Is there a causal link between folate status and schizophrenia? Evidence from genetic association studies
Why this work is in the frame
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Bibliographic record
Abstract
Folate and vitamin B12 status, through their critical involvement in DNA synthesis and methylation, may be causally related to the risk of schizophrenia. However, associations with blood status measures may reflect reverse causation or inadequate control for confounders. We aimed to synthesize evidence on the possible causal link between folate/vitamin B12 status and schizophrenia using genetic variants as instrumental variables. MEDLINE, Embase, PsycINFO, and the Cochrane Database of Systematic Reviews were searched for Mendelian Randomization studies that investigated a causal relationship between genetic instruments for folate/vitamin B12 status and schizophrenia onset or progression. We assessed the risk of bias using the Newcastle Ottawa Scale. Odds ratios and 95% confidence intervals were estimated using random effects models. We found 34 case–control studies. None used a formal instrumental variable analysis. Most of the studies had high methodological quality for assessing genetic association. The methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T, A1298C) were most studied and homozygosity for the variants showed significant positive associations with the risk of schizophrenia (OR677TT vs 677CC = 1.26 (1.03, 1.55) and OR1298CC vs 1298AA = 1.58 (1.17, 2.13)). Heterozygosity for the variants showed attenuated associations in the same direction as homozygosity. Subgroups of age, sex, ethnicity, and folic acid fortification implementation were mostly underpowered to detect effects with precision. Evidence on the association of MTHFR polymorphisms with schizophrenia symptoms or the relationship between other gene polymorphisms and the risk of schizophrenia was severely limited. We identified significant associations between the MTHFR C677T and A1298C polymorphisms and the risk of schizophrenia at an aggregate level.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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 it