Debban Catherine L, Ambalavanan Amirthagowri, Ghosh Auyon, Li Zhonglin, Buschur Kristina L, Ma Yanlin, George Elizabeth, Pistenmaa Carrie, Bertoni Alain G, Oelsner Elizabeth C, Michos Erin D, Moraes Theo J, Jacobs David R, Christenson Stephanie, Bhatt Surya P, Kaner Robert J, Simons Elinor, Turvey Stuart E, Vameghestahbanati Motahareh, Engert James C, Kirby Miranda, Bourbeau Jean, Tan Wan C, Gabriel Stacey B, Gupta Namrata, Woodruff Prescott G, Subbarao Padmaja, Ortega Victor E, Bleecker Eugene R, Meyers Deborah A, Rich Stephen S, Hoffman Eric A, Barr R Graham, Cho Michael H, Bossé Yohan, Duan Qingling, Manichaikul Ani, Smith Benjamin M
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
Department of Biomedical and Molecular Sciences, School of Computing, Queen's University, Kingston, Ontario, Canada.
Am J Respir Crit Care Med. 2024 Dec 15;210(12):1421-1431. doi: 10.1164/rccm.202401-0011OC.
Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. We performed a genome-wide association study of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate genome-wide association study and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort ( = 1,278) and adults from the UKBiobank ( = 369,157). CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating (hedgehog interacting protein), , and as potential molecular targets based on colocalization of their expression. A higher dysanapsis genetic risk score was associated with obstructive spirometry among 5-year-old children and among adults in the fifth, sixth, and seventh decades of life. CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development, and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endophenotype link between the genetic variations associated with lung function and COPD.
发育性失配是指在生命早期出现的气道树管径与肺大小之间的不匹配。通过计算机断层扫描（CT）评估的发育性失配在成年早期就很明显，并与生命后期的慢性阻塞性肺疾病（COPD）风险相关。通过研究与CT评估的发育性失配相关的遗传因素，我们旨在阐明其在整个生命周期中的分子基础和生理意义。我们对11951名成年人进行了CT评估的发育性失配的全基因组关联研究，其中包括来自两项基于人群的研究和两项COPD富集研究的个体。我们应用共定位分析来整合全基因组关联研究以及来自全血和肺的基因表达数据。与发育性失配相关的遗传变异被合并为一个遗传风险评分，用于检验与来自一个基于人群的出生队列的儿童（n = 1278）和英国生物银行的成年人（n = 369157）的肺功能之间的关联。CT评估的发育性失配与19个基因区域中21个独立信号的遗传变异相关，基于其表达的共定位，表明HHIP（刺猬相互作用蛋白）、FOXF1和MIR17HG是潜在的分子靶点。较高的发育性失配遗传风险评分与5岁儿童以及50、60和70岁成年人的阻塞性肺量计测定结果相关。CT评估的发育性失配与先前涉及肺发育的基因变异有关，并且发育性失配遗传风险与从生命早期到老年期的阻塞性肺功能有关。发育性失配可能代表了与肺功能和COPD相关的遗传变异之间的一种内表型联系。
