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Heritability and genome-wide association study of diffusing capacity of the lung

By Natalie Terzikhan, Fangui Sun, Fien M. Verhamme, Hieab Adams, Daan Loth, Ken R Bracke, Bruno H. C. Stricker, Lies Lahousse, Josée Dupuis, Guy G. Brusselle, George T. O’Connor

Posted 09 Apr 2018
bioRxiv DOI: 10.1101/277343 (published DOI: 10.1183/13993003.00647-2018)

Background: Although several genome wide association studies (GWAS) have investigated the genetics of pulmonary ventilatory function, little is known about the genetic factors that influence gas exchange. Aim: To investigate the heritability of, and genetic variants associated with the diffusing capacity of the lung. Methods: GWAS was performed on diffusing capacity, measured by carbon monoxide uptake (DLCO) and per alveolar volume (DLCO/VA) using the single-breath technique, in 8,372 individuals from two population-based cohort studies, the Rotterdam Study and the Framingham Heart Study. Heritability was estimated in related (n=6,246) and unrelated (n=3,286) individuals. Results: Heritability of DLCO and DLCO/VA ranged between 23% and 28% in unrelated individuals and between 45% and 49% in related individuals. Meta-analysis identified a genetic variant in GPR126 that is significantly associated with DLCO/VA. Gene expression analysis of GPR126 in human lung tissue revealed a decreased expression in patients with COPD and subjects with decreased DLCO/VA. Conclusion: DLCO and DLCO/VA are heritable traits, with a considerable proportion of variance explained by genetics. A functional variant in GPR126 gene region was significantly associated with DLCO/VA. Pulmonary GPR126 expression was decreased in patients with COPD.

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