Journal Article

SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease

Bourque, G, Le Guennec, K, Munter, H M, Lambert, J-C, Lathrop, M, Letenneur, L, Nicolas, G, Garnier, J-G, Génin, E, Olaso, R, Deleuze, J-F, Campion, D, Rovelet-Lecrux, A, Hannequin, D, Grenier-Boley, B, Quenez, O, Frebourg, T, Boland, A, Dartigues, J-F, Rousseau, S, Bellenguez, C, Redon, R, Wallon, D, Charbonnier, C, Bacq, D, Richard, A-C, Amouyel, P, Meyer, V

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/71 / 38/77 / 631/208 / 631/337 / Age / Alleles / Alzheimer Disease / Alzheimer Disease - genetics / Alzheimer's disease / Amyloid beta-Peptides / Amyloid beta-Protein Precursor / Amyloid beta-Protein Precursor - genetics / Amyloid beta-Protein Precursor - metabolism / Behavioral Sciences / Biological Psychology / Biomarkers / Case-Control Studies / Exome / Family medical history / Female / France / Gene Frequency / Genetic aspects / Genetic Predisposition to Disease / Genetic Predisposition to Disease - genetics / Genetic Variation / Health aspects / Health risk assessment / Humans / Hypotheses / LDL-Receptor Related Proteins / LDL-Receptor Related Proteins - genetics / LDL-Receptor Related Proteins - metabolism / Life Sciences / Male / Medicine / Medicine & Public Health / Membrane Transport Proteins / Membrane Transport Proteins - genetics / Membrane Transport Proteins - metabolism / Middle Aged / Neurodegenerative diseases / Neuropsychology / Neurosciences / Odds Ratio / original-article / Pharmacotherapy / Psychiatry / Risk Factors / β-Amyloid