Polymorphisms in the <i>WWOX</i> gene are associated with brain glucose metabolism and influence cerebrospinal fluid p‐tau181 levels
Bibliographic record
Abstract
Abstract Background Genome‐wide association studies (GWAS) studies can be a powerful tool for identifying new single nucleotide polymorphisms (SNPs) associated with multifactorial diseases. Previous GWAS have identified more than 20 genes as potential factors of genetic susceptibility in Alzheimer’s disease (AD). One of them is the protein coding gene WW Domain Containing Oxidoreductase (WWOX), which is highly expressed in mature astrocytes and neurons. Here, we investigated the association between WWOX SNPs, 18F‐FDG PET neuroimaging and cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 181 (p‐tau181) in elderly individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Methods Data was acquired from 537 participants (CU= 195; MCI= 314; AD= 28) of the ADNI database. The brain glucose metabolism was estimated using the standard uptake value ratio (SUVr, cerebellum as reference) of FDG‐PET. The presence of the SNPs were integrated to FDG PET images using voxel‐wise generalized linear regression models adjusted for age, gender, diagnostic status, and years of education (RMINC package). Through the Wilcoxon test we determined if the SNPs presence influenced p‐tau181 levels in CSF. All statistical analyzes were performed in the R statistical computing software (version 4.1.2) (significance level of p < 0.05). Results Sixty‐seven WWOX SNPs were statistically associated with 18F‐FDG PET signal. Voxel‐wise analyses demonstrated that the top ten WWOX SNPs with the highest number of voxels altered in the FDG‐PET images were associated with cortical hypermetabolism (Figure 1, top three). Thirteen WWOX SNPs were significantly associated with lower p‐tau181 concentration in the CSF, including rs7193539 (p = 0.0004), rs7206890 (p = 0.0061), and rs11859281 (p = 0.0009), compared to the reference genotype. Conclusion Several SNPs of the WWOX gene were significantly correlated to brain metabolism. The presence of the SNPs can influence p‐tau181 levels, suggesting a role of WWOX in AD, as reported in other previous studies. Our findings suggest a protective effect of these WWOX gene variants. Additional studies are needed to better understand the biological implications of our findings.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.000 |
| 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 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".