SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data

Massive parallel sequencing recently allowed the identification of three genes carrying a higher burden of rare, protein-truncating and missense predicted damaging variants in Alzheimer disease (AD) cases as compared to controls: TREM2 , SORL1 , and ABCA7 . SORL1 encodes SorLA, a key protein involve...

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Bibliographic Details
Published in:Acta neuropathologica 2019-08, Vol.138 (2), p.173-186
Main Authors: Campion, Dominique, Charbonnier, Camille, Nicolas, Gaël
Format: Article
Language:English
Subjects:
Advertising executives
Age
Alzheimer's disease
Amyloid precursor protein
Bioinformatics
Chromosomes
Comparative analysis
Data processing
Fibronectin
Gene frequency
Genetic aspects
Genetic diversity
Literature reviews
Medical research
Medicine
Medicine & Public Health
Medicine, Experimental
Meta-analysis
Neurodegenerative diseases
Neurosciences
Pathology
Proteins
Review
Risk factors
Secretion
Single nucleotide polymorphisms
Single-nucleotide polymorphism
Systematic review
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Summary:Massive parallel sequencing recently allowed the identification of three genes carrying a higher burden of rare, protein-truncating and missense predicted damaging variants in Alzheimer disease (AD) cases as compared to controls: TREM2 , SORL1 , and ABCA7 . SORL1 encodes SorLA, a key protein involved in the processing of the amyloid-beta (Aβ) precursor protein (APP) and the secretion of the Aβ peptide, the aggregation of which triggers AD pathophysiology. Common SORL1 single nucleotide polymorphisms had originally been associated with AD with modest odds ratios (ORs). The association of AD with rare SORL1 coding variants has been demonstrated at the gene level by aggregating protein-truncating (PTV) and rare predicted damaging missense variants. In addition to the loss of SorLA function induced by PTVs, a few missense variants were studied in vitro, showing diverse degrees of decreased SorLA function and leading to increased Aβ secretion. However, the exact functional consequences of most of the missense variants remain to be determined as well as corresponding levels of AD risk. Hereby we review the evidence of the association of SORL1 common and rare variants with AD risk and conduct a meta-analysis of published data on SORL1 rare variants in five large sequencing studies. We observe a significant enrichment in PTVs with ORs of 12.29 (95% confidence interval = [4.22–35.78]) among all AD cases and 27.50 [7.38–102.42] among early-onset cases. Rare [minor allele frequency (MAF) 
ISSN:0001-6322
1432-0533
DOI:10.1007/s00401-019-01991-4