| Summary: | 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: <i>CLU</i>, encoding the fluid-phase complement inhibitor clusterin; <i>CR1</i> encoding complement receptor 1 (CR1); and recently, <i>C1S</i> 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 <i>CLU</i> and <i>CR1</i> genes with LOAD but showed no significant associations for the complement gene-set when excluding <i>CLU</i> and <i>CR1</i>. No significant association with other complement genes, including <i>C1S</i>, was seen in the IGAP dataset; however, these may emerge from larger datasets.
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