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Cited by 195Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

A genome-wide association study for late-onset Alzheimer's disease using DNA pooling

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Abraham, Richard, Moskvina, Valentina, Sims, Rebecca, Hollingworth, Paul, Morgan, Angharad, Georgieva, Lyudmila, Dowzell, Kimberley, Cichon, Sven +5 more·2008·BMC Medical Genomics
DOI 10.1186/1755-8794-1-44PMC PMC2570675
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Abstract

Background: Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case – control sample, reducing costs through the use of DNA pooling. Methods: DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case – control sample used to construct the pools. Results: Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach. For 109 SNPs outside the APOE locus, we obtained uncorrected p-values ≤ 0.05 for 74 after individual genotyping. To further test these associations, we added control data from 1400 subjects from the 1958 Birth Cohort with the evidence for association increasing to 3.4 × 10-6 for our strongest finding, rs727153. rs727153 lies 13 kb from the start of transcription of lecithin retinol acyltransferase (phosphatidylcholine – retinol O-acyltransferase, LRAT). Five of seven tag SNPs chosen to cover LRAT showed significant association with LOAD with a SNP in intron 2 of LRAT, showing greatest evidence of association (rs201825, p-value = 6.1 × 10-7). Conclusion: We have validated the pooling method for GWA studies by both identifying the APOE locus and by observing a strong enrichment for significantly associated SNPs. We provide evidence for LRAT as a novel candidate gene for LOAD. LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in 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 [2]

    The Results report a much stronger association at APOE than elsewhere in this genome-wide study, and the Discussion says APOE is well replicated while other loci of smaller effect remain to be identified. The paper does not establish that *all* prior AD genome-wide association studies found this pattern; it specifically mentions one other GWAS that observed APOE. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • 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 [89]

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Research works printed but not linked: 37

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Authors
Abraham, R., Moskvina, V., Sims, R., Hollingworth, P., Morgan, A., Georgieva, L., Dowzell, K., Cichon, S., Hillmer, A. M., O'Donovan, M. C., Williams, J., Owen, M. J., & Kirov, G.
Affiliations
  • Cardiff University (GB)
  • University of Bonn (DE)
Corresponding author
Owen, Michael J
ORCID
Venue
BMC Medical Genomics
Publisher
Springer Science and Business Media LLC
Published
2008-09-29
Volume
1
Issue
1
Pages
44-44
ISSN
1755-8794 (ISSN-L)
DOI
10.1186/1755-8794-1-44
PMC
PMC2570675
OpenAlex
W2076831307
Cited by
195
References
46
Citations by year
2026: 3 · 2025: 4 · 2024: 4 · 2023: 8 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 10 · 2017: 10 · 2016: 12 · 2015: 11 · 2014: 10 · 2013: 15 · 2012: 19
FWCI
16.75
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Medical Genomics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
Funders
  • Alzheimer's Research Trust
  • Medical Research Council
  • Cambridge Institute for Medical Research, University of Cambridge
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, DNA pooling, genome-wide association study, apolipoprotein E, LRAT, genetic susceptibility loci, tag SNPs, 1958 British birth cohort, neurodegenerative disease genetics, apolipoproteins

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