independent sets consisting of exploratory and validation samples, respectively, with only the APOE-e3*3 genotype, were used for screening with a high density of exploratory SNP markers. Results: On chromosome 10q, six SNPs exhibited replicated significant associations on meta-analysis of both sample sets. These SNPs were clustered in a locus spanning 220 kb at genomic position 101 Mb, and three of the six SNPs were located in the dynamin-binding protein (DNMBP) gene. Quantitative real-time RT-PCR analysis demonstrated that neuropathologically confirmed AD brains exhibit a significant reduction of DNMBP mRNA compared with agematched ones. Conclusions: DNMBP was discovered as a scaffold protein that brings the dynamin and actin regulatory proteins together, and is concentrated at synapses. On microarray analysis, the gene expression related to synaptic vesicle trafficking was found to be decreased in the frontal cortex of AD patients. Amyloid peptide (A ) induces a decrease in the dynamin I level at synaptic sites in rat cultured hippocampal neurons. In view of the fact that synaptic dysfunction precedes A deposition in the brains of AD patients, our observations raise the possibility that DNMBP, as one of risk factors, might play a predominant role in the early stage of LOAD with APOE-e3*3 or lacking the APOE-e4 allele.