Abstract
Background: Early-life growth adversity is important to later-life health, but precision assessment in adulthood is challenging. We evaluated whether the difference between attained and genotype-predicted adult height ("height-GaP") would associate with prospectively ascertained early-life growth adversity and later-life all-cause and cardiovascular mortality.
Methods: Data were first analyzed from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4582; 56/43% female/male) and UKBiobank (n = 483,385; 54/46% female/male). Genotype-predicted height was calculated using a multi-ancestry polygenic height score. Height-GaP was calculated as the difference between measured and genotype-predicted adult height. Early-life growth conditions were ascertained prospectively via standardized procedures (ALSPAC) and mortality via death register (UKBiobank). Regression models examined: (i) adult height-GaP as the outcome with early-life growth conditions as predictors; and (ii) mortality as the outcome with adult height-GaP as predictor. All models were adjusted for age, sex, genotype-predicted height and genetic ancestry. Analyses were replicated in the Dunedin Multidisciplinary Health and Development Study (DMHDS; n = 855; 49/51% female/male) and the Multi-Ethnic Study of Atherosclerosis (MESA; n = 6352; 52/48% female/male).
Results: Here we show that among ALSPAC participants (median [IQR] age: 24 [18-25] years at height-GaP assessment), lower gestational age at birth, greater pre- and post-natal deprivation indices, tobacco smoke exposure and less breastfeeding are associated with larger adult height-GaP deficit (p < 0.01). Among UKBiobank participants (mean ± SD age: 56 ± 8 years at height-GaP assessment), height-GaP deficit is associated with death from all-causes (adjusted hazard ratio comparing highest-to-lowest height-GaP deficit quartile [aHR]: 1.25 95%CI: 1.21-1.29), atherosclerotic cardiovascular disease (aHR: 1.32 95%CI: 1.23-1.42) and coronary heart disease (aHR: 1.64 95%CI: 1.49-1.81). Early- and later-life height-GaP associations replicate in DMHDS and MESA.
Conclusions: This study introduces a precision index of early-life growth adversity deployable in adulthood to investigate the developmental origins of longevity and improve health equity across the life course.