Adverse exposures and events during the period of early-life growth are increasingly recognized as important to later-life disease risk. For example, up to 50% of chronic obstructive pulmonary disease (COPD) has been linked to impaired lung growth early in life. A challenge to understanding and exploiting this knowledge is the lack of a simple method to quantify the cumulative impact of adverse early-life growth conditions among adults. This amendment proposes to validate a novel quantitative index of early-life growth conditions that can be deployed across the lifespan.

A recent genome-wide association study of 5.4M adults reported a saturated map of genetic variants associated with height that accounts for over 90% of trait heritability and explains up to 45% of trait variance.5 Since human height is determined in part by genetics and in part by early-life growth conditions, it follows that the difference between measured height and genotype-predicted height (height-GaP) may represent a quantitative and cumulative index of adverse early-life growth conditions. In support of this hypothesis, analysis of UKBiobank data demonstrated that a larger height-GaP deficit was associated with several retrospectively ascertained early-life factors known to adversely affect growth, as well as subsequent all-cause and respiratory mortality.

Retrospective assessment of early-life growth conditions limit the strength of inferences that can made from these UKBiobank observations and motivate this amendment to our current ALSPAC proposal, which is already examining a genotype-based index and lung function.