Burden of Common Complex Disease Variants in the Exomes of Two Healthy Centenarian Brothers
Bibliographic record
Abstract
BACKGROUND: It is not understood whether long-term good health is promoted by the absence of disease risk variants, the presence of protective variants, or both. We characterized the exomes of two exceptionally healthy centenarian brothers aged 106 and 109 years who had never been diagnosed with cancer, cardiovascular disease, diabetes, Alzheimer's disease, or major pulmonary disease. OBJECTIVE: The aim of this study was to gain insight into whether exceptional health and longevity are a result of carrying fewer disease-associated variants than typical individuals. METHODS: We compared the number of disease-associated alleles, and the proportion of alleles predicted to be functionally damaging, between the centenarian brothers and published population data. Mitochondrial sequence reads were extracted from the exome data in order to analyze mitochondrial variants. RESULTS: The brothers carry a similar number of common disease-associated variants and predicted damaging variants compared to reference groups. They did not carry any high-penetrance clinically actionable variants. They carry mitochondrial haplogroup T, and one brother has a single heteroplasmic variant. CONCLUSION: Although our small sample size does not allow for definitive conclusions, a healthy aging and longevity phenotype is not necessarily due to a decreased burden of common disease-associated variants. Instead, it may be rare 'positive' variants that play a role in this desirable phenotype.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".