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

Article type: Research Article

Authors: Ferrari, Raffaele^{a; 1} | Grassi, Mario^{b; 1} | Graziano, Francesca^b | Palluzzi, Fernando^b | Archetti, Silvana^c | Bonomi, Elisa^d | Bruni, Amalia C.^e | Maletta, Raffaele G.^e | Bernardi, Livia^e | Cupidi, Chiara^e | Colao, Rosanna^e | Rainero, Innocenzo^f | Rubino, Elisa^f | Pinessi, Lorenzo^f | Galimberti, Daniela^g | Scarpini, Elio^g | Serpente, Maria^g | Nacmias, Benedetta^h | Piaceri, Irene^h | Bagnoli, Silvia^h | Rossi, Giacominaⁱ | Giaccone, Giorgioⁱ | Tagliavini, Fabrizioⁱ | Benussi, Luisa^l | Binetti, Giuliano^{l; m} | Ghidoni, Roberta^l | Singleton, Andrewⁿ | Hardy, John^o | Momeni, Parastoo^p | Padovani, Alessandro^d | Borroni, Barbara^{d; *}

Affiliations: [a] Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK | [b] Department of Brain and Behavioural Sciences, Medical and Genomic Statistics Unit, University of Pavia, Pavia, Italy | [c] Department of Laboratories, III Laboratory of Analysis, Brescia Hospital, Brescia, Italy | [d] Department of Clinical and Experimental Science, Neurology Unit, University of Brescia, Italy | [e] Neurogenetic Regional Centre ASPCZ Lamezia Terme, Lamezia Terme, Italy | [f] Department of Neuroscience, Neurology I, University of Torino and Cittá della Salute e della Scienza di Torino, Turin, Italy | [g] Department of Pathophysiology and Transplantation, Neurology Unit, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy | [h] Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy | [i] Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy | [l] Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [m] MAC Memory Center, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy | [n] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA | [o] Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK | [p] Department of Internal Medicine, Laboratory of Neurogenetics, Texas Tech University Health Science Center, Lubbock, TX, USA

Correspondence: [*] Correspondence to: Barbara Borroni, MD, Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Tel.: +39 0303995632; Fax: +39 0303995027; E-mail: borroni@inwind.it..

Note: [1] These authors equally contributed to this work.

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.

Keywords: Age at onset, frontotemporal dementia, GWAS, polymorphism

DOI: 10.3233/JAD-160949

Journal: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1271-1278, 2017