C9orf72, AAO and ancestry help discriminating behavioural from language variants in FTLD cohorts

Objective: We sought to characterise C9orf72 expansions in relation to genetic ancestry and age at onset (AAO), and to use these parameters to discriminate the behavioural from the language variant syndrome, in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. Methods: We evaluated expansions frequency in the entire cohort (n=1396; bvFTD [n=800], PPA [n=495] and FTLD-MND [n=101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher’s Exact, ANOVA with Tukey post-hoc tests, and logistic and non-linear mixed-effects model regressions. Results: We found C9orf72 pathogenic expansions in 4% of all cases (56/1396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MNDs (11.9%), 40/800 bvFTDs (5%) and 4/495 of PPAs (0.8%). While addressing population-substructure through principal component analysis (PCA), we defined 2 patients groups with Central/Northern (n=873) and Southern European (n=523) ancestry. The proportion of expansion carriers was significantly higher in bvFTDs compared to PPAs (5% vs. 0.8% [p=2.17x10-5; OR=6.4; CI:2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs. 1.8% [p=1.1x10-2; OR=2.5; CI:1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry and AAO) predicted a diagnosis of bvFTD with 64% accuracy. Conclusions: Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry and a diagnosis of bvFTD, implying to complex genetic risk-architectures differently underpinning the behavioural and language variant syndromes.