Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy
Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ et al.. European journal of human genetics : EJHG, 2017-05-24
Topic: Amyloid, tau and blood-test diagnosis
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 -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.
Key findings
- 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.
- More common SORL1 variants (ExAC-MAF≥1 × 10 -5 ) were not associated with increased AD risk, even when predicted strongly damaging.
Why it matters
This study developed a strategy to classify SORL1 gene variants as pathogenic or benign based on how damaging they are predicted to be and how rare they are. It found that strongly damaging, extremely rare SORL1 variants increased Alzheimer's risk by 12-fold, while more common SORL1 variants were not associated with increased risk.
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Study details
- Evidence strengthLow
How this study scored 50/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (European journal of human genetics : EJHG) |
| Journal's citation record | 2 / 4 | European Journal of Human Genetics: journal h-index 178 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2017 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 138 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 12.5 citations a year over 11 year(s) since 2017 |
| Impact for its field and year | 3 / 6 | Cited 6.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 7 other studies in this library |
| Still being cited | 2 / 4 | Cited 40 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Philip Scheltens: h-index 181 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 28537274) |
| Free to read | 2 / 2 | Free to read |
| Total | 50 / 100 | — |
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Read the original
- DOI: 10.1038/ejhg.2017.87
- PubMed: 28537274
- Original source →
- Free full text: European Journal of Human Genetics →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Holstege, H., van der Lee, S. J., Hulsman, M., Wong, T. H., van Rooij, J. G., Weiss, M., et al. (2017). Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. European journal of human genetics : EJHG. https://doi.org/10.1038/ejhg.2017.87
Vancouver
Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, et al. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. European journal of human genetics : EJHG. 2017. doi:10.1038/ejhg.2017.87. PMID: 28537274.
BibTeX
@article{holstege2017-28537274,
author = {Holstege, H. and van der Lee, S. J. and Hulsman, M. and Wong, T. H. and van Rooij, J. G. and Weiss, M. and Louwersheimer, E. and Wolters, F. J. and others},
title = {{Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy}},
journal = {European journal of human genetics : EJHG},
year = {2017},
doi = {10.1038/ejhg.2017.87},
pmid = {28537274},
url = {https://doi.org/10.1038/ejhg.2017.87}
}
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