Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease

Ryozo Kuwano, Akinori Miyashita, Hiroyuki Arai, Takashi Asada, Masaki Imagawa, Mikio Shoji, Susumu Higuchi, Katsuya Urakami, Akiyoshi Kakita, Hitoshi Takahashi, Tamao Tsukie, Shinichi Toyabe, Kohei Akazawa, Ichiro Kanazawa, Yasuo Ihara, Akihiko Nunomura, Shigeru Chiba, Satoshi Takahashi, Naoki Tomita, Jyunzo ItoHaruo Hanyu, Hideo Kimura, Shin Kitamura, Hitoshi Shinotoh, Hiroyuki Iwamoto, Masahiko Takahashi, Yasuo Harigaya, Masaki Ikeda, Masakuni Amari, Takeo Takahashi, Ryoichi Nakano, Masatoyo Nishizawa, Masaichi Suga, Makoto Hasegawa, Yasuhiro Kawase, Kenichi Honda, Toshiro Kumanishi, Yukiyosi Takeuchi, Atsushi Ishikawa, Masahiro Morita, Fumihito Yoshii, Hiroyasu Akatsu, Kenji Kosaka, Masahito Yamada, Tsuyoshi Hamaguchi, Satoshi Masuzugawa, Etsuro Matsubara, Takeshi Kawarabayashi, Takeo Takao, Nobuko Ota, Ken Sasaki, Yoshikatsu Fujisawa, Kenji Nakata, Yosuke Wakutani, Kenji Nakashima, Toshiyuki Hayabara, Terumi Ooya, Mitsuo Takahashi, Tatsuo Yamada, Taihei Miyakawa, Eiichiro Uyama, Takefumi Yuzuriha, Ryuji Nakagawa, Shizushi Yoshimoto, Kayoko Serikawa

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

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 ε4 variant of APOE, because about half of AD patients have the APOE-ε3* 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-ε3* 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-ε3*3 genotype or lacking the ε4 allele, and DNMBP may be one of the susceptibility genes for AD.

Original languageEnglish
Pages (from-to)2170-2182
Number of pages13
JournalHuman molecular genetics
Volume15
Issue number13
DOIs
Publication statusPublished - 2006 Jul
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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