ONSET AGE MODIFIER FOR GRN-ASSOCIATED FRONTOTEMPORAL LOBAR DEGENERATION

Abstract

Loss-of-function mutations in the granulin gene (GRN) are a major cause of frontotemporal lobar degeneration (FTLD). Onset ages of GRN carriers are remarkably variable, both in and between families, and indicate the involvement of onset age modifiers. We aim at identifying potential genetic modifiers of onset age in an extended Belgian founder family segregating the GRN IVS1+5 G>C null mutation and comprising 82 GRN carriers. Onset age in this family varies from 45 to 80 years with an average onset age of 63.1 ± 7.7 years (n=79). Short tandem repeat-based quantitative trait loci (QTL) mapping and single nucleotide polymorphism-based finemapping using Loki (Heath,1997). Sanger sequencing or multiplex PCR (www.agilent.com; Goossens et al, 2009) followed by Illumina MiSeq massive parallel sequencing to genotype variants in the complete pedigree (n=175). QTL mapping pointed to a QTL for onset age on chromosome 12 with substantial evidence of linkage (average Bayes’ factor = 6.9). We selected QTL variants from whole genome (n=23) and exome (n=41) sequencing data of GRN carriers and identified 635 variants in the QTL, of which 15 are located in exonic regions. For each of these 15 variants, we estimated the effect on onset age. We identified 7 variants with a significant effect on onset age. Four are located in a 3’ untranslated region, two in a 5’ untranslated region and one is a missense variant. Patients who are homozygous carriers of the top associated variant, developed disease on average 9.4 ± 2.2 years earlier in comparison to homozygous carriers of the wild-type allele (p=0.00006). Other exonic QTL variants have an even larger effect size, with homozygous carriers developing disease on average 12.8 ± 3.5 years earlier in comparison to patients homozygous for the wild-type allele. In an extended GRN founder family we identified a QTL for onset age as well as exonic variants within this locus that have a significant effect on onset age. Further investigations will focus on identifying the functional onset age-modifying variant. Onset age modifiers could represent interesting targets for disease-delaying therapies, which are currently not available for FTLD patients.