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

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