Scientific publications

Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European Early-Onset Dementia Consortium study

May 15, 2015 | Magazine: Neurobiology of Aging

Cuyvers E(1), van der Zee J(1), Bettens K(1), Engelborghs S(2), Vandenbulcke M(3), Robberecht C(1), Dillen L(1), Merlin C(1), Geerts N(1), Graff C(4), Thonberg H(4), Chiang HH(5), Pastor P(6), Ortega-Cubero S(7), Pastor MA(8), Diehl-Schmid J(9), Alexopoulos P(9), Benussi L(10), Ghidoni R(10), Binetti G(10), Nacmias B(11), Sorbi S(11), Sanchez-Valle R(12), Lladó A(12), Gelpi E(13), Almeida MR(14), Santana I(14), Clarimon J(15), Lleó A(15), Fortea J(15), de Mendonça A(16), Martins M(16), Borroni B(17), Padovani A(17), Matěj R(18), Rohan Z(19), Ruiz A(20), Frisoni GB(21), Fabrizi GM(22), Vandenberghe R(23), De Deyn PP(24), Van Broeckhoven C(25), Sleegers K(26); BELNEU Consortium and of the EU EOD Consortium.


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.

CITATION  Neurobiol Aging. 2015 May;36(5):2005.e15-22. doi: 10.1016/j.neurobiolaging.2015.02.014.