Human Molecular Genetics Advance Access originally published online on July 17, 2006
Human Molecular Genetics 2006 15(17):2560-2568; doi:10.1093/hmg/ddl178
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DAPK1 variants are associated with Alzheimer's disease and allele-specific expression
1 Celera Diagnostics, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA, 2 Departments of Psychiatry, Neurology, Genetics and Biology, Washington University, St Louis, MO 63110, USA, 3 Department of Psychological Medicine and Biostatistics and Bioinformatics Unit, Cardiff University, Wales College of Medicine, Cardiff CF14 4XN, UK, 4 Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge CB2 2XY, UK, 5 Department of Public Health and Primary Care, Institute of Public Health, Cambridge CB2 2SR, UK, 6 National, Institute on Aging, Bethesda, MD 20892, USA, 7 Departments of Old Age Psychiatry and Neuroscience, MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, London SE5 8AF, UK and 8 Department of Neurosciences, University of California, San Diego, CA 92093, USA
* To whom correspondence should be addressed. Tel: +1 5107496283; Fax: +1 5107496200; Email: yonghong.li{at}celeradiagnostics.com
Received May 2, 2006; Revised July 7, 2006; Accepted July 11, 2006
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.
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