221-LB: Identification of PAM as Novel Monogenic Diabetes Gene
Bibliographic record
Abstract
Background/Objectives: Various biological mechanisms involved in type 2 diabetes (T2D) have been unveiled through converging evidence in common variants from Genome wide association studies (GWAS) and rare or low frequency variants (RV/LFV) from Exome wide association studies (EXWAS). We hypothesized that a two-pronged approach interrogating both RV/LFV and common variants could yield identification of new pathways involved in T2D. Methods: Protein-altering RV/LFV burden was tested for T2D association in an EXWAS of 11,731 cases and 149,613 controls in the UKBiobank. Significant encoded proteins were then investigated using 2-sample Mendelian randomization for causal association with T2D and related variables. Protein quantitative trait loci were estimated in the Prospective Urban and Rural Epidemiological study (N=11,020) and tested against GWAS-summary statistics of T2D and related traits from 10 consortia. Results: At the EXWAS significance threshold (P=0.05/19,589=2.55×10-6), we identified loss-of-function RV/LFV in GCK and PAM, which encode the proteins glucokinase and peptidylgycine α-amidating monooxygenase respectively, to be associated with T2D risk. Deleterious mutations in the PAM gene were associated with an 29% increase in T2D risk (OR per RV/LFV=1.29; 95%CI=1.17-1.43; P=7.17×10-7). This association was driven by a low frequency variant, rs78408340-G present in 2.6% of T2D cases and only in 1.8% of controls. MR analyses confirmed that 1 SD decrease in PAM circulating levels was consistently associated with increased T2D risk (OR=1.16; 95%CI=1.14-1.19; P=9.54×10-52) and HbA1c (%) (β=0.0047; 95%CI= 0.00051-0.0090; P=0.028), and decreased post-prandial insulin (mU/L) secretion (β=-0.060; 95% CI=-0.083(-)-0.036; P=8.32×10-7). Conclusion: We identified PAM variants as a novel cause of monogenic diabetes and demonstrated a strong causal effect of circulating PAM levels on T2D risk and post-prandial insulin secretion. This supports further investigation of PAM as a therapeutic T2D target. Disclosure J. Feiner: None. N. Perrot: None. M. Chong: Research Support; Bayer Inc. R. Lali: None. R. Morton: None. P. Mohammadi-Shemirani: None. S. Yusuf: None. H. C. Gerstein: Advisory Panel; Abbott Diagnostics, Eli Lilly and Company, Sanofi. Research Support; Novo Nordisk. Advisory Panel; Novo Nordisk. Research Support; Eli Lilly and Company, Sanofi. Advisory Panel; Kowa Company, Ltd., Hanmi Pharm. Co., Ltd. Other Relationship; Zuellig Pharma Holdings Pte. Ltd., DKSH, AstraZeneca. G. Pare: Research Support; Bayer Inc. Advisory Panel; Bayer Inc., Amgen Inc., Novartis AG. M. Pigeyre: None. Funding Bayer; Canadian Institutes of Health Research
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".