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The impact of complement genes on the risk of late-onset Alzheimer's disease

Carpanini, Sarah M., Harwood, Janet C., Baker, Emily, Torvell, Megan, Sims, Rebecca, Williams, Julie and Morgan, B. Paul 2021. The impact of complement genes on the risk of late-onset Alzheimer's disease. Genes 12 (3) , 443. 10.3390/genes12030443

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Late-onset Alzheimer’s disease (LOAD), the most common cause of dementia, and a huge global health challenge, is a neurodegenerative disease of uncertain aetiology. To deliver effective diagnostics and therapeutics, understanding the molecular basis of the disease is essential. Contemporary large genome-wide association studies (GWAS) have identified over seventy novel genetic susceptibility loci for LOAD. Most are implicated in microglial or inflammatory pathways, bringing inflammation to the fore as a candidate pathological pathway. Among the most significant GWAS hits are three complement genes: CLU, encoding the fluid-phase complement inhibitor clusterin; CR1 encoding complement receptor 1 (CR1); and recently, C1S encoding the complement enzyme C1s. Complement activation is a critical driver of inflammation; changes in complement genes may impact risk by altering the inflammatory status in the brain. To assess complement gene association with LOAD risk, we manually created a comprehensive complement gene list and tested these in gene-set analysis with LOAD summary statistics. We confirmed associations of CLU and CR1 genes with LOAD but showed no significant associations for the complement gene-set when excluding CLU and CR1. No significant association with other complement genes, including C1S, was seen in the IGAP dataset; however, these may emerge from larger datasets.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an open access article distributed under the Creative Commons Attribution License
Publisher: MDPI
ISSN: 2073-4425
Funders: Dementia Research Institute
Date of First Compliant Deposit: 11 June 2021
Date of Acceptance: 16 March 2021
Last Modified: 28 Sep 2022 08:10

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