| Title: |
Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease |
| Authors: |
FinnGen; Martiskainen, Henna; Willman, Roosa-Maria; Harju, Päivi; Heikkinen, Sami; Heiskanen, Mette; Müller, Stephan A.; Sinisalo, Rosa; Takalo, Mari; Mäkinen, Petra; Kuulasmaa, Teemu; Pekkala, Viivi; del Rey, Ana Galván; Juopperi, Sini-Pauliina; Jeskanen, Heli; Kervinen, Inka; Saastamoinen, Kirsi; Niiranen, Marja; Heikkinen, Sami V.; Kurki, Mitja I.; Marttila, Jarkko; Mäkinen, Petri I.; Rostalski, Hannah; Hietanen, Tomi; Ngandu, Tiia; Lehtisalo, Jenni; Bellenguez, Céline; Lambert, Jean-Charles; Haass, Christian; Rinne, Juha; Hakumäki, Juhana; Rauramaa, Tuomas; Krüger, Johanna; Soininen, Hilkka; Haapasalo, Annakaisa; Lichtenthaler, Stefan F.; Leinonen, Ville; Solje, Eino; Hiltunen, Mikko; Palotie, Aarno; Mäkelä, Tomi P.; Kaprio, Jaakko; Ruddock, Minna; Perola, Markus; Raivio, Taneli; Ripatti, Samuli; Carpen, Olli Mikael; Tienari, Pentti; Färkkilä, Martti; Kauppi, Paula; Taskinen, Marja-Riitta; Tuomi, Tiinamaija; Meretoja, Tuomo; Joensuu, Heikki; Pussinen, Pirkko; Salo, Tuula; Palotie, Ulla; Laivuori, Hannele; Heikinheimo, Oskari; Kalliala, Ilkka; Hovatta, Iiris; Isometsä, Erkki; Mäkitie, Antti; Toppila-Salmi, Sanna; Åberg, Fredrik; Havulinna, Aki; Palta, Priit; Lemmelä, Susanna; Ganna, Andrea; Rämö, Joel; Strausz, Satu; Palotie, Tuula; Palin, Kimmo |
| Contributors: |
Institute for Molecular Medicine Finland; Helsinki Institute of Life Science HiLIFE; HUS Group; Research Programs Unit; Aarno Palotie / Principal Investigator; Genomics of Neurological and Neuropsychiatric Disorders; Helsinki Institute of Life Science HiLIFE, Joint Activities; Department of Biochemistry and Developmental Biology; Mäkelä Lab; Department of Physiology; Department of Public Health; Samuli Olli Ripatti / Principal Investigator; Complex Disease Genetics; Faculty Common Matters (Faculty of Social Sciences); Research Program in Systems Oncology; HUS Radiology and Pathology; Precision Cancer Pathology; Olli Mikael Carpen / Principal Investigator; HUS Neurocenter; Department of Neurosciences; Clinicum; HUS Abdominal Center; Department of Medicine; HUS Inflammation Center; Marja-Riitta Taskinen Research Group; Tiinamaija Tuomi Research Group; HUS Comprehensive Cancer Center; Department of Oncology; Heikki Joensuu / Principal Investigator; HUS Head and Neck Center; Department of Oral and Maxillofacial Diseases; Medicum; HUS Gynecology and Obstetrics; Department of Obstetrics and Gynecology; Mind and Matter; Department of Psychology; Iiris Hovatta / Principal Investigator; Department of Psychiatry; HUS Psychiatry; Korva-, nenä- ja kurkkutautien klinikka; Department of Pathology; IV kirurgian klinikka; Data Science Genetic Epidemiology Lab; ATG - Applied Tumor Genomics; Lauri Antti Aaltonen / Principal Investigator |
| Publisher Information: |
BMC |
| Publication Year: |
2025 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Alzheimer's disease; Dap12; Genetics; Nasu-Hakola disease; Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy; Tyrobp; Neurosciences |
| Description: |
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. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
We are thankful for the NHD patients and their families, and other sample donors for their participation in the study. We acknowledge Research Nurse Tanja Kumpulainen for her valuable work. We acknowledge the Biobank of Eastern Finland and Auria Biobank for access to biobank samples and/or recontacting biobank sample donors. The computational analyzes for WGS, RNA-sequencing, and proteome data were performed on servers provided by UEF Bioinformatics Center, University of Eastern Finland, Finland. Immunohistochemistry and live cell imaging with IncuCyte were carried out using infrastructure of UEF Cell and Tissue Imaging Unit, University of Eastern Finland, Biocenter Kuopio and Biocenter Finland. Illustration in Fig. 5A was created with BioRender.com. We acknowledge the participants and investigators of FinnGen study. Following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta), Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/) and Arctic Biobank (https://www.oulu.fi/en/university/faculties-and-units/faculty-medicine/northern-finland-birth-cohorts-and-arctic-biobank). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). Finnish Biobank Cooperative -FINBB (https://finbb.fi/) is the coordinator of BBMRI-ERIC operations in Finland.; https://hdl.handle.net/10138/596234; 105004338015; 001478659800001 |
| Availability: |
https://hdl.handle.net/10138/596234 |
| Rights: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.3D9A4207 |
| Database: |
BASE |