Is there a causal link between folate status and schizophrenia? Evidence from genetic association studies
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.033 | 0.187 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.005 | 0.008 |
| Bibliometrics | 0.008 | 0.008 |
| Science and technology studies | 0.001 | 0.003 |
| Scholarly communication | 0.005 | 0.004 |
| Open science | 0.003 | 0.002 |
| Research integrity | 0.004 | 0.003 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".