Journal
HUMAN GENETICS
Volume 137, Issue 4, Pages 305-314Publisher
SPRINGER
DOI: 10.1007/s00439-018-1883-2
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Funding
- Alzheimer's Research UK
- Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, NG7 2UH, UK
- Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, UK
- Centre for Public Health, School of Medicine, Queen's University Belfast, BT9 7BL, UK
- Department of Psychiatry, University of Bonn, Bonn, Germany
- School of Clinical Sciences, John James Laboratories, University of Bristol, Bristol, BS16 1LE, UK
- Emma R. L. C. VardySalford Royal NHS Foundation Trust
- Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, UK
- University of Oxford (OPTIMA), Oxford, OX3 9DU, UK
- Clinical and Experimental Science, University of Southampton, Southampton, SO17 1BJ, UK
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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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