TY - JOUR
T1 - DAPK1 variants are associated with Alzheimer's disease and allele-specific expression
AU - Li, Yonghong
AU - Grupe, Andrew
AU - Rowland, Charles
AU - Nowotny, Petra
AU - Kauwe, John S.K.
AU - Smemo, Scott
AU - Hinrichs, Anthony
AU - Tacey, Kristina
AU - Toombs, Timothy A.
AU - Kwok, Shirley
AU - Catanese, Joseph
AU - White, Thomas J.
AU - Maxwell, Taylor J.
AU - Hollingworth, Paul
AU - Abraham, Richard
AU - Rubinsztein, David C.
AU - Brayne, Carol
AU - Wavrant-De Vrièze, Fabienne
AU - Hardy, John
AU - O'Donovan, Michael
AU - Lovestone, Simon
AU - Morris, John C.
AU - Thal, Leon J.
AU - Owen, Michael
AU - Williams, Julie
AU - Goate, Alison
N1 - Funding Information:
We thank the families/individuals for their invaluable participation in this study, John Sninsky and Sam Broder for stimulating discussions, and our colleagues at Celera Diagnostics for providing expert technical support. We acknowledge Mary Coats and Elizabeth Grant for coordinating the Washington University material, Mary Sundsmo for coordinating the University of California, San Diego, case material, Pamela Moore and Dragana Turic for providing clinical/DNA samples from the MRC UK Genetic Resource for LOAD. Funding for this work was partly provided by the National Institute of Health [Alzheimer’s Disease Research Center Grants P50 AG05681 (J.C.M.), P50 AG05131 (L.T.); RO1 AG16208 (A. Goate) and PO1 AG03991 (J.C.M.)], the Medical Research Council, UK (J.W., M.O., M.O’D. and S.L.), and the Alzheimer’s Research Trust (J.W., M.O., M.O’D. and S.L.). P.N. was partly supported by Missouri’s Alzheimer’s Disease and related Disorders Program. J.S.K.K. is a Ford Foundation Predoctoral Fellow and was supported by NIH training grant T32 HG00045. T.J.M. was supported by MICORTEX and NIH grant GM065509. J.H. was supported by the NIH intramural program and also by the VERUM Foundation (DIADEM project). D.C.R. is a Wellcome Trust Senior Research Fellow in Clinical Science.
Funding Information:
A. Grupe, C.R., K.T., T.A.T., S.K., J.C., T.J.W.) are employed by Celera Diagnostics. A. Goate received research funding from and was a consultant to Celera Diagnostics. M.O. and J.W. received research funding from Celera Diagnostics.
PY - 2006/9/1
Y1 - 2006/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33747876259&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddl178
DO - 10.1093/hmg/ddl178
M3 - Article
C2 - 16847012
AN - SCOPUS:33747876259
SN - 0964-6906
VL - 15
SP - 2560
EP - 2568
JO - Human molecular genetics
JF - Human molecular genetics
IS - 17
ER -