Complement receptor 1 gene (CR1) intragenic duplication and risk of Alzheimer’s disease
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Abstract
Single nucleotide variants (SNVs) within and surrounding the complement receptor 1 (CR1) gene show some of the strongest genome-wide association signals with late-onset Alzheimer's disease. Some studies have suggested that this association signal is due to a duplication allele (CR1-B) of a low copy repeat (LCR) within the CR1 gene, which increases the number of complement C3b/C4b-binding sites in the mature receptor. In this study, we develop a triplex paralogue ratio test assay for CR1 LCR copy number allowing large numbers of samples to be typed with a limited amount of DNA. We also develop a CR1-B allele-specific PCR based on the junction generated by an historical non-allelic homologous recombination event between CR1 LCRs. We use these methods to genotype CR1 and measure CR1-B allele frequency in both late-onset and early-onset cases and unaffected controls from the United Kingdom. Our data support an association of late-onset Alzheimer's disease with the CR1-B allele, and confirm that this allele occurs most frequently on the risk haplotype defined by SNV alleles. Furthermore, regression models incorporating CR1-B genotype provide a better fit to our data compared to incorporating the SNV-defined risk haplotype, supporting the CR1-B allele as the variant underlying the increased risk of late-onset Alzheimer's disease.
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The analyses nominate alternative candidates at three AD risk loci: CR2 at 1q32.2, PILRA at 7q22.1, and PRSS8 at 16p11.2.
“Our analyses also nominate alternative candidates at three AD risk loci. First, the association at 1q32.2 has been linked to CR153–55, but we observed a colocalized association for both CR1 and CR2 levels with AD risk (Supp. Fig. 23).”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [54]
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Western, D., Timsina, J., Wang, L., Wang, C., Yang, C., Phillips, B., Wang, Y., Liu, M., Ali, M., Beric, A., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01972-8 · Cited by 111 · see citing works
- Authors
- ARUK Consortium, Kucukkilic, E., Brookes, K., Barber, I., Guetta-Baranes, T., Morgan, K., & Hollox, E. J.
- Affiliations
- University of Leicester (GB)
- University of Nottingham (GB)
- Corresponding author
- Hollox, Edward J.
- Venue
- Human Genetics
- Published
- 2018-04
- Volume
- 137
- Issue
- 4
- Pages
- 305-314
- ISSN
- 0018-7348 (ISSN-L)
- 0340-6717
- 1432-1203
- PMC
- PMC5937907
- OpenAlex
- W2952845963
- Cited by
- 33
- References
- 8
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 2 · 2021: 8 · 2020: 4 · 2019: 1 · 2018: 1
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Human Genetics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Nottingham ePrints (University of Nottingham) (acceptedVersion)
- Nottingham Trent University's Institutional Repository (Nottingham Trent Repository) (acceptedVersion)
- Repository@Nottingham (University of Nottingham) (acceptedVersion, other-oa)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- Alzheimer’s Research UK
- 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
- complement receptor 1, intragenic duplication, late-onset Alzheimer's disease, early-onset Alzheimer's disease, single nucleotide variants, risk haplotype, allele-specific PCR, non-allelic homologous recombination, copy number
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Binding Sites, Complement C3b, Female, Genotype, United Kingdom, Humans, Male, Middle Aged, Risk Factors, Receptors, Complement 3b, Genetic Predisposition to Disease, Gene Duplication, Polymorphism, Single Nucleotide, Complement C4b-Binding Protein, Genome-Wide Association Study, DNA Copy Number Variations
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