Nacmias, B. (Benedetta)

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    Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort
    (Elsevier BV, 2018) Dillen, L. (Lubina); Benussi, L. (Luisa); Verheijen, J. (Jan); Binetti, G. (Giuliano); Vandenberghe, R. (Rik); Sanchez-Valle, R. (Raquel); Borroni, B. (Barbara); Gelpi, E. (Ellen); Ghidoni, R. (Roberta); Almeida, M.R. (Maria Rosario); Pastor, P. (Pau); Diehl-Schmid, J. (Janine); Graff, C. (Caroline); Gómez-Tortosa, E. (Estrella); Engelborghs, S. (S.); Matej, R. (Radoslav); Bossche, T. (Tobi) van den; Cruts, M. (Marc); Nacmias, B. (Benedetta); Pastor, M.A. (María A.); Tsolaki, M. (Magda); Gijselinck, I. (Ilse); Ruiz, A. (Agustín); Mendonça, A. (Alexandre) de; Clarimon, J. (Jordi); Van-Broeckhoven, C. (Christine); De-Deyn, P.P. (Peter Paul); Zeem, J. (Julie) van der; Lladó, A. (Albert); Heeman, B. (Bavo); Sleegers, K. (Kristine)
    TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer’s disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer’s disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFkB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13e1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts.
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    Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis
    (2020) Boeve, B.F. (Bradley F.); Blesa, R. (Rafael); Petersen, R.C. (Ronald C.); Schlachetzki, J.C.M. (Johannes C. M.); Thompson, E. (Elizabeth); Scarpini, E. (Elio); Graf-Radford, N.R. (Neill R.); Benussi, L. (Luisa); Ortega-Cubero, S. (Sara); Riemenschneider, M. (Matthias); Baker, M. (Matt); Giaccone, G. (Giorgio); Tagliavini, F. (Fabrizio); Spillantini, M.G. (Maria Grazia); Piguet, O. (Olivier); Ibach, B. (Bernd); Dickson, D.W. (Dennis W.); Hjermind, L.E. (Lena E.); Forloni, G. (Gianluigi); Nilsson, C. (Christer); Pijnenburg, Y.A.L. (Yolande A. L.); Serpente, M. (Maria); Grifths, T.D. (Timothy D.); Morris, C.M. (Christopher M.); Pickering-Brown, S. (Stuart); Seelaar, H. (Harro); Landqvist-Waldö, M. (Maria); Binetti, G. (Giuliano); Rosen, H. (Howard); Albani, D. (Diego); Perneczky, R. (Robert); Heutink, P. (Peter); Brice, A. (Alexis); Mann, D.M.A. (David M.A.); Trojanowski, J.Q. (John Q.); Ferrari, R. (Rafaele); Ferrucci, L. (Luigi); Padovani, A. (Alessandro); Danek, A. (Adrian); Rossor, M.N. (Martin N.); Leber, I. (Isabelle); Grafman, J. (Jordan); Sorrentino, P. (Paolo); Graf, C. (Caroline); Novelli, V. (Valeria); Dobson-Stone, C. (Carol); Gu, W. (Wei); Cruchaga, C. (Carlos); Hernandez, D.G. (Dena G.); Fenoglio, C. (Chiara); Deramecourt, V. (Vincent); Anfossi, M. (Maria); Zhao, H. (Huashuo); Franceschi, M. (Massimo); Borroni, B. (Barbara); Grossman, M. (Murray); Kapogiannis, D. (Dimitrios); Van-der-Zee, J. (Julie); Bernardi, L. (Livia); Vercelletto, M. (Martine); Rogaeva, E. (Ekaterina); Hodges, J.R. (John R.); Richardson, A. (Anna); Ghidoni, R. (Roberta); Mayhaus, M. (Manuel); Scheltens, P. (Philip); McKeith, I.G. (Ian G.); Rollin, A. (Adeline); Frangipane, F. (Francesca); Pastor, P. (Pau); Wassermann, E.M. (Eric M.); Rainero, I. (Innocenzo); Nalls, M.A. (Michael A.); Rohrer, J.D. (Jonathan D.); Van-Swieten, J.C. (John C.); Josephs, K.A. (Keith A.); Diehl-Schmid, J. (Janine); Momeni, P. (Parastoo); Fox, N.C. (Nick C.); Jaros, E. (Evelyn); Uphill, J. (James); Rossi, G. (Giacomina); Piaceri, I. (Irene); Lebouvier, T. (Thibaud); Halliday, G.M. (Glenda M.); Bagnoli, S. (Silvia); Schofeld, P.R. (Peter R.); Lleó, A. (Alberto); Cruts, M. (Marc); Nacmias, B. (Benedetta); Puca, A.A. (Annibale A.); Ramasamy, A. (Adaikalavan); Singleton, A.B. (Andrew B.); Mead, S. (Simon); Alexopoulos, P. (Panagiotis); Baborie, A. (Atik); Haan, E. (Eric); Miller, B.L. (Bruce L.); Pasquier, F. (Florence); Wang, T. (Ting); Rowe, J.B. (James B.); Razquin, C. (Cristina); Van-Deerlin, V.M. (Vivianna M.); Milan, G. (Graziella ); Bartley, L. (Lauren); Collinge, J. (John); Pinessi, L. (Lorenzo); Hernández, I. (Isabel); Rademakers, R. (Rosa); Sorbi, S. (Sandro); Attems, J. (Johannes); Capozzo, R. (Rosa); Morris, H.R. (Huw R.); Hardy, J. (John); Nielsen, J.E. (Jørgen E.); Kristiansen, M. (Mark); Smirne, N. (Nicoletta); Galimberti, D. (Daniela); Maletta, R. (Rafaele); Zeng, P. (Ping); Knopman, D. (David); Ruiz, A. (Agustín); Karydas, A.M. (Anna M.); Pichler, S. (Sabrina); Brooks, W.S. (William S.); Nilsson, K. (Karin); Dopper, E.G.P. (Elise G. P.); Rubino, E. (Elisa); Clarimon, J. (Jordi); Hannequin, D. (Didier); Huey, E.D. (Edward D.); Alonso, E. (Elena); Pietrini, P. (Pietro); Cappa, S.F. (Stefano F.); Van-Broeckhoven, C. (Christine); Gerhard, A. (Alexander); Rollinson, S. (Sara); Thomas, A.J. (Alan J.); Conidi, M.E. (Maria Elena); Tierney, M.C. (Michael C.); Bruni, A.C. (Amalia C.); Rizzu, P. (Patrizia); Gallo, M. (Maura); Cairns, N.J. (Nigel J.); Chiang, H.H. (Huei Hsin); Kurz, A. (Alexander); Kwok, J.B.J. (John B. J.); Gao, Y. (Yixin); Parisi, J.E. (Joseph E.); Seely, W.W. (William W.); Yu, X. (Xinghao); St-George Hyslop, P. (Peter); Boada, M. (Mercè); Snowden, J.S. (Julie S.); Gasparoni, G. (Gilles); Warren, J.D. (Jason D.); Postiglione, A. (Alfredo); Logroscino, G. (Giancarlo); Mackenzie, I.R.A. (Ian R.A.); Cupidi, C. (Chiara); Golfer, V. (Véronique)
    We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genomewide association studies (n= ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n= ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect efect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the infuence of LTL and ALS in the European population.