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

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.

Genetic loci modulating amyloid-beta levels in a mouse model of Alzheimer's disease

“…Linkage disequilibrium at 1q44 was reported in a study of 100 AD cases and 100 controls (Zubenko et al 1998), linkage at 2q22 and 2q24 was detected in a linkage study of 88 LOAD families (Lee et al 2004), and linkage at 9q34 was detected in a study of 466 families (Pericak-Vance et al 2000), close to the 9q33 syntenic region reported here. This 9q33 syntenic region is also close to a major region of interest in human AD on chromosome 9q, but lies slightly outside the 9q21-31 region typically identified with the strongest support, and does not contain the DAPK1 gene recently implicated in an association study (Li et al 2006). Unlike the more extensively reported areas of linkage on human chromosomes 9, 10, and 12, these syntenic human linkage findings have not been replicated by multiple studies, suggesting that they are unlikely to explain a major part of the observed heritability of AD risk.…”

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

“…With relevance to neurobiological mechanisms such as neuronal apoptosis and APP trafficking, early genetic studies of LOAD have identified several candidate genes (e.g. DAPK1 [11] and SORL1 [12,13]), but they are still insufficient to completely reveal the genetic factors for AD. A more thorough and efficient approach is required to study the genetic factors of complex diseases like AD.…”

DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity

“…29 A genome-wide SNP study reveals the association of DAPK with LOAD. 9 Furthermore, mice with a deletion in DAPK kinase domain exhibit an enhanced spatial memory. 30 Although these studies implicate a potential impact of DAPK on AD, our finding that DAPK enhances MARK-induced tau phosphorylation and tau toxicity provides a molecular linkage of DAPK to tauopathy-related neurodegenerative disorders, such as AD.…”

“…1,7,8 A further connection of DAPK to neuronal diseases comes from a largescale genetic study, which identifies the association of two single nucleotide polymorphisms (SNPs) in DAPK with lateonset Alzheimer's disease (LOAD). 9 However, the causal relationship between DAPK and LOAD has not been established.…”