Effect of genetic clusters related to insulin resistance on neurological traits in diverse populations from the Trans‐Omics for Precision Medicine Program
Bibliographic record
Abstract
Abstract Background Insulin resistance (IR) is a major risk factor for Alzheimer’s disease (AD) and is primarily driven by obesity, another AD risk factor. The biological mechanism by which IR predisposes to AD is unknown. Genetic clustering analyses of type 2 diabetes (T2D) loci can help characterize which mechanism of impaired insulin action may be involved in AD and related traits. Method We constructed five genetic clusters related to IR (Obesity, Lipodystrophy, Liver/Lipid, ALP [alkaline phosphatase] negative, and Hyper‐Insulin Secretion) based on a recent clustering analysis of T2D loci (PMID: 36538063). We evaluated the association of each cluster with the Homeostatic Model Assessment for Insulin Resistance (HOMA‐IR) and neurological traits (AD, dementia, general cognitive function, and four brain MRI volumes) in >38k participants (36% men, mean age 55yrs (14.5)) of diverse race or ethnicity, from the Trans‐Omics for Precision Medicine (TOPMed) Program. We conducted pooled and race/ethnicity‐stratified association analyses (European‐50%, African‐American‐22.5%, and Hispanic/Latino‐21%). We used logistic or linear mixed‐effect models, adjusted for age, sex, study, and the first 11 genetic principal components. We accounted for relatedness and allowed for heterogeneous variances across studies. Result We confirmed the association of each IR genetic cluster with HOMA‐IR in the pooled analysis (2.6E‐66≤P≤2E‐4) and detected significant to suggestive associations in group‐stratified analyses (6.3E‐39≤P≤0.05), except for the Hyper‐Insulin Secretion cluster in African‐Americans (P = 0.30). The genetic clusters were not significantly associated with neurological outcomes after multiple testing adjustment (P = 0.05/Ngroups/Nclusters/Noutcomes = 0.05/4/5/7 = 3.6×10−4). We observed nominal associations (P<0.05) for two genetic clusters. The Lipodystrophy cluster was negatively associated with intracranial volume in the pooled analysis (beta = ‐0.51, P = 0.003) as well as in European (beta = ‐0.47, P = 0.02) and Hispanic/Latino (beta = ‐1.23, P = 0.01) participants. The Hyper‐Insulin Secretion cluster was negatively associated with hippocampal volume in Hispanic/Latino participants (beta = ‐0.005, P = 0.03), and positively associated with AD and dementia (OR = 1.02 [1.001‐1.038], P = 0.03) in European participants. Conclusion Our findings are consistent with the literature suggesting that IR may be associated with lower brain volumes and increased AD risk. Our analyses shed light on two biological mechanisms of impaired insulin action potentially involved in AD and related traits, with genetic associations that may differ by race or ethnicity. Funding: R00AG066849
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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 | 0.006 | 0.008 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.003 |
| Bibliometrics | 0.002 | 0.003 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".