Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants
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 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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Prior genome-wide association studies of AD all identified strong evidence for association to APOE but less convincing evidence implicating other genes.
“All have identified strong evidence for association to APOE, but less convincing evidence implicating other genes2 -9 .”
From Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease (2009) · cites this paper as [7]
APOE4 increases the risk for developing Alzheimer's disease by 2.5-4-fold in heterozygous carriers and 12-15-fold in homozygous carriers.
“APOE4 increases the risk for developing AD by 2.5-4-fold in heterozygous and 12-15-fold in homozygous carriers (Corder et al., 1993; Grupe et al., 2007; Corneveaux et al., 2010), however the risk is affected by factors such as sex or population ancestry (Belloy et al., 2023).”
From APOE genotype-dependent differences in human astrocytic energy metabolism (2025) · cites this paper as Grupe et al., 2007
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- Authors
- 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., Lovestone, S., Holmans, P., O'Donovan, M., Morris, J. C., Thal, L., Goate, A., Owen, M. J., & Williams, J.
- Affiliations
- Cardiff University (GB)
- Washington University in St. Louis (US)
- University of Cambridge (GB)
- Trinity College Dublin (IE)
- King's College London (GB)
- University of California San Diego (US)
- Corresponding author
- Grupe, Andrew
- Williams, Julie
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-02-22
- Volume
- 16
- Issue
- 8
- Pages
- 865-873
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2166966137
- Cited by
- 289
- References
- 0
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 6 · 2023: 11 · 2022: 9 · 2021: 8 · 2020: 5 · 2019: 12 · 2018: 12 · 2017: 17 · 2016: 10 · 2015: 8 · 2014: 9 · 2013: 9 · 2012: 23
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Wellcome Trust (064354)
- Alzheimer's Research Trust
- Medical Research Council
- National Institute on Aging (P50AG005131, P50AG005681, P01AG003991, R01AG016208)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- late-onset Alzheimer's disease, genetic susceptibility, single nucleotide polymorphisms, chromosome 19, apolipoprotein E, linkage disequilibrium, APOE ε4, missense mutations, candidate genes, genome-wide association study
- MeSH terms
- Aged, Alzheimer Disease, Chromosome Mapping, Female, Genetic Markers, Genotype, United Kingdom, Humans, Genetic Linkage, Male, Middle Aged, United States, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Gene Silencing
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