Journal
NEUROBIOLOGY OF AGING
Volume 59, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2017.07.001
Keywords
SORL1; ABCA7; TREM2; Alzheimer's disease
Categories
Funding
- Clinical Research Hospital Program from French Ministry of Health (GMAJ, PHRC) [2008/067]
- CNR-MAJ
- JPND PERADES
- GENMED labex
- FP7 AgedBrainSysBio
- France Genomique National infrastructure
- Agence Nationale pour la Recherche [ANR-10-INBS-09]
- Centre National de Genotypage
- National Foundation for Alzheimer's disease and related disorders
- Institut Pasteur de Lille, Inserm, FRC (Fondation pour la Recherche sur le Cerveau)
- Lille Metropole Communaute Urbaine council
- French government's LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer's disease)
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We performed whole-exome and whole-genome sequencing in 927 late-onset Alzheimer disease (LOAD) cases, 852 early-onset AD (EOAD) cases, and 1273 controls from France. We assessed the evidence for gene-based association of rare variants with AD in 6 genes for which an association with such variants was previously claimed. When aggregating protein-truncating and missensepredicted damaging variants, we found exome-wide significant association between EOAD risk and rare variants in SORL1, TREM2, and ABCA7. No exome-wide significant signal was obtained in the LOAD sample, and significance of the order of 10(-6) was observed in the whole AD group for TREM2. Our study confirms previous gene-level results for TREM2, SORL1, and ABCA7 and provides a clearer insight into the classes of rare variants involved. Despite different effect sizes and varying cumulative minor allele frequencies, the rare protein-truncating and missense-predicted damaging variants in TREM2, SORL1, and ABCA7 contribute similarly to the heritability of EOAD and explain between 1.1% and 1.5% of EOAD heritability each, compared with 9.12% for APOE epsilon 4. (C) 2017 Elsevier Inc. All rights reserved.
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