Human Molecular Genetics Advance Access published online on February 22, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm031
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Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants
1 Celera Diagnostics, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA 2 Department of Psychological Medicine & Biostatistics and Bioinformatics Unit, Wales School of Medicine, Cardiff University, Cardiff CF14 4XN, UK 3 Rosetta Inpharmatics, 401 Terry Ave. North, Seattle, WA 98109, USA 4 Departments of Psychiatry, Neurology & Genetics Washington University School of Medicine, St. Louis, MO 63110, USA 5 Dept.s Public Health & Primary Care and Medical Genetics, Cambridge University, Cambridge, UK, CB2 2XY 6 Dept.s Psychiatry and Institute of Neurology, Trinity College, Dublin 8, Ireland 7 Department of Neuroscience, Institute of Psychiatry, King's College London, London, SE5 8AF, UK 8 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
* To whom correspondence should be addressed at Department of Psychological Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, williamsj{at}cardiff.ac.uk; or at Celera Diagnostics, 1401 Harbor Bay Parkway, Alameda, CA 94502, andrew.grupe{at}celeradiagnostics.com
Received February 12, 2007; Revised February 14, 2007; Accepted February 14, 2007
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 US (1808 LOAD cases and 2062 controls). Allele frequencies of 17,343 gene based putative functional 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 4 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 with the APOE 
4 and 2/3 variants (0.09 < D' < 1). Two of the 3 SNPs can be regarded as study-wide significant (expected number of false-positives reaching the observed significance level < 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 (GALP) gene (p = 0.00005, OR = 1.2, false positive rate (FPR) = 0.87).
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