Height variation independent of known genetic variants and health in later life: a cohort study

Background
Adult-attained height is associated with later-life health, but it reflects both genetic and non-genetic influences. The health implications of height variation not explained by known common height-associated genetic variants remain unclear.
Objective
To examine associations of residual height (height variation independent of known genetic variants) with multiple disease incidence and all-cause mortality in later life.
Methods
In this cohort study of 407,366 adults of European ancestry (aged 40-70) in UK Biobank (2006-2010), sex- and age-specific genetically predicted height was estimated from 9,863 height-associated variants, adjusted for 30 principal components of ancestry. Residual height was calculated as the difference between observed and genetically predicted height. Plasma proteomics (2,054 proteins; OlinkTM Explore) were profiled. Deaths and 49 incident diseases were ascertained through national registries. Multivariable Cox models estimated associations of residual height and related proteins with disease incidence and mortality.
Results
Higher residual height (mean [SD], 0.0 [4.8]) was associated with more favorable self-reported pre-adulthood exposures (e.g., later birth years, no maternal smoking around birth, being breastfed as a baby, no adoption experience, and lower childhood adversity scores) and lower hazard ratios of 32 out of 49 diseases (median follow-up=∼12.5 years). Using participants with residual height within ±0.5 SDs from the mean as reference, those with residual height <-2 SDs had higher adjusted hazard ratios of mortality (1.61; 95% confidence interval 1.50, 1.72), multimorbidity (1.28; 1.12, 1.46), cardiovascular disease (1.45; 1.32, 1.60), psychiatric/neurological disease (1.38; 1.28, 1.48), and other disease categories (e.g., diabetes, digestive, and musculoskeletal diseases). In contrast, higher genetically predicted height was associated with higher incidence of 19 diseases, including subtypes of cancer, non-atherosclerotic cardiovascular diseases, and musculoskeletal diseases, as well as higher all-cause mortality. We identified 806 plasma proteins related to inflammation, immune response, and autophagy via TNF, NF-κB, PI3K-Akt, and JAK-STAT signaling pathways, which were associated with residual height and multiple diseases and mortality.ConclusionHigher residual height was associated with lower disease incidence and mortality, with associations distinct from those for genetically predicted height.