Multi-ancestry genome-wide association study reveals novel genetic signals for lung function decline
Bibliographic record
Abstract
Abstract Rationale Accelerated decline in lung function contributes to the development of chronic respiratory disease. Despite evidence for a genetic component, few genetic associations with lung function decline have been identified. Objectives To evaluate genome-wide associations and putative downstream functionality of genetic variants with lung function decline in diverse general population cohorts. Methods We conducted genome-wide association study (GWAS) analyses of decline in the forced expiratory volume in the first second (FEV 1 ), forced vital capacity (FVC), and their ratio (FEV 1 /FVC) in participants across six cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. Genotypes were imputed to TOPMed (CHARGE cohorts) or Haplotype Reference Consortium (HRC) (UK Biobank) reference panels, and GWAS analyses used generalized estimating equation models with robust standard error. Models were stratified by cohort, ancestry, and sex, and adjusted for important lung function confounders and genotype principal components. Results were combined in cross-ancestry and ancestry-specific meta-analyses. Selected top variants were tested for replication in two independent COPD-enriched cohorts. Measurements and Main Results Our discovery analyses included 52,056 self-reported White (N=44,988), Black (N=5,788), Hispanic (N=550), and Chinese American (N=730) participants with a mean of 2.3 spirometry measurements and 8.6 years of follow-up. Functional mapping of GWAS meta-analysis results identified 361 distinct genome-wide significant (p<5E-08) variants in one or more of the FEV 1 , FVC, and FEV 1 /FVC decline phenotypes, which overlapped with previously reported genetic signals for several related pulmonary traits. Of these, 8 variants, or 20.5% of the variant set available for replication testing, were nominally associated (p<0.05) with at least one decline phenotype in COPD-enriched cohorts (White [N=4,778] and Black [N=1,118]). Using the GWAS results, gene-level analysis implicated 38 genes, including eight ( XIRP2 , GRIN2D , SATB1 , MARCHF4 , SIPA1L2 , ANO5 , H2BC10 , and FAF2 ) with consistent associations across ancestries or decline phenotypes. Annotation class analysis revealed significant enrichment of several regulatory processes for corticosteroid biosynthesis and metabolism. Drug repurposing analysis identified 43 approved compounds targeting eight of the implicated 38 genes. Conclusions Our multi-ancestry GWAS meta-analyses identified numerous genetic loci associated with lung function decline. These findings contribute knowledge to the genetic architecture of lung function decline, provide evidence for a role of endogenous corticosteroids in the etiology of lung function decline, and identify drug targets that merit further study for potential repurposing to slow lung function decline and treat lung disease.
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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 | 0.003 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.003 |
| 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) | 0.002 | 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".