title: 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.
authors.affiliation: Celera Diagnostics, Alameda, CA 94502, USA. yonghong.li@celeradiagnostics.com
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Li
authors.forename: Andrew
authors.initials: A
authors.lastname: Grupe
authors.forename: Charles
authors.initials: C
authors.lastname: Rowland
authors.forename: Petra
authors.initials: P
authors.lastname: Nowotny
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Scott
authors.initials: S
authors.lastname: Smemo
authors.forename: Anthony
authors.initials: A
authors.lastname: Hinrichs
authors.forename: Kristina
authors.initials: K
authors.lastname: Tacey
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Toombs
authors.forename: Shirley
authors.initials: S
authors.lastname: Kwok
authors.forename: Joseph
authors.initials: J
authors.lastname: Catanese
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: White
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Maxwell
authors.forename: Paul
authors.initials: P
authors.lastname: Hollingworth
authors.forename: Richard
authors.initials: R
authors.lastname: Abraham
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.forename: Fabienne
authors.initials: F
authors.lastname: Wavrant-De Vrièze
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Thal
authors.forename: Michael
authors.initials: M
authors.lastname: Owen
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
mesh_terms: 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
chemical_list: D051017:Apoptosis Regulatory Proteins; D005819:Genetic Markers; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases