Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1
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Bibliographic record
Abstract
Abstract Huntington’s disease is caused by an expanded CAG tract in HTT . The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington’s disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. We developed a method for calling perfect and imperfect repeats from exome-sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington’s disease via regression analysis. We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR ( p = 2.1 × 10 −9 ), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1 , translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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 it