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Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study
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International audience. Background Loss-of-function mutations in progranulin (GRN) cause frontotemporal dementia. Patients with GRN mutations present with a uniform subtype of TDP-43 pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed at identifying potential genetic factors modifying disease onset and disease risk in GRN mutation carriers. Methods In the discovery stage, genome-wide logistic and linear regression analyses were performed to test association of genetic variants with disease risk (case/control status) and age at onset. Suggestive loci (p<10−5) were genotyped in a replication cohort, followed by a meta-analysis. The effect of genome-wide significant variants at the novel GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin protein (PGRN) levels was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were performed to test for a direct interaction between GFRA2 and PGRN Findings Previously ascertained patients and controls were enrolled in the current study between October 2014 and October 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1,146 controls free of neurodegenerative disorders collected from 34 research centers located in North America, Australia and Europe. In the replication stage, 210 patients, including 67 symptomatic GRN mutation carriers and 143 pathologically-confirmed non-GRN FTLD-TDP type A patients, and 1,798 controls free of neurodegenerative diseases were recruited from 26 sites, of which 20 sites overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery, replication or meta-analysis. However, in the case/control analysis, we replicated the previously reported TMEM106B association (meta-analysis:rs1990622, p=3·54×10−16, OR=0·54, 95% CI: 0·46 − 0·63), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (meta-analysis: rs36196656, p=1·58×10−8, OR=1·49, 95% CI: 1·30 − 1·71). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA levels in cerebellar tissue. No effect of rs36196656 on plasma and cerebrospinal fluid PGRN levels was detected by ELISA; however, co-immunoprecipitation experiments in HEK cells did suggest a direct binding of PGRN and GFRA2. Interpretation The identification of TMEM106B and GFRA2 as potential modifiers of disease risk in GRN carriers raises the possibility that TMEM106B and GFRA2-related pathways are targets for therapies; yet, the biological interaction between PGRN and these disease modifiers requires further study. These potential genetic modifiers might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling,especially in the context of asymptomatic individuals.
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