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Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European early-onset dementia consortium study

Autores: Cuyvers, E.; Van der Zee, J.; Bettens, K.; Engelborghs, S.; Vandenbulcke, M.; Robberecht, C.; Dillen, L.; Merlin, C.; Geerts, N.; Graff, C.; Thonberg, H.; Chiang, H.; Pastor Muñoz, Pau; Ortega Cubero, Sara; Pastor, María A.; Diehl-Schmid, J.; Alexopoulos, P.; Benussi, L.; Ghidoni, R.; Binetti, G.; Nacmias, B.; Sorbi, S.; Sánchez-Valle, R.; Lladó, A.; Gelpi, E.; Almeida, M. R.; Santana, I.; Clarimon, J.; Lleó, A.; Fortea, J.; De Mendonça, A.; Martins, M.; Borroni, B.; Padovani, A.; Matej, R.; Rohan, Z.; Ruiz, A.; Frisoni, G. B.; Fabrizi, G. M.; Vandenberghe, R.; De Deyn, P. P.; Van Broeckhoven, C.; Sleegers, K.; BELNEU Consortium; EU EOD Consortium
Título de la revista: NEUROBIOLOGY OF AGING
ISSN: 0197-4580
Volumen: 36
Número: 5
Páginas: 2005.e15 - 2005.e22
Fecha de publicación: 2015
Meta-analysis of existing genome-wide association studies on Alzheimer's disease (AD) showed subgenome-wide association of an intronic variant in the sequestosome 1 (SQSTM1) gene with AD. We performed targeted resequencing of SQSTM1 in Flanders-Belgian AD patients selected to be enriched for a genetic background (n = 435) and geographically matched nonaffected individuals (n = 872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European early-onset dementia cohorts (926 early-onset Alzheimer's disease [EOAD] patients and 1476 nonaffected individuals). Of the 61 detected exonic variants in SQSTM1, the majority were rare (n = 57). Rare variant (minor allele frequency <0.01) burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts. Common variants p.D292= and p.R312= showed nominal association with AD (odds ratiop.D292= = 1.11 [95% confidence interval = 1-1.22], p = 0.04), only when including the Flanders-Belgian cohort in the meta-analysis. We cannot exclude a role of SQSTM1 genetic variability in late-onset AD, but our data indicate that SQSTM1 does not play a major role in the etiology of EOAD.