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{Multi-ancestry genome-wide association study reveals novel genetic signals for lung function decline
Tuesday,2025-02-11 14:49 America/Los_Angeles — ecterry
| Title | {Multi-ancestry genome-wide association study reveals novel genetic signals for lung function decline |
| Publication Type | Journal Article |
| Year of Publication | 2024 |
| Authors | Patchen, BK, Zhang, J, Gaddis, N, Bartz, TM, Chen, J, Debban, C, Leonard, H, Nguyen, NQ, Seo, J, Tern, C, Allen, R, DeMeo, DL, Fornage, M, Melbourne, C, Minto, M, Moll, M, O'Connor, G, Pottinger, T, Psaty, BM, Rich, SS, Rotter, JI, Silverman, EK, Stratford, J, R. Barr, G, Cho, MH, Gharib, SA, Manichaikul, A, North, K, Oelsner, EC, Simonsick, EM, Tobin, MD, Yu, B, Choi, SH, Dupuis, J, Cassano, PA, Hancock, DB |
| Journal | medRxiv |
| Date Published | Nov |
| Abstract | 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.\ To evaluate genome-wide associations and putative downstream functionality of genetic variants with lung function decline in diverse general population cohorts.\ /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.\ ) 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.\ 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. |
ePub date:
24/11