• Lung Physiology

In healthy adults, 70%–80% of our vital capacity can be exhaled in a single second when measured by spirometry. This is made possible by the combination of a highly elastic lung, a low-resistance airway tree and recruitable respiratory muscles. Reduced spirometric values do not necessarily indicate disease, however, since forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC) and the ratio of FEV₁/FVC all decrease as part of normal ageing. Much of lung function is determined by genetics: approximately 40% of lung function can be explained by familial heritability,1 and genome-wide association studies have identified hundreds of genetic variants associated with lung function that, when combined, account for around 6%–12% of this heritability.2 Understanding the genetic control of lung function can give vital insights into the nature of disease and ultimately help us develop preventative treatments.

Mendelian randomisation (MR) is a statistical construct that exploits the relationship between genetic variants and biological features to identify causal associations. In what is known as instrumental variable analysis, the effect of a genetic variant on an exposure (eg, a blood protein) and an outcome (eg, a phenotype or disease) is used to determine the effect of the exposure on the outcome. The ‘randomisation’ element comes from the random allocation of alleles during meiosis: this allows comparison between two groups who differ only by the level of the exposure—akin to treatment arms in a randomised controlled trial—and hence a causal inference can be made. For an easy-to-understand description of …