Genome-wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease
Open accessAbstract
Only Apolipoprotein E polymorphisms have been consistently associated with the risk of late-onset Alzheimer disease (LOAD), but they represent only a minority of the underlying genetic effect. To identify additional LOAD risk loci, we performed a genome-wide association study (GWAS) on 492 LOAD cases and 498 cognitive controls using Illumina's HumanHap550 beadchip. An additional 238 cases and 220 controls were used as a validation data set for single-nucleotide polymorphisms (SNPs) that met genome-wide significance. To validate additional associated SNPs (p < 0.0001) and nominally associated candidate genes, we imputed SNPs from our GWAS using a previously published LOAD GWAS(1) and the IMPUTE program. Association testing was performed with the Cochran-Armitage trend test and logistic regression, and genome-wide significance was determined with the False Discovery Rate-Beta Uniform Mixture method. Extensive quality-control methods were performed at both the sample and the SNP level. The GWAS confirmed the known APOE association and identified association with a 12q13 locus at genome-wide significance; the 12q13 locus was confirmed in our validation data set. Four additional highly associated signals (1q42, 4q28, 6q14, 19q13) were replicated with the use of the imputed data set, and six candidate genes had SNPs with nominal association in both the GWAS and the joint imputated data set. These results help to further define the genetic architecture of LOAD.
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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 [3]
Seven of the earliest GWAS, each of which used less than 2,000 cases, identified only APOE as significantly associated with Alzheimer's disease.
“seven of the earliest GWAS, each of which used less than 2,000 cases, identified only APOE as significantly associated with AD [84–90].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [86]
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- Authors
- Beecham, G. W., Martin, E. R., Li, Y.-J., Slifer, M. A., Gilbert, J. R., Haines, J. L., & Pericak-Vance, M. A.
- Affiliations
- University of Miami (US)
- Duke University (US)
- Vanderbilt University Medical Center (US)
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 84
- Issue
- 1
- Pages
- 35-43
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2668056
- OpenAlex
- W2171998949
- Cited by
- 260
- References
- 6
- Citations by year
- 2025: 3 · 2024: 6 · 2023: 5 · 2022: 8 · 2021: 9 · 2020: 6 · 2019: 3 · 2018: 11 · 2017: 13 · 2016: 16 · 2015: 13 · 2014: 19 · 2013: 18 · 2012: 26
- FWCI
- 28.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- National Institutes of Health (5r01ag027944-05, 7r01ag019757-06)
- National Institute on Aging (AG20135, AG19757, R01-AG027944, R01-AG019757, R01AG020135, U24AG021886)
- National Institute of Neurological Disorders and Stroke (NS31 153, R01NS031153)
- 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 loci, chromosome 12q13, apolipoprotein E, single nucleotide polymorphisms, candidate genes, genetic architecture, imputation, 19q13
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Chromosomes, Human, Pair 12, Female, Humans, Male, Middle Aged, Risk, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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