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C9orf72 , age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts
Neurology, 2020-12, Vol.95 (24), p.e3288
2020
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Autor(en) / Beteiligte
Titel
C9orf72 , age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts
Ist Teil von
  • Neurology, 2020-12, Vol.95 (24), p.e3288
Ort / Verlag
United States
Erscheinungsjahr
2020
Quelle
MEDLINE
Beschreibungen/Notizen
  • We sought to characterize expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [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 exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. We found pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components 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 bvFTD compared to PPA (5% vs 0.8% [ = 2.17 × 10 ; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [ = 1.1 × 10 ; 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. Our results indicate correlation between pathogenic expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.
Sprache
Englisch
Identifikatoren
ISSN: 0028-3878
eISSN: 1526-632X
DOI: 10.1212/WNL.0000000000010914
Titel-ID: cdi_pubmed_primary_32943482
Format
–
Schlagworte
Age of Onset, Aged, Aged, 80 and over, Aphasia, Primary Progressive - genetics, Aphasia, Primary Progressive - physiopathology, C9orf72 Protein - genetics, Cohort Studies, DNA Repeat Expansion, Europe, Female, Frontotemporal Dementia - genetics, Frontotemporal Dementia - physiopathology, Frontotemporal Lobar Degeneration - genetics, Frontotemporal Lobar Degeneration - physiopathology, Geography, Humans, Male, Mediterranean Region, Middle Aged, Principal Component Analysis, Scandinavian and Nordic Countries, Syndrome

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