title: Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease.
abstract: The apolipoprotein E (APOE) gene has been consistently shown to be a major genetic risk factor; however, all cases of Alzheimer's disease (AD) cannot be attributed to the epsilon4 variant of APOE, because about half of AD patients have the APOE-epsilon3*3 genotype. To identify an additional genetic risk factor(s), we performed large-scale single nucleotide polymorphism (SNP)-based association analysis of 1526 late-onset AD patients and 1666 control subjects in a Japanese population. We prepared two independent sets consisting of exploratory and validation samples, respectively, with only the APOE-epsilon3*3 genotype, and first carried out genotyping for the exploratory set with 1206 SNPs in the region between 60 and 107 Mb on chromosome 10q that is implicated by linkage studies as containing an AD susceptibility locus. Thirty-five SNPs that showed significant values (P<0.01) were followed-up to detect any association with the validation samples. Finally, six SNPs exhibited replicated significant associations (P=0.000035-0.00048) on meta-analysis of both 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 age-matched ones (P<0.0169). Thus, we confirmed the association of DNMBP with AD individuals with the APOE-epsilon3*3 genotype or lacking the epsilon4 allele, and DNMBP may be one of the susceptibility genes for AD.
authors.affiliation: Genome Science Branch, Center for Bioresource-Based Researches, Brain Research Institute, Niigata University, Niigata, Japan. ryosun@gene.med.niigata-u.ac.jp
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
authors.forename: Akinori
authors.initials: A
authors.lastname: Miyashita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Takashi
authors.initials: T
authors.lastname: Asada
authors.forename: Masaki
authors.initials: M
authors.lastname: Imagawa
authors.forename: Mikio
authors.initials: M
authors.lastname: Shoji
authors.forename: Susumu
authors.initials: S
authors.lastname: Higuchi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Urakami
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Tamao
authors.initials: T
authors.lastname: Tsukie
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyabe
authors.forename: Kohei
authors.initials: K
authors.lastname: Akazawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kanazawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ihara
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D003598:Cytoskeletal Proteins; C482331:DNMBP protein, human