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- Title
DAPK1 variants are associated with Alzheimer's disease and allele-specific expression.
- Authors
Li, Yonghong; Grupe, Andrew; Rowland, Charles; Nowotny, Petra; Kauwe, John S K; Smemo, Scott; Hinrichs, Anthony; Tacey, Kristina; Toombs, Timothy A; Kwok, Shirley; Catanese, Joseph; White, Thomas J; Maxwell, Taylor J; Hollingworth, Paul; Abraham, Richard; Rubinsztein, David C; Brayne, Carol; Wavrant-De Vrièze, Fabienne; Hardy, John; O'Donovan, Michael; Lovestone, Simon; Morris, John C; Thal, Leon J; Owen, Michael; Williams, Julie; Goate, Alison
- Abstract
Genetic factors play an important role in the etiology of late-onset Alzheimer's disease (LOAD). We tested gene-centric single nucleotide polymorphisms (SNPs) on chromosome 9 and identified two SNPs in the death-associated protein kinase, DAPK1, that show significant association with LOAD. SNP rs4878104 was significantly associated with LOAD in our discovery case-control sample set (WU) and replicated in each of two initial validation case-control sample sets (P<0.05, UK1, SD). The risk-allele frequency of this SNP showed a similar direction in three other case-control sample sets. A meta-analysis of the six sample sets combined, totaling 2012 cases and 2336 controls, showed an allelic P-value of 0.0016 and an odds ratio (OR) of 0.87 (95%CI: 0.79-0.95). Minor allele homozygotes had a consistently lower risk than major allele homozygotes in the discovery and initial two replication sample sets, which remained significant in the meta-analysis of all six sample sets (OR=0.7, 95%CI: 0.58-0.85), whereas the risk for heterozygous subjects was not significantly different from that of major allele homozygotes. A second SNP, rs4877365, which is in high linkage disequilibrium with rs4878104 (r2=0.64), was also significantly associated with LOAD (meta P=0.0017 in the initial three sample sets). Furthermore, DAPK1 transcripts show differential allelic gene expression, and both rs4878104 and rs4877365 were significantly associated with DAPK1 allele-specific expression (P=0.015 to <0.0001). These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD.
- Publication
Human molecular genetics, 2006, Vol 15, Issue 17, p2560
- ISSN
0964-6906
- Publication type
Journal Article
- DOI
10.1093/hmg/ddl178