Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants.


This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case-control sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P = 6.94E - 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOEepsilon4 and epsilon2/3 variants (0.09 < D'<1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P = 0.0010-0.00006; odds ratio (OR) = 1.07-1.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P = 0.00005, OR = 1.2, false positive rate = 0.87).

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@article{Grupe2007EvidenceFN, title={Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants.}, author={Andrew Grupe and Richard Abraham and Yonghong Li and Charles Rowland and Paul Hollingworth and Angharad R. Morgan and Luke Jehu and Ricardo Segurado and David Stone and Eric E. Schadt and Maha C Karnoub and P. Nowotny and Kristina M. Tacey and Joseph J. Catanese and John Sninsky and Carol Brayne and David C Rubinsztein and Michael Gill and Brian A Lawlor and Simon Lovestone and Peter Holmans and Michael C. O'Donovan and John C. Morris and Leon Thal and Alison M. Goate and Michael J. Owen and Julie Williams}, journal={Human molecular genetics}, year={2007}, volume={16 8}, pages={865-73} }