Human Molecular Genetics Advance Access originally published online on February 22, 2007
Human Molecular Genetics 2007 16(8):865-873; 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 and Biostatistics and Bioinformatics Unit, Wales School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK, 3 Rosetta Inpharmatics, 401 Terry Avenue North, Seattle, WA 98109, USA, 4 Department of Psychiatry, 5 Department of Neurology and 6 Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, USA, 7 Department of Public Health and Primary Care and 8 Department of Medical Genetics, Cambridge University, Cambridge CB2 2XY, UK, 9 Department of Psychiatry and 10 Institute of Neurology, Trinity College, Dublin 8, Ireland, 11 Department of Neuroscience, Institute of Psychiatry King's College London, London SE5 8AF, UK and 12 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
* To whom correspondence should be addressed. Tel: +1 2920743247; Fax: +1 2920746554; Email: williamsj{at}cardiff.ac.uk or andrew.grupe{at}celeradiagnostics.com
Received November 1, 2006; Revised January 12, 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 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 APOE
4 and 2/3 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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