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

Andrew Grupe, Richard Abraham, Yonghong Li, Charles Rowland, Paul Hollingworth, Angharad Morgan, Luke Jehu, Ricardo Segurado, David Stone, Eric Schadt, Maha Karnoub, Petra Nowotny, Kristina Tacey, Joseph Catanese, John Sninsky, Carol Brayne, David Rubinsztein, Michael Gill, Brian Lawlor, Simon LovestonePeter Holmans, Michael O'Donovan, John C. Morris, Leon Thal, Alison Goate, Michael J. Owen, Julie Williams

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Abstract

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 APOEε4 and ε2/3 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).

Original languageEnglish
Pages (from-to)865-873
Number of pages9
JournalHuman molecular genetics
Volume16
Issue number8
DOIs
StatePublished - Apr 15 2007

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    Grupe, A., Abraham, R., Li, Y., Rowland, C., Hollingworth, P., Morgan, A., Jehu, L., Segurado, R., Stone, D., Schadt, E., Karnoub, M., Nowotny, P., Tacey, K., Catanese, J., Sninsky, J., Brayne, C., Rubinsztein, D., Gill, M., Lawlor, B., ... Williams, J. (2007). Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants. Human molecular genetics, 16(8), 865-873. https://doi.org/10.1093/hmg/ddm031