In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95 CI: -4.64 to -3.07, p<2×10 -16 ) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5 of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.

Ferrari, R., Grassi, M., Graziano, F., Palluzzi, F., Archetti, S., Bonomi, E., et al. (2017). Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia. JOURNAL OF ALZHEIMER'S DISEASE, 56(4), 1271-1278 [10.3233/JAD-160949].

Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

Graziano, Francesca;
2017

Abstract

In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95 CI: -4.64 to -3.07, p<2×10 -16 ) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5 of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.
Articolo in rivista - Articolo scientifico
Age at onset; Frontotemporal dementia; GWAS; Polymorphism; Adult; Age of Onset; Aged; Aged, 80 and over; Cohort Studies; Frontotemporal Dementia; Genetic Association Studies; Humans; Italy; Linear Models; Middle Aged; Polymorphism, Single Nucleotide; Principal Component Analysis; Genetic Loci; Neuroscience (all); Clinical Psychology; Geriatrics and Gerontology; Psychiatry and Mental Health
English
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1278
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Ferrari, R., Grassi, M., Graziano, F., Palluzzi, F., Archetti, S., Bonomi, E., et al. (2017). Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia. JOURNAL OF ALZHEIMER'S DISEASE, 56(4), 1271-1278 [10.3233/JAD-160949].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/222969
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