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Complement receptor 1 gene (CR1) intragenic duplication and risk of Alzheimer’s disease

Kucukkilic, Ezgi; Brookes, Keeley; Barber, Imelda; Guetta-Baranes, Tamar; Morgan, Kevin; Hollox, Edward

Authors

Ezgi Kucukkilic

Keeley Brookes

Imelda Barber

Tamar Guetta-Baranes

KEVIN MORGAN kevin.morgan@nottingham.ac.uk
Professor of Human Genomics and Molecular Genetics

Edward Hollox



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 (PRT) 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 bitter fit to our data compared to incorporating the SNP-defined risk haplotype, supporting the CR1-B allele as the variant underlying the increased risk of late-onset Alzheimer’s disease.

Citation

Kucukkilic, E., Brookes, K., Barber, I., Guetta-Baranes, T., Morgan, K., & Hollox, E. (in press). Complement receptor 1 gene (CR1) intragenic duplication and risk of Alzheimer’s disease. Human Genetics, https://doi.org/10.1007/s00439-018-1883-2

Journal Article Type Article
Acceptance Date Mar 19, 2018
Online Publication Date Apr 19, 2018
Deposit Date Mar 22, 2018
Publicly Available Date Apr 19, 2018
Journal Human Genetics
Print ISSN 0340-6717
Electronic ISSN 1432-1203
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Book Title Complement receptor 1 gene (CR1) intragenic duplication and risk of Alzheimer's disease
DOI https://doi.org/10.1007/s00439-018-1883-2
Public URL http://eprints.nottingham.ac.uk/id/eprint/50597
Publisher URL https://link.springer.com/article/10.1007%2Fs00439-018-1883-2
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0


10.1007%2Fs00439-018-1883-2.pdf (1.5 Mb)
PDF

Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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