MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease

Abstract

Biallelic loss-of-function variants inTYROBPandTREM2cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some otherTREM2variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleteriousTYROBPvariants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1-4 ofTYROBPand causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelicTYROBPdeletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelicTYROBPdeletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelicTYROBPdeletion carrier with NHD-type bone cysts. Mechanistically, monoallelicTYROBPdeletion leads to decreased levels of DAP12 protein (encoded byTYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelicTYROBPdeletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies ofTYROBP. Collectively, our findings indicateTYROBPdeletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.