Year: 2017
Type: article
Study design: Observational Study
Abstract: Objective: To quantify the effect of genetic factors and generations influencing the age at onset (AAO) in families with frontotemporal lobar dementia (FTD) due to C9ORF72 hexanucleotide repeat expansions and GRN mutations. Methods: We studied 504 affected individuals from 133 families with C9ORF72 repeat expansions and 90 FTD families with mutations in GRN, 2 major genes responsible for FTD and/or amyotrophic lateral sclerosis. Intrafamilial correlations of AAO were analyzed, and variance component methods were used for heritability estimates. Generational effects on hazard rates for AAO were assessed using mixed-effects Cox proportional hazard models. Results: A generational effect influencing AAO was detected in both C9ORF72 and GRN families. Nevertheless, the estimated proportion of AAO variance explained by genetic factors was high in FTD caused by C9ORF72 repeat expansions (44%; p = 1.10e−4), 62% when the AAO of dementia was specifically taken into account (p = 8.10e−5), and to a lesser degree in GRN families (26%; p = 0.17). Intrafamilial correlation analyses revealed a significant level of correlations in C9ORF72 families according to the degree of kinship. A pattern of intrafamilial correlations also suggested potential X-linked modifiers acting on AAO. Nonsignificant correlation values were observed in GRN families. Conclusions: Our results provide original evidence that genetic modifiers strongly influence the AAO in C9ORF72 carriers, while their effects seem to be weaker in GRN families. This constitutes a rational to search for genetic biomarkers, which could help to improve genetic counseling, patient care, and monitoring of therapeutic trials.
Source: Neurology Genetics
Institutions: Centre National de la Recherche Scientifique, Inserm, École Pratique des Hautes Études, Université Paris Sciences et Lettres, Sorbonne Université, Institut des Sciences Moléculaires, Institut du Cerveau, Université Pierre-et-Marie-Curie, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Fondazione IRCCS Istituto Neurologico Carlo Besta, Université de Lille, Centre Hospitalier Universitaire de Rouen, Centre Hospitalier Universitaire de Toulouse, Hôpital Purpan, Hôpital Paule de Viguier, Hôpital de La Grave, Toulouse NeuroImaging Center, Génétique, Génomique Fonctionnelle et Biotechnologies, Santé Internationale de la mère et de l'enfant
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,300
Funders: Eli Lilly and Company, FORUM Pharmaceuticals, Agence Nationale de la Recherche, Bundesministerium für Bildung und Forschung, Fondation pour la Recherche Médicale, Fonds Wetenschappelijk Onderzoek, Fondation de France, Association France Parkinson, Fondation Roger de Spoelberch, Assistance publique-Hôpitaux de Paris, Vlaamse regering, Parkinson Vereniging
OpenAlex ID: W2773991902