Human Molecular Genetics Advance Access originally published online on June 1, 2006
Human Molecular Genetics 2006 15(13):2170-2182; doi:10.1093/hmg/ddl142
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Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease
1 Genome Science Branch, Center for Bioresource-Based Researches, Brain Research Institute, Niigata University, Niigata 951-8585, Japan, 2 Center for Transdisciplinary Research, Niigata University, Niigata 951-8585, Japan, 3 Department of Geriatric and Complementary Medicine, Advanced Research Center for Asian Traditional Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan, 4 Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan, 5 Department of Neuropsychiatry, Imagawa Clinic, Fukushima-ku, Osaka 553-0003, Japan, 6 Department of Neurology, Neuroscience and Biophysiological Science, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan, 7 Division of Clinical Research, Kurihama Alcoholism Center, National Hospital Organization, Yokosuka 239-0841, Japan, 8 Department of Biological Regulation, Section of Environment and Health Science, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan, 9 Department of Pathology and the Resource Branch for Brain Disease, Brain Research Institute, Niigata University, Niigata 951-8585, Japan, 10 Department of Medical Informatics, Niigata University, Niigata 951-8520, Japan, 11 National Center for Neurology and Psychiatry, Kodaira 187-8502, Japan and 12 Department of Neuropathology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
* To whom correspondence should be addresssed: Tel: +81 25 227 2343; fax: +81 25 227 0793; Email: ryosun{at}gene.med.niigata-u.ac.jp
Received April 25, 2006; Accepted May 24, 2006
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 
4 variant of APOE, because about half of AD patients have the APOE-3*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-3*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-3*3 genotype or lacking the 4 allele, and DNMBP may be one of the susceptibility genes for AD.
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