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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 ORCID:, Williams, Julie ORCID: and Morgan, B. Paul ORCID: 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: 18 Jun 2024 01:05

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