Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Julie van der Zee, Tim Van Langenhove, Gabor G. Kovacs, Lubina Dillen, William Deschamps, Sebastiaan Engelborghs, Radoslav Matěj, Mathieu Vandenbulcke, Anne Sieben, Bart Dermaut, Katrien Smets, Philip Van Damme, Céline Merlin, Annelies Laureys, Marleen Van Den Broeck, Maria Mattheijssens, Karin Peeters, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Barbara Borroni, Alessandro Padovani, Silvana Archetti, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Isabel Hernández, Mercè Boada, Agustín Ruiz, Alexandre de Mendonça, Gabriel Miltenberger-Miltényi, Frederico Simões do Couto, Sandro Sorbi, Benedetta Nacmias, Silvia Bagnoli, Caroline Graff, Huei-Hsin Chiang, Håkan Thonberg, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Giovanni B. Frisoni, Christian Bonvicini, Matthis Synofzik, Walter Maetzler, Jennifer Müller vom Hagen, Ludger Schöls, Tobias B. Haack, Tim M. Strom, Holger Prokisch, Oriol Dols-Icardo, Jordi Clarimón, Alberto Lleó, Isabel Santana, Maria Rosário Almeida, Beatriz Santiago, Michael T. Heneka, Frank Jessen, Alfredo Ramirez, Raquel Sanchez-Valle, Albert Llado, Ellen Gelpi, Stayko Sarafov, Ivailo Tournev, Albena Jordanova, Eva Parobkova, Gian Maria Fabrizi, Silvia Testi, Eric Salmon, Thomas Ströbel, Patrick Santens, Wim Robberecht, Peter De Jonghe, Jean-Jacques Martin, Patrick Cras, Rik Vandenberghe, Peter Paul De Deyn, Marc Cruts, Kristel Sleegers, Christine Van Broeckhoven

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.