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Centenarian controls increase variant effect sizes by an average twofold in an extreme case-extreme control analysis of Alzheimer's disease
Tesi N, van der Lee SJ, Hulsman M, Jansen IE, Stringa N, van Schoor N, Meijers-Heijboer H, Huisman M et al.. European journal of human genetics : EJHG, 2018-09-26
Topic: Amyloid, tau and blood-test diagnosis
The detection of genetic loci associated with Alzheimer's disease (AD) requires large numbers of cases and controls because variant effect sizes are mostly small. We hypothesized that variant effect sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be maximally enriched or depleted with disease-associated genetic variants. We used 1,073 extensively phenotyped AD cases with relatively young age at onset as extreme cases (66.3 ± 7.9 years), 1,664 age-matched controls (66.0 ± 6.5 years) and 255 cognitively healthy centenarians as extreme controls (101.4 ± 1.3 years).
Key findings
- We hypothesized that variant effect sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be maximally enriched or depleted with disease-associated genetic variants.
- We used 1,073 extensively phenotyped AD cases with relatively young age at onset as extreme cases (66.3 ± 7.9 years), 1,664 age-matched controls (66.0 ± 6.5 years) and 255 cognitively healthy centenarians as extreme controls (101.4 ± 1.3 years).
- We estimated the effect size of 29 variants that were previously associated with AD in genome-wide association studies.
- Comparing extreme AD cases with centenarian controls increased the variant effect size relative to published effect sizes by on average 1.90-fold (SE = 0.29, p = 9.0 × 10 -4 ).
Why it matters
Using centenarians as extreme controls increased variant effect sizes by an average twofold in this genetic analysis of Alzheimer's disease. It is a study design finding and does not report a treatment, cure or prevention.
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Study details
- Study designcase-control study
- Evidence strengthModerate
How this study scored 52/100
Published in a peer-reviewed journal, and it is a case-control study. Scored zero for 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 | 6 / 12 | A case-control study |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2019 — 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 | 4 / 7 | Cited 66 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 7.3 citations a year over 9 year(s) since 2019 |
| Impact for its field and year | 3 / 6 | Cited 4.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 2 / 4 | Cited 17 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Henne H. Holstege: h-index 43 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Vrije Universiteit Amsterdam: institution h-index 1,014 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30258121) |
| Free to read | 2 / 2 | Free to read |
| Total | 52 / 100 | — |
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Read the original
- DOI: 10.1038/s41431-018-0273-5
- PubMed: 30258121
- 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
Tesi, N., van der Lee, S. J., Hulsman, M., Jansen, I. E., Stringa, N., van Schoor, N., et al. (2019). Centenarian controls increase variant effect sizes by an average twofold in an extreme case-extreme control analysis of Alzheimer's disease. European journal of human genetics : EJHG. https://doi.org/10.1038/s41431-018-0273-5
Vancouver
Tesi N, van der Lee SJ, Hulsman M, Jansen IE, Stringa N, van Schoor N, et al. Centenarian controls increase variant effect sizes by an average twofold in an extreme case-extreme control analysis of Alzheimer's disease. European journal of human genetics : EJHG. 2019. doi:10.1038/s41431-018-0273-5. PMID: 30258121.
BibTeX
@article{tesi2019-30258121,
author = {Tesi, N. and van der Lee, S. J. and Hulsman, M. and Jansen, I. E. and Stringa, N. and van Schoor, N. and Meijers-Heijboer, H. and Huisman, M. and others},
title = {{Centenarian controls increase variant effect sizes by an average twofold in an extreme case-extreme control analysis of Alzheimer's disease}},
journal = {European journal of human genetics : EJHG},
year = {2019},
doi = {10.1038/s41431-018-0273-5},
pmid = {30258121},
url = {https://doi.org/10.1038/s41431-018-0273-5}
}
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