White matter hyperintensities and Alzheimer’s disease susceptibility: a genome‐wide interaction study
Bibliographic record
Abstract
Abstract Background White matter hyperintensities (WMH) are commonly observed on MRI in Alzheimer’s disease (AD), but the molecular pathways underlying their relationships with the ATN biomarkers remain unclear. The aim of this study was to identify genetic variants that may modify the relationship between WMH and the ATN biomarkers. Method This genome‐wide interaction study (GWIS) included individuals with AD, MCI, and normal cognition from ADNI (n = 1012). WMH were measured from FLAIR MRI using an automated atlas‐based segmentation. CSF Aβ42, tau, and p‐tau concentrations were measured using Roche Elecsys immunoassays. Hippocampal volumes were obtained using FreeSurfer. Interaction effects between single nucleotide polymorphisms (SNP) and WMH volumes on ATN biomarkers were assessed using linear regression models, adjusting for age, sex, diagnosis, MMSE, APOE‐ε4 status, head‐size, and 4 genetic principal components in PLINK2. Linkage disequilibrium‐based clumping (LD: 0.5; physical distance: 250kb) was performed in PLINK1.9, visualized with LocusZoom. Significant SNP‐WMH interactions discovered in ADNI were validated in participants from the Sunnybrook Dementia Study (n = 433) and UK Biobank (n = 16720). Result A 30‐SNP intergenic locus on chromosome 18 (lowest p‐value‐SNP: rs72899960 T>A, β = 227.0 pg/ml, SE = 10.2, p = 2.30 × 10‐8, MAF = 11.1%, Imputation‐R2>0.99%, n = 848) achieved genome‐wide significance interacting with WMH to predict Aβ42, with the nearest gene being a novel long noncoding RNA (lncRNA), ENSG00000286844 (‐360KB). A 9‐SNP intronic locus on chromosome 11 (lowest p‐value‐SNP: rs3912008 C>T, β = 0.25 cm3, SE = 0.044, p = 1.47 × 10‐8, MAF = 22.6%, Imputation‐R2>99%, n = 987) achieved genome‐wide significance interacting with WMH to predict hippocampal volume, and was found within the microRNA gene MIR4300HG. Both SNPs showed additive moderation effects such that associations between WMH and ATN markers in major allele homozygotes were diminished in heterozygotes, and diminished further in minor allele homozygotes. The interaction between MIR4300HG‐rs3912008 and WMH in predicting hippocampal volume replicated in dominant models in both the Sunnybrook Dementia Study (F1,431 = 7.98, coefficient = 0.14 cm3, SE = 0.05, p = 0.005) and in UK Biobank (F1,16623 = 5.32, coefficient = 0.025 cm3, SE = 0.011, p = 0.021). Conclusion Genomic variants moderate relationships between WMH and ATN biomarkers suggesting a novel regulatory role for a long non‐coding RNA, and the involvement of microRNA MIR4300HG. This interaction study may help identify the contribution of specific genes and the potential pathways involved in the relationships between WMH and AD biomarkers.
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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 | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".