Abstract MP84: Trans-ethnic Meta-analysis of Exome Chip Data Reveals Novel Low-frequency Variants Contributing to Central Adiposity
Bibliographic record
Abstract
Central adiposity is a leading risk factor for cardiovascular disease, and genetic factors contribute both to fat distribution, measured as waist-to-hip ratio adjusted for BMI (WHRa), and to differences in central adiposity prevalence. To date, 49 loci have been associated with WHRa, based on studies of common [minor allele frequency (MAF) ≥5%] single nucleotide variants (SNVs), primarily in European descent populations. Our aim was to identify low frequency (LFV: MAF <5%) and rare (RV: MAF <1%) coding variants associated with WHRa using Exome-Chip data from 344,369 individuals of European (84%), South Asian (8%), African (5%), East Asian(2%), and Hispanic/Latino (1%) ancestry. We performed fixed effects meta-analyses of study-specific WHRa associations stratified by sex and ancestry and then combined across strata for both SNV and gene-based results. We used a strict definition of variants annotated as damaging by 5 algorithms to perform gene-based analyses using the sequence kernel association test (SKAT). Analyses included up to 284,499 SNVs (218,195 with MAF<5%), and 15,063 genes with at least one SNV that met our inclusion criteria. Five LFVs reached chip-wide significance (CWS: P<2.5E-7) in our all ancestry sex-combined analyses, including one novel non-synonymous LFV in RAPGEF3 [MAF=0.01, β (SE) = -0.09 (0.012), P=1.28E-13]. In addition, one novel RV reached CWS in men for UGGT2 [MAF<0.01, β (SE) = -0.142 (0.025), P=9.71E-9], and one RV reached CWS in women for ACVR1C [MAF<0.01, β (SE) = -0.09 (0.018), P=1.09E-7]. Gene-based analyses identified RAPGEF3 (P=1.18E-11) as significantly associated with WHRa in the all ancestry sex combined analyses after correction for multiple tests (P<2.5E-6), though conditional analysis revealed that this result is driven by the top SV identified in this region. RAPGEF3 also shows a significant association (p=4.68E-12) in all ancestry, sex combined gene-based analysis of BMI. RAPGEF3 is expressed in subcutaneous and visceral adipose tissue, and has been implicated in insulin regulation. RAPGEF3 plays a role in the GLP1 pathway, which controls insulin secretion in response to blood glucose concentration. Our results highlight the importance of large-scale genomic studies for identifying LFV and RV influencing central fat distribution. Understanding these genetic effects may provide insights into the progression of central adiposity and highlight potential population-specific variants that increase susceptibility.
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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 | 0.010 | 0.018 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.005 | 0.021 |
| Bibliometrics | 0.003 | 0.005 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.001 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 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".