Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study

Publication date: June 2018Source: The Lancet Neurology, Volume 17, Issue 6Author(s): Cyril Pottier, Xiaolai Zhou, Ralph B Perkerson, Matt Baker, Gregory D Jenkins, Daniel J Serie, Roberta Ghidoni, Luisa Benussi, Giuliano Binetti, Adolfo López de Munain, Miren Zulaica, Fermin Moreno, Isabelle Le Ber, Florence Pasquier, Didier Hannequin, Raquel Sánchez-Valle, Anna Antonell, Albert Lladó, Tammee M Parsons, NiCole A FinchSummaryBackgroundLoss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers.MethodsThe study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was asses...
Source: The Lancet Neurology - Category: Neurology Source Type: research