DAPK1 variants are associated with Alzheimer's disease and allele-specific expression.
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.
Li
Yonghong
Y
Celera Diagnostics, Alameda, CA 94502, USA. yonghong.li@celeradiagnostics.com
Grupe
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A
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C
Nowotny
Petra
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Kauwe
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JS
Smemo
Scott
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Hinrichs
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Tacey
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Toombs
Timothy A
TA
Kwok
Shirley
S
Catanese
Joseph
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White
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Hollingworth
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Abraham
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David C
DC
Brayne
Carol
C
Wavrant-De Vrièze
Fabienne
F
Hardy
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O'Donovan
Michael
M
Lovestone
Simon
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Morris
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JC
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Owen
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Goate
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D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D016022:Case-Control Studies; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D030561:Databases, Nucleic Acid; D064550:Death-Associated Protein Kinases; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide
D051017:Apoptosis Regulatory Proteins; D005819:Genetic Markers; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases