Lung Development Genes and Adult Lung Function

• Published in: American journal of respiratory and critical care medicine 2020-09, Vol.202 (6), p.853-865
• Main Authors: Portas, Laura, Pereira, Miguel, Shaheen, Seif O, Wyss, Annah B, London, Stephanie J, Burney, Peter G J, Hind, Matthew, Dean, Charlotte H, Minelli, Cosetta
• Format: Article
• Language: English
• Subjects: Adult; Adults; Aged; Aged, 80 and over; Developmental Biology; Epidemiology; Female; Genes; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study; Growth and Development - genetics; Humans; Lung - growth & development; Lung diseases; Male; Middle Aged; Original; Polymorphism, Single Nucleotide; Respiratory Function Tests; Respiratory Physiological Phenomena - genetics; Risk Factors; United Kingdom
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201912-2338OC

Poor lung health in adult life may occur partly through suboptimal growth and development, as suggested by epidemiological evidence pointing to early life risk factors. To systematically investigate the effects of lung development genes on adult lung function. Using UK Biobank data, we tested the association of 391 genes known to influence lung development with FVC and FEV /FVC. We split the dataset into two random subsets of 207,616 and 138,411 individuals, using the larger subset to select the most promising signals and the smaller subset for replication. We identified 55 genes, of which 36 (16 for FVC, 19 for FEV /FVC, and one for both) had not been identified in the largest, most recent genome-wide study of lung function. Most of these 36 signals were intronic variants; expression data from blood and lung tissue showed that the majority affect the expression of the genes they lie within. Further testing of 34 of these 36 signals in the CHARGE and SpiroMeta consortia showed that 16 replicated after Bonferroni correction and another 12 replicated at nominal significance level. Of the 55 genes, 53 fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-to-cell adhesion; extracellular matrix), suggesting that these specific processes are important for adult lung health. Our study demonstrates the importance of lung development genes in regulating adult lung function and influencing both restrictive and obstructive patterns. Further investigation of these developmental pathways could lead to druggable targets.