Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease.
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.
Kuwano
Ryozo
R
Genome Science Branch, Center for Bioresource-Based Researches, Brain Research Institute, Niigata University, Niigata, Japan. ryosun@gene.med.niigata-u.ac.jp
Miyashita
Akinori
A
Arai
Hiroyuki
H
Asada
Takashi
T
Imagawa
Masaki
M
Shoji
Mikio
M
Higuchi
Susumu
S
Urakami
Katsuya
K
Kakita
Akiyoshi
A
Takahashi
Hitoshi
H
Tsukie
Tamao
T
Toyabe
Shinichi
S
Akazawa
Kohei
K
Kanazawa
Ichiro
I
Ihara
Yasuo
Y
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
D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D003598:Cytoskeletal Proteins; C482331:DNMBP protein, human