SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease.
Research paper by
G G Nicolas, C C Charbonnier, D D Wallon, O O Quenez, C C Bellenguez, B B Grenier-Boley, S S Rousseau, A-C AC Richard, A A Rovelet-Lecrux, K K Le Guennec, D D Bacq, J-G JG Garnier, R R Olaso, A A Boland, V V Meyer, J-F JF Deleuze, P P Amouyel, H M HM Munter, G G Bourque, M M Lathrop, T T Frebourg, R R Redon, L L Letenneur, J-F JF Dartigues, E E Génin, J-C JC Lambert, D D Hannequin, D D Campion,
The SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.Molecular Psychiatry advance online publication, 25 August 2015; doi:10.1038/mp.2015.121.