Mutations in the gene progranulin (GRN) account for 5-20% of patients with frontotemporal dementia with a positive family history. Pathogenic mutations in progranulin are heterozygous mutations and cause disease through 50% loss of the functional progranulin protein. However, penetrance of these mutations is incomplete, with some carriers yet to develop symptoms at old age. In a genome-wide association study (GWAS) in GRN mutation carriers, Transmembrane protein 106B (TMEM106B) was identified as genetic modifier of disease penetrance. Despite the repeatedly demonstrated risk-modulating and disease-modifying protective effect of TMEM106B in neurodegenerative brain disease, TMEM106B genotyping is not routinely implemented in diagnostic profiling, not even in GRN mutation carriers. This highlights the need for additional research to systematically assess the genotype and phenotype of GRN mutation carriers.
Research goal: To provide sufficient evidence that screening for TMEM106B is justified in a diagnostic setting
Population-based study in the UK Biobank with the following aims:
1. Identify GRN mutation carriers in the UK Biobank cohort
2. In those with a GRN mutation, investigate the TMEM106B haplotype and correlation with clinical phenotype (affected/unaffected, age at sample collection)
We would like to demonstrate that there are GRN mutation carriers that are still healthy despite relatively old age and that this is driven by the TMEM106B haplotype.