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.

GAB2 is not associated with late-onset Alzheimer's disease in Japanese

“…10. We did not genotype additional SNPs to the 10 ones reported by Reiman et al, 8 as strong LD (|D 0 |40.8) was observed across the GAB2 (see Supplementary Figure 1).…”

“…We are very grateful to the members of JGSCAD for the collection of blood samples: the members were listed previously. 10,11 We also thank K Horigome, M Hirose, N Yahata, K Takadono, N Takei, T Tsukie, T Gohno and M…”

“…10,11 The LOAD patients were clinically validated, and satisfied the criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association for a diagnosis of probable AD.…”

“…A large proportion (79.4%) of the subjects are the same as in our previous overall sample set. 10,11 To construct two subsample sets, the All set was stratified as to the APOE-e4…”

A Study of the Impact of Death Receptor 4 (DR4) Gene Polymorphisms in Alzheimer’s Disease

“…The death receptors for TRAIL, DR4 and DR5, contain cysteine rich repeats in the extracellular domain that bind to TRAIL causing receptor trimerisation and subsequent apoptosis (6,7). There is evidence suggesting that caspases play a role in Alzheimer's disease, Parkinson's disease, and dementia associated with Human Immunodeficiency Virus infection (8)(9)(10).…”