Mutations in GRN are an important cause of frontotemporal lobar degeneration (FTLD), with 2 loci — TMEM106B and GFRA2 — shown to harbor genetic variants that are able to modify disease risk and are thus likely to inform genetic counseling in families and might assist in the development of future clinical trial designs, according to the results of a genome-wide association study published in Lancet Neurology.
The study was conducted in 3 stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide and logistic and linear regression analyses were performed to examine the association of genetic variants with risk for disease (case or control status) and age at onset in those with a GRN mutation and controls who were free of neurodegenerative disorders. Suggestive loci (P <1×10–5) underwent genotyping in a replication cohort of patients and controls, followed by a meta-analysis.
The study enrolled participants between September 16, 2014, and October 5, 2017. Following quality control measures, statistical analyses conducted in the discovery phase included 382 unrelated symptomatic GRN mutation carriers and 1146 controls who were free of neurodegenerative disorders enrolled from 34 research centers in the United States, Canada, Europe, and Australia. In the replication stage of the study, 210 patients (67 who were symptomatic GRN mutation carriers and 143 participants with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls who were free of neurodegenerative conditions were recruited from 26 sites, with 20 of these sites overlapping with those in the discovery stage.
There was no genome-wide significant association with age at disease onset identified in the discovery or replication stages or in the meta-analysis. In the case-control analysis, however, the investigators replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio 0.54; 95% CI, 0.46-0.63; P =3.54×10–16) and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with risk for disease (rs36196656 meta-analysis odds ratio 1.49; 95% CI, 1.30=1.71; P <1.58×10–8). Based on expression analysis, the risk-associated allele at rs36196656 significantly decreased GFRA2 mRNA concentrations in cerebellar tissue (P =.04).
The investigators concluded that TMEM106B-related and GFRA2-related pathways might serve as future targets for FTLD therapy. The biologic interaction between progranulin and these potential disease modifiers warrants further study.
Pottier C, Zhou X, Perkerson RB III, B et al. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol. 2018;17:548-558.