Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease

Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants 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 of TYROBP and causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelic TYROBP deletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelic TYROBP deletion 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 monoallelic TYROBP deletion carrier with NHD-type bone cysts. Mechanistically, monoallelic TYROBP deletion leads to decreased levels of DAP12 protein (encoded by TYROBP ) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP . Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting. ### Competing Interest Statement CH collaborates with Denali Therapeutics and is a member of the advisory boards of AviadoBio and Cure Ventures. The other authors declare that they have no competing interests. ### Funding Statement This study was funded by the following: Research Council of Finland (to HM, MH, MT, VL). Faculty of Health Sciences, University of Eastern Finland (to HM, MT). Sigrid Juselius Foundation (to MH, VL, ES, TN). The Strategic Neuroscience Funding of the University of Eastern Finland (to MH, AH, VL, ES). Alzheimer's Association (to MH). The State Research Funding KUH-VTR (to VL, ES). Doctoral Programme in Molecular Medicine (to RMW, HJ). Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Nuerology, SyNergy (to CH and SFL) and a Koselleck Project (to CH). JPco-fuND 2019 Personalised Medicine for Neurodegenerative Diseases; PMG-AD (to CH, SFL, JCL, and MH). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Medical Research Ethics committee of Wellbeing Services County of North Savo gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data associated with this study are present in the paper or the Supplementary Materials. The study participant consent does not allow opening the sequencing (WGS, RNA-seq) or proteomic data generated and analyzed during the current study, but they are available from the corresponding authors (H.M. or M.H.) on reasonable request. Summary statistics from each FinnGen data release will be made publicly available after a one-year embargo period and can be accessed freely at www.finngen.fi/en/access_results. For individual level data, the Finnish biobank data can be accessed through the Fingenious services (https://site.fingenious.fi/en/) managed by FINBB. Access to Finnish Health register data can be applied from Findata (https://findata.fi/en/data/).