Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia

Mishra, A.; Ferrari, R.; Hardy, P. Heutink: J.; Pijnenburg, Y.; Posthuma, D.; Ferrari, on behalf of the International FTD-Genomics Consortium: R.; Hernandez, D. G.; Nalls, M. A.; Rohrer, J. D.; Ramasamy, A.; Kwok, J. B. J.; Dobson-Stone, C.; Schofield, P. R.; Halliday, G. M.; Hodges, J. R.; Piguet, O.; Bartley, L.; Thompson, E.; Haan, E.; Herna´ Ndez, I.; Ruiz, A.; Boada, M.; Borroni, B.; Padovani, A.; Cruchaga, C.; Cairns, N. J.; Benussi, L.; Binetti, G.; Ghidoni, R.; Forloni, G.; Albani, D.; Galimberti, D.; Fenoglio, C.; Serpente, M.; Scarpini, E.; Clarimo´ N, J.; Lleo´, A.; Blesa, R.; Landqvist Waldo, M.; Nilsson, K.; Nilsson, C.; Mackenzie, I. R. A.; Hsiung, G-Y. R.; Mann, D. M. A.; Grafman, J.; Morris, C. M.; Attems, J.; Griffiths, T. D.; Mckeith, I. G.; Thomas, A. J.; Pietrini, P.; Huey, E. D.; Wassermann, E. M.; Baborie, A.; Jaros, E.; Tierney, M. C.; Pastor, P.; Razquin, C.; Ortega- Cubero, S.; Alonso, E.; Perneczky, R.; 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, J. B.; Schlachetzki, J. C. M.; Uphill, J.; Collinge, J.; Mead, S.; Danek, A.; Van Deerlin, V. M.; Grossman, M.; Trojanowski, J. Q.; Van Der Zee, J.; Cruts, M.; Van Broeckhoven, C.; Cappa, S. F.; Leber, I.; Hannequin, D.; Golfier, V.; Vercelletto, M.; Brice, A.; Nacmias, B.; Sorbi, S.; Bagnoli, S.; Piaceri, I.; Nielsen, J. E.; Hjermind, L. E.; Riemenschneider, M.; Mayhaus, M.; Ibach, B.; Gasparoni, G.; Pichler, S.; Gu, W.; Rossor, M. N.; Fox, N. C.; Warren, J. D.; Spillantini, M. G.; Morris, H. R.; Rizzu, P.; Heutink, P.; Snowden, J. S.; Rollinson, S.; Richardson, A.; Gerhard, A.; Bruni, A. C.; Maletta, R.; Frangipane, F.; Cupidi, C.; Bernardi, L.; Anfossi, M.; Gallo, M.; Conidi, M. E.; Smirne, N.; Rademakers, R.; Baker, M.; Dickson, D. W.; Graff-Radford, N. R.; Petersen, R. C.; Knopman, D.; Josephs, K. A.; Boeve, B. F.; Parisi, J. E.; Seeley, W. W.; Miller, B. L.; Karydas, A. M.; Rosen, H.; Van Swieten, J. C.; Dopper, E. G. P.; Seelaar, H.; Pijnenburg, Y. A. L.; Scheltens, P.; Logroscino, G.; Capozzo, R.; Novelli, V.; Puca, A. A.; Franceschi, M.; Postiglione, A.; Milan, G.; Sorrentino, P.; Kristiansen, M.; Chiang, H-H.; Graff, C.; Pasquier, F.; Rollin, A.; Deramecourt, V.; Lebouvier, T.; Kapogiannis, D.; Ferrucci, L.; Pickering-Brown, S.; Singleton, A. B.; Hardy, J.; Momeni, P.

doi:10.1093/brain/awx066

Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ɛ2 and ɛ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology.