Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Broce, Iris; Karch, Celeste M; Wen, Natalie; Fan, Chun C; Wang, Yunpeng; Tan, Chin Hong; Kouri, Naomi; Ross, Owen A; Höglinger, Günter U; Muller, Ulrich; Hardy, John; Momeni, Parastoo; Hess, Christopher P; Dillon, William P; Miller, Zachary A; Bonham, Luke W; Rabinovici, Gil D; Rosen, Howard J; Schellenberg, Gerard D; Franke, Andre; Karlsen, Tom H; Veldink, Jan H; Ferrari, Raffaele; Hernandez, Dg; Nalls, Ma; Rohrer, Jd; Ramasamy, A; Kwok, Jbj; Dobson-Stone, C; Brooks, Ws; Schofield, Pr; Halliday, Gm; Hodges, Jr; Piguet, O; Bartley, L; Thompson, E; Haan, E; Hernández, I; Ruiz, A; Boada, M; Borroni, B; Padovani, A; Cruchaga, C; Cairns, Nj; Benussi, L; Binetti, G; Ghidoni, R; Forloni, G; Galimberti, D; Fenoglio, C; Serpente, M; Scarpini, E; Clarimón, J; Lleó, A; Blesa, R; Waldö, Ml; Nilsson, K; Nilsson, C; Mackenzie, Ira; Hsuing, Gyr; Mann, Dma; Grafman, J; Morris, Cm; Attems, J; Griffiths, Td; Mckeith, Ig; Thomas, Aj; Pietrini, P; Huey, Ed; Wasserman, Em; Baborie, A; Jaros, E; Tierney, Mc; Pastor, P; Razquin, C; Ortega-Cubero, S; Alonso, E; Perneczky, E; Diehl-Schmid, J; Alexopoulos, P; Kurz, A; Rainero, I; Rubino, E; Pinessi, L; Rogaeva, E; St George-Hyslop, P; Rossi, G; Tagliavini, F; Giaccone, G; Rowe, Jb; Schlachetzki, Jcm; Uphill, J; Collinge, J; Mead, S; Danek, A; Van Deerlin, Vm; Grossmann, M; Trojanowski, Q; Van Der Zee, J; Deschamps, W; Van Langenhove, T; Cruts, M; Van Broeckhoven, C; Cappa, Sf; Le Ber, I; Hannequin, D; Golfier, V; Vercelletto, M; Brice, A; Nacmias, B; Sorbi, S; Bagnoli, S; Piaceri, I; Nielsen, Je; Hjermind, Le; Riemenschneider, M; Mayhaus, M; Ibach, B; Gasparoni, G; Pichler, S; Gu, W; Rossor, Mn; Fox, Nc; Warren, Jd; Spillantini, Mg; Morris, Hr; Rizzu, P; Heutnik, P; Snowden, J; Rollinson, S; Richardson, A; Gerhard, A; Bruni, Ac; Maletta, R; Frangipane, F; Cupidi, C; Bernardi, L; Anfossi, M; Gallo, M; Conidi, Me; Smirne, N; Rademakers, R; Baker, M; Dickson, Dw; Graff-Radford, Nr; Peterson, Rc; Knopman, D; Josephs, Ka; Boeve, Bf; Parisi, Je; Seeley, Ww; Miller, Bl; Karydas, Am; Rosen, H; Van Swieten, Jc; Dopper, Egp; Seelaar, H; Pijnenburg, Yal; Scheltens, P; Logroscino, G; Capozzo, R; Novelli, V; Puca, Aa; Franceschi, M; Postiglione, A; Milan, G; Sorrentino, P; Kristiansen, M; Chiang, Hh; Graff, C; Pasquier, F; Rollin, A; Deramecourt, V; Lebert, F; Kapogiannis, D; Ferucci, L; Pickering-Brown, S; Singleton, Ab; Hardy, J; Momeni, P; Yokoyama, Jennifer S; Miller, Bruce L; Andreassen, Ole A; Dale, Anders M; Desikan, Rahul S; Sugrue, Leo P

doi:10.1371/journal.pmed.1002487

BACKGROUND: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. CONCLUSIONS: We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies / Broce, I., Karch, C.M., Wen, N., Fan, C.C., Wang, Y., Tan, C.H., Kouri, N., Ross, O.A., Höglinger, G.U., Muller, U., Hardy, J., Momeni, P., Hess, C.P., Dillon, W.P., Miller, Z.A., Bonham, L.W., Rabinovici, G.D., Rosen, H.J., Schellenberg, G.D., Franke, A., et al.. - In: PLOS MEDICINE. - ISSN 1549-1277. - ELETTRONICO. - 15:(2018), pp. e1002487-0. [10.1371/journal.pmed.1002487]