Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis
Authors: Gao Yixin , Wang Ting , Yu Xinghao ,   International FTD-Genomics Consortium (IFGC), Ferrari Raffaele , Hernandez Dena G. , Nalls Michael A. , Rohrer Jonathan D. , Ramasamy Adaikalavan , Kwok John B. J. , Dobson-Stone Carol , Brooks William S. , Schofield Peter R. , Halliday Glenda M. , Hodges John R. , Piguet Olivier , Bartley Lauren , Thompson Elizabeth , Haan Eric , Hernández Isabel , Ruiz Agustín , Boada Mercè , Borroni Barbara , Padovani Alessandro , Cruchaga Carlos , Cairns Nigel J. , Benussi Luisa , Binetti Giuliano , Ghidoni Roberta , Forloni Gianluigi , Albani Diego , Galimberti Daniela , Fenoglio Chiara , Serpente Maria , Scarpini Elio , Clarimón Jordi , Lleó Alberto , Blesa Rafael , Waldö Maria Landqvist , Nilsson Karin , Nilsson Christer , Mackenzie Ian R. A. , Hsiung Ging-Yuek R. , Mann David M. A. , Grafman Jordan , Morris Christopher M. , Attems Johannes , Griffiths Timothy D. , McKeith Ian G. , Thomas Alan J. , Pietrini Pietro , Huey Edward D. , Wassermann Eric M. , Baborie Atik , Jaros Evelyn , Tierney Michael C. , Pastor Pau , Razquin Cristina , Ortega-Cubero Sara , Alonso Elena , Perneczky Robert , Diehl-Schmid Janine , Alexopoulos Panagiotis , Kurz Alexander , Rainero Innocenzo , Rubino Elisa , Pinessi Lorenzo , Rogaeva Ekaterina , George-Hyslop Peter St , Rossi Giacomina , Tagliavini Fabrizio , Giaccone Giorgio , Rowe James B. , Schlachetzki Johannes C. M. , Uphill James , Collinge John , Mead Simon , Danek Adrian , Van Deerlin Vivianna M. , Grossman Murray , Trojanowski John Q. , van der Zee Julie , Cruts Marc , Van Broeckhoven Christine , Cappa Stefano F. , Leber Isabelle , Hannequin Didier , Golfier Véronique , Vercelletto Martine , Brice Alexis , Nacmias Benedetta , Sorbi Sandro , Bagnoli Silvia , Piaceri Irene , Nielsen Jørgen E. , Hjermind Lena E. , Riemenschneider Matthias , Mayhaus Manuel , Ibach Bernd , Gasparoni Gilles , Pichler Sabrina , Gu Wei , Rossor Martin N. , Fox Nick C. , Warren Jason D. , Spillantini Maria Grazia , Morris Huw R. , Rizzu Patrizia , Heutink Peter , Snowden Julie S. , Rollinson Sara , Richardson Anna , Gerhard Alexander , Bruni Amalia C. , Maletta Raffaele , Frangipane Francesca , Cupidi Chiara , Bernardi Livia , Anfossi Maria , Gallo Maura , Conidi Maria Elena , Smirne Nicoletta , Rademakers Rosa , Baker Matt , Dickson Dennis W. , Graff-Radford Neill R. , Petersen Ronald C. , Knopman David , Josephs Keith A. , Boeve Bradley F. , Parisi Joseph E. , Seeley William W. , Miller Bruce L. , Karydas Anna M. , Rosen Howard , van Swieten John C. , Dopper Elise G. P. , Seelaar Harro , Pijnenburg Yolande A. L. , Scheltens Philip , Logroscino Giancarlo , Capozzo Rosa , Novelli Valeria , Puca Annibale A. , Franceschi Massimo , Postiglione Alfredo , Milan Graziella , Sorrentino Paolo , Kristiansen Mark , Chiang Huei-Hsin , Graff Caroline , Pasquier Florence , Rollin Adeline , Deramecourt Vincent , Lebouvier Thibaud , Kapogiannis Dimitrios , Ferrucci Luigi , Pickering-Brown Stuart , Singleton Andrew B. , Hardy John , Momeni Parastoo , Zhao Huashuo , Zeng Ping 
Published: July 2020

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide 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 effect 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 influence of LTL and ALS in the European population.