Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10−5) increased AD risk by 12-fold (95% CI 4.2–34.3; P=5 × 10−9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10−5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ɛ4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice.
Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy
H. Holstege,H. Holstege,S. Lee,S. Lee,M. Hulsman,M. Hulsman,T. H. Wong,J. Rooij,M. Weiss,E. Louwersheimer,F. Wolters,N. Amin,A. Uitterlinden,Albert Hofman,Albert Hofman,M. Ikram,J. Swieten,J. Swieten,H. Meijers-Heijboer,W. Flier,M. Reinders,C. Duijn,C. Duijn,P. Scheltens
Published 2017 in European Journal of Human Genetics
ABSTRACT
PUBLICATION RECORD
- Publication year
2017
- Venue
European Journal of Human Genetics
- Publication date
2017-05-24
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- alzheimer disease
The neurodegenerative disease outcome used in the case-control analyses.
Aliases: AD
- combined annotation dependent depletion (cadd) score
A computational score used to estimate how damaging a genetic variant is predicted to be.
Aliases: CADD score, CADD
- exome aggregation consortium (exac) database
A population reference database used here to determine whether SORL1 variants were present and to obtain their allele frequencies.
Aliases: ExAC
- minor allele frequency (maf)
The population frequency of the less common allele at a variant site, used here as a rarity threshold.
Aliases: MAF
- protein-truncating sorl1 mutations
SORL1 variants that are expected to introduce premature termination and shorten the encoded protein.
Aliases: truncating SORL1 mutations, protein truncating variants
- sorl1 genetic variants
DNA sequence changes in the SORL1 gene that were examined for association with Alzheimer disease.
Aliases: SORL1 variants
- variant classification strategy
A rule-based scheme developed to categorize SORL1 variants into pathogenicity subtypes using annotation and frequency thresholds.
Aliases: pathogenicity screen, clinical interpretation strategy
REFERENCES
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