Immune-related genetic enrichment in frontotemporal dementia
Authors
Iris Broce, Celeste Karch, Natalie Wen, Chun Fan, Yunpeng Wang, Chin Hong Tan, Naomi Kouri, Owen Ross, Günter Höglinger, Ulrich Muller, John Hardy, Parastoo Momeni, Christopher Hess, William Dillon, Zachary Miller, Luke Bonham, Gil Rabinovici, Howard Rosen, Gerard Schellenberg, Andre Franke, Tom Karlsen, Jan Veldink, Raffaele Ferrari, Jennifer Yokoyama, Bruce Miller, Ole Andreassen, Anders Dale, Rahul Desikan, Leo Sugrue, R Ferrari, DG Hernandez, MA Nalls, JD Rohrer, A Ramasamy, JBJ Kwok, C Dobson-Stone, PR Schofield, GM Halliday, JR Hodges, O Piguet, L Bartley, E Thompson, E Haan, I Hernández, A Ruiz, M Boada, B Borroni, A Padovani, C Cruchaga, NJ Cairns, L Benussi, G Binetti, R Ghidoni, G Forloni, D Albani, D Galimberti, C Fenoglio, M Serpente, E Scarpini, J Clarimón, A Lleó, R Blesa, M Landqvist Waldö, K Nilsson, C Nilsson, IRA Mackenzie, G-Y Hsiung, DMA Mann, J Grafman, CM Morris, J Attems, TD Griffiths, IG McKeith, AJ Thomas, P Pietrini, ED Huey, EM Wassermann, A Baborie, E Jaros, MC Tierney, P Pastor, C Razquin, S Ortega-Cubero, E Alonso, R Perneczky, J Diehl-Schmid, P Alexopoulos, A Kurz, I Rainero, E Rubino, L Pinessi, E Rogaeva, St George-Hyslop, G Rossi, F Tagliavini, G Giaccone, JB Rowe, JCM Schlachetzki, J Uphill, J Collinge, S Mead, A Danek, VM Van Deerlin, M Grossman, JQ Trojanowski, van der Zee, M Cruts, Van Broeckhoven, SF Cappa, I Leber, D Hannequin, V Golfier, M Vercelletto, A Brice, B Nacmias, S Sorbi, S Bagnoli, I Piaceri, JE Nielsen, LE Hjermind, M Riemenschneider, M Mayhaus, B Ibach, G Gasparoni, S Pichler, W Gu, MN Rossor, NC Fox, JD Warren, MG Spillantini, HR Morris, P Rizzu, P Heutink, JS Snowden, S Rollinson, A Richardson, A Gerhard, AC Bruni, R Maletta, F Frangipane, C Cupidi, L Bernardi, M Anfossi, M Gallo, ME Conidi, N Smirne, R Rademakers, M Baker, DW Dickson, NR Graff-Radford, RC Petersen, D Knopman, KA Josephs, BF Boeve, JE Parisi, WW Seeley, BL Miller, AM Karydas, H Rosen, JC van Swieten, EGP Dopper, H Seelaar, YAL Pijnenburg, P Scheltens, G Logroscino, R Capozzo, V Novelli, AA Puca, M Franceschi, A Postiglione, G Milan, P Sorrentino, M Kristiansen, H-H Chiang, C Graff, F Pasquier, A Rollin, V Deramecourt, T Lebouvier, D Kapogiannis, L Ferrucci, S Pickering-Brown, AB Singleton, J Hardy, P Momeni
Year of publication
2017Journal
UKNVolume
-Issue
-Abstract
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.
Methods and findings
Using large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with ‘FTD-related disorders’ namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) – and one or more immune-mediated diseases including Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) < 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen ( HLA) region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci within LRRK2 (Leucine Rich Repeat Kinase 2) , TBKBP1 (TANK-binding kinase 1 Binding Protein 1), and PGBD5 (PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types.
Conclusions
We show considerable 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 risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.