We previously reported a granulin (GRN) null mutation, originating from a common founder, in multiple Belgian families with frontotemporal dementia. Here, we used data of a 10-year follow-up study to describe in detail the clinical heterogeneity observed in this extended founder pedigree. We identified 85 patients and 40 unaffected mutation carriers, belonging to 29 branches of the founder pedigree. Most patients (74.4%) were diagnosed with frontotemporal dementia, while others had a clinical diagnosis of unspecified dementia, Alzheimer's dementia or Parkinson's disease. The observed clinical heterogeneity can guide clinical diagnosis, genetic testing, and counseling of mutation carriers. Onset of initial symptomatology is highly variable, ranging from age 45 to 80 years. Analysis of known modifiers, suggested effects of GRN rs5848, microtubule-associated protein tau H-1/H-2, and chromosome 9 open reading frame 72 G(4)C(2) repeat length on onset age but explained only a minor fraction of the variability. Contrary, the extended GRN founder family is a valuable source for identifying other onset age modifiers based on exome or genome sequences. These modifiers might be interesting targets for developing disease-modifying therapies. (C) 2018 The Authors. Published by Elsevier Inc. ; Belgian Science Policy Office Interuniversity Attraction Poles program; Flemish government initiated Methusalem excellence program; Flemish government initiated Impulse Program on Networks for Dementia Research; Queen Elisabeth Medical Foundation; Alzheimer Research Foundation; Research Foundation Flanders (FWO); Agency for Innovation by Science and Technology Flanders (IWT); University of Antwerp Research Fund; Belgium; IWT; FWO
In: Gao , Y , Wang , T , Yu , X , Ferrari , R , Hernandez , D G , Nalls , M A , Rohrer , J D , Ramasamy , A , Kwok , J B J , Dobson-Stone , C , Brooks , W S , Schofield , P R , Halliday , G M , Hodges , J R , Piguet , O , Bartley , L , Thompson , E , Haan , E , Hernández , 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 , Clarimón , J , Lleó , A , Blesa , R , Waldö , M L , 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 , George-Hyslop , P S , 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 , Zhao , H , Zeng , P & International FTD-Genomics Consortium (IFGC) 2020 , ' Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis ' , Scientific Reports , vol. 10 , no. 1 , 12184 . https://doi.org/10.1038/s41598-020-68848-9
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.