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

Li, Yonghong, O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Brayne, Carol, Rowland, Charles, Owen, Michael John ORCID: https://orcid.org/0000-0003-4798-0862, Morris, John C and Maxwell, Taylor J 2006. DAPK1 variants are associated with Alzheimer's disease and allele-specific expression. Human Molecular Genetics 15 (17) , pp. 2560-2568. 10.1093/hmg/ddl178

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Subjects:	R Medicine > R Medicine (General)
Publisher:	Oxford University Press
ISSN:	0964-6906
Last Modified:	31 Oct 2022 09:46
URI:	https://orca.cardiff.ac.uk/id/eprint/82399

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