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DAPK1 variants are associated with Alzheimer's disease and allele-specific expression

2006; Oxford University Press; Volume: 15; Issue: 17 Linguagem: Inglês

10.1093/hmg/ddl178

1460-2083

Yonghong Li, Andrew Grupe, Charles M. Rowland, Petra Nowotny, John Kauwe, Scott Smemo, Anthony L. Hinrichs, Kristina Tacey, Timothy A. Toombs, Shirley Kwok, Joseph J. Catanese, Thomas J. White, Taylor J. Maxwell, Paul Hollingworth, Richard Abraham, David C. Rubinsztein, Carol Brayne, Fabienne Wavrant‐De Vrièze, John Hardy, Michael O’Donovan, Simon Lovestone, Christopher M. Morris, Leon J. Thal, Michael J. Owen, Julie Williams, Alison Goate,

Neurological diseases and metabolism

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.