Patchen Bonnie K, Zhang Jingwen, Gaddis Nathan, Bartz Traci M, Chen Jing, Debban Catherine, Leonard Hampton, Nguyen Ngoc Quynh, Seo Jungkun, Tern Courtney, Allen Richard, DeMeo Dawn L, Fornage Myriam, Melbourne Carl, Minto Melyssa, Moll Matthew, O'Connor George, Pottinger Tess, Psaty Bruce M, Rich Stephen S, Rotter Jerome I, Silverman Edwin K, Stratford Jeran, Graham Barr R, Cho Michael H, Gharib Sina A, Manichaikul Ani, North Kari, Oelsner Elizabeth C, Simonsick Eleanor M, Tobin Martin D, Yu Bing, Choi Seung Hoan, Dupuis Josee, Cassano Patricia A, Hancock Dana B
Division of Nutritional Sciences, Cornell University.
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA.
medRxiv. 2024 Nov 27:2024.11.25.24317794. doi: 10.1101/2024.11.25.24317794.
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.
We conducted genome-wide association study (GWAS) analyses of decline in the forced expiratory volume in the first second (FEV), forced vital capacity (FVC), and their ratio (FEV/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.
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, FVC, and FEV/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 (, , , , , , , and ) 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.
肺功能加速下降会导致慢性呼吸道疾病的发生。尽管有证据表明存在遗传因素，但与肺功能下降相关的基因关联却很少被发现。
评估不同普通人群队列中基因变异与肺功能下降的全基因组关联及假定的下游功能。
我们对基因组流行病学心脏与衰老研究队列（CHARGE）联盟的六个队列以及英国生物银行中的参与者进行了全基因组关联研究（GWAS）分析，以研究第一秒用力呼气量（FEV）、用力肺活量（FVC）及其比值（FEV/FVC）的下降情况。将基因型推算到TOPMed（CHARGE队列）或单倍型参考联盟（HRC）（英国生物银行）参考面板上，GWAS分析使用具有稳健标准误差的广义估计方程模型。模型按队列、血统和性别分层，并针对重要的肺功能混杂因素和基因型主成分进行调整。结果在跨血统和血统特异性的荟萃分析中进行合并。在两个独立的慢性阻塞性肺疾病（COPD）富集队列中对选定的顶级变异进行复制测试。
我们的发现分析纳入了52,056名自我报告的白人（N = 44,988）、黑人（N = 5,788）、西班牙裔（N = 550）和华裔美国人（N = 730）参与者，平均进行了2.3次肺量计测量，随访时间为8.6年。GWAS荟萃分析结果的功能图谱在FEV、FVC和FEV/FVC下降表型中的一个或多个中鉴定出361个不同的全基因组显著（p < 5E-08）变异，这些变异与先前报道的几种相关肺部特征的遗传信号重叠。其中，8个变异（占可用于复制测试的变异集的20.5%）在COPD富集队列（白人[N = 4,778]和黑人[N = 1,118]）中与至少一种下降表型存在名义上的关联（p < 0.05）。利用GWAS结果进行的基因水平分析涉及38个基因，包括8个（、、、、、、和）在不同血统或下降表型中具有一致关联的基因。注释类别分析显示，皮质类固醇生物合成和代谢的几个调节过程有显著富集。药物再利用分析确定了43种针对38个相关基因中的8个的批准化合物。
我们的多血统GWAS荟萃分析确定了许多与肺功能下降相关的基因位点。这些发现为肺功能下降的遗传结构提供了知识，为内源性皮质类固醇在肺功能下降病因中的作用提供了证据，并确定了值得进一步研究以进行潜在再利用以减缓肺功能下降和治疗肺部疾病的药物靶点。
