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

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: https://nottingham-repository.worktribe.com/output/926923
• Publisher URL: https://link.springer.com/article/10.1007%2Fs00439-018-1883-2