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: https://orcid.org/0000-0002-3885-1199, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259 and Morgan, B. Paul ORCID: https://orcid.org/0000-0003-4075-7676 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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Abstract

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
URI:	https://orca.cardiff.ac.uk/id/eprint/141877

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