title: Defining the association of TMEM106B variants among frontotemporal lobar degeneration patients with GRN mutations and C9orf72 repeat expansions.
abstract: TMEM106B was identified as a risk factor for frontotemporal lobar degeneration (FTD) with TAR DNA-binding protein 43 kDa inclusions. It has been reported that variants in this gene are genetic modifiers of the disease and that this association is stronger in patients carrying a GRN mutation or a pathogenic expansion in chromosome 9 open reading frame 72 (C9orf72) gene. Here, we investigated the contribution of TMEM106B polymorphisms in cohorts of FTD and FTD with amyotrophic lateral sclerosis patients from France and Italy. Patients carrying the C9orf72 expansion (n = 145) and patients with GRN mutations (n = 76) were compared with a group of FTD patients (n = 384) negative for mutations and to a group of healthy controls (n = 552). In our cohorts, the presence of the C9orf72 expansion did not correlate with TMEM106B genotypes but the association was very strong in individuals with pathogenic GRN mutations (p = 9.54 × 10(-6)). Our data suggest that TMEM106B genotypes differ in FTD patient cohorts and strengthen the protective role of TMEM106B in GRN carriers. Further studies are needed to determine whether TMEM106B polymorphisms are associated with other genetic causes for FTD, including C9orf72 repeat expansions.
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UPMC Univ Paris 06 UM75, Inserm U1127, CNRS UMR 7225, Paris, France.
authors.forename: Serena
authors.initials: S
authors.lastname: Lattante
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UPMC Univ Paris 06 UM75, Inserm U1127, CNRS UMR 7225, Paris, France; Centre de référence Démences Rares, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Serpente
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UPMC Univ Paris 06 UM75, Inserm U1127, CNRS UMR 7225, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rivaud-Péchoux
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UPMC Univ Paris 06 UM75, Inserm U1127, CNRS UMR 7225, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Camuzat
authors.affiliation: Centre de référence Démences Rares, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; Département de Génétique et Cytogénétique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Clot
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UPMC Univ Paris 06 UM75, Inserm U1127, CNRS UMR 7225, Paris, France; Département de Génétique et Cytogénétique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UPMC Univ Paris 06 UM75, Inserm U1127, CNRS UMR 7225, Paris, France. Electronic address: edor.kabashi@icm-institute.org.
authors.forename: Edor
authors.initials: E
authors.lastname: Kabashi
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics; D000073885:C9orf72 Protein; D015331:Cohort Studies; D005260:Female; D005602:France; D057174:Frontotemporal Lobar Degeneration / Q000150:complications / Q000235:genetics*; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007558:Italy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D000077153:Progranulins; D011506:Proteins / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; D011506:Proteins; C556915:TMEM106B protein, human
keywords: C9orf72; FTD; FTD-ALS; GRN; TMEM106B; rs1990622; rs3173615