Genetische modificatie van de aanvangsleeftijd in GRN-geassocieerde frontotemporale lobaire degeneratie
28 september 2017
UAntwerpen, Campus Drie Eiken, Gebouw Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (route: UAntwerpen, Campus Drie Eiken
16 - 18 uur
Christine Van Broeckhoven, Marc Cruts
Doctoraatsverdediging Eline Wauters - Departement Biomedische Wetenschappen
Frontotemporal lobar degeneration (FTLD) is the second most common cause of neurodegenerative dementia at young age. Loss-of-function mutations in GRN, the gene encoding granulin, account for 10 to 25% of the patients. Most GRN mutation carriers present clinically with frontotemporal dementia (FTD), but GRN mutations are in rare occasions also observed in patients presenting with other neurodegenerative diseases such as Alzheimer’s dementia (AD) and Parkinson’s disease. Another striking feature is the wide variability of onset age, which can span up to 40 years within one family.
This points to the existence of modifiers affecting the onset age of GRN-associated neurodegeneration. We aimed at identifying genetic modifiers of onset age using a family-based approach. We started from a Belgian GRN founder pedigree which was identified in 2006. Since the discovery, we have identified in total 85 patients and 40 yet unaffected mutation carriers, who belonged to 29 different branches of the pedigree. We investigated the effect on onset age of known risk variations for FTD and AD. We identified moderate onset age-modifying effects of variations in GRN, MAPT and C9orf72.
However, they could not explain the whole onset age range of the family. This pointed towards the involvement of other modifiers. We performed a short tandem repeat-based quantitative trait locus (QTL) mapping in the family and identified a QTL for onset age. Finemapping, using single nucleotide polymorphism genotype data, indicated a region of 320 kb where four protein coding genes are located. Tagging variations of this region were genotyped in the complete founder pedigree. Heterozygous and homozygous variation carriers of the top associated variant developed disease on average 9.0 and 7.9 years later in comparison to homozygous carriers of the wild-type allele.
Association analysis of the same variations in a Belgian cohort of unrelated FTD patients with known onset age and without GRN mutation, pointed to the same variant. The identification of genetic modifiers of onset age might enhance our understanding of the pathomechanisms of FTLD. In the future, when the functional variations are identified and additional onset age modifiers are found, this information could be relevant in the context of disease prognosis and genetic counseling. Further, these modifiers might represent targets for disease-modifying or disease-delaying therapies.