Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease
Henna Martiskainen, Roosa-Maria Willman, Päivi Harju, Sami Heikkinen, Mette Heiskanen, Stephan A. Müller, Rosa Sinisalo, Mari Takalo, Petra Mäkinen, Teemu Kuulasmaa, Viivi Pekkala, Ana Galván del Rey, Sini-Pauliina Juopperi, Heli Jeskanen, Inka Kervinen, Kirsi Saastamoinen, FinnGen, Aarno Palotie, Mark Daly, Bridget Riley-Gills, Howard Jacob, Coralie Viollet, Slavé Petrovski, Chia-Yen Chen, Sally John, George Okafo, Robert Plenge, Joseph Maranville, Mark McCarthy, Rion Pendergrass, Jonathan Davitte, Kirsi Auro, Simonne Longerich, Anders Mälarstig, Anna Vlahiotis, Katherine Klinger, Clement Chatelain, Matthias Gossel, Karol Estrada, Robert Graham, Dawn Waterworth, Chris O´Donnell, Nicole Renaud, Tomi P. Mäkelä, Jaakko Kaprio, Minna Ruddock, Petri Virolainen, Antti Hakanen, Terhi Kilpi, Markus Perola, Jukka Partanen, Taneli Raivio, Jani Tikkanen, Raisa Serpi, Kati Kristiansson, Veli-Matti Kosma, Jari Laukkanen, Marco Hautalahti, Outi Tuovila, Jeffrey Waring, Bridget Riley-Gillis, Fedik Rahimov, Ioanna Tachmazidou, Zhihao Ding, Marc Jung, Hanati Tuoken, Shameek Biswas, Neha Raghavan, Adriana Huertas-Vazquez, Jae-Hoon Sul, Xinli Hu, Åsa Hedman, Ma´en Obeidat, Jonathan Chung, Jonas Zierer, Mari Niemi, Samuli Ripatti, Johanna Schleutker, Mikko Arvas, Olli Carpén, Reetta Hinttala, Johannes Kettunen, Arto Mannermaa, Katriina Aalto-Setälä, Mika Kähönen, Johanna Mäkelä, Reetta Kälviäinen, Valtteri Julkunen, Anne Remes, Jukka Peltola, Minna Raivio, Pentti Tienari, Roosa Kallionpää, Juulia Partanen, Adam Ziemann, Nizar Smaoui, Anne Lehtonen, Susan Eaton, Heiko Runz, Sanni Lahdenperä
Abstract
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.