Adult height and risk of 50 diseases: a combined epidemiological and genetic analysis

Abstract

BackgroundAdult height is associated with risk of several diseases, but the breadth of such associations and whether these associations are primary or due to confounding are unclear. We examined the association of adult height with 50 diseases spanning multiple body systems using both epidemiological and genetic approaches, the latter to identify un-confounded associations and possible underlying mechanisms.MethodsWe examined the associations for adult height (using logistic regression adjusted for potential confounders) and genetically determined height (using a two-sample Mendelian randomisation approach with height-associated genetic variants as instrumental variables) in 417,434 individuals of white ethnic background participating in the UK Biobank. We undertook pathway analysis of height-associated genes to identify biological processes that could link height and specific diseases.ResultsHeight was associated with 32 diseases and genetically determined height associated with 12 diseases. Of these, 11 diseases showed a concordant association in both analyses, with taller height associated with reduced risks of coronary artery disease (odds ratio per standard deviation (SD) increase in height ORepi = 0.80, 95% CI 0.78–0.81; OR per SD increase in genetically determined height ORgen = 0.86, 95% CI 0.82–0.90), hypertension (ORepi = 0.83, 95% CI 0.82–0.84; ORgen = 0.88, 95% CI 0.85–0.91), gastro-oesophageal reflux disease (ORepi = 0.85, 95% CI 0.84–0.86; ORgen = 0.94, 95% CI 0.92–0.97), diaphragmatic hernia (ORepi = 0.81, 95% CI 0.79–0.82; ORgen = 0.91, 95% CI 0.88–0.94), but increased risks of atrial fibrillation (ORepi = 1.42, 95% CI 1.38–1.45; ORgen = 1.33, 95% CI 1.26–1.40), venous thromboembolism (ORepi = 1.18, 95% CI 1.16–1.21; ORgen = 1.15, 95% CI 1.11–1.19), intervertebral disc disorder (ORepi = 1.15, 95% CI 1.13–1.18; ORgen = 1.14, 95% CI 1.09–1.20), hip fracture (ORepi = 1.19, 95% CI 1.12–1.26; ORgen = 1.27, 95% CI 1.17–1.39), vasculitis (ORepi = 1.15, 95% CI 1.11–1.19; ORgen = 1.20, 95% CI 1.14–1.28), cancer overall (ORepi = 1.09, 95% CI 1.08–1.11; ORgen = 1.06, 95% CI 1.04–1.08) and breast cancer (ORepi = 1.08, 95% CI 1.06–1.10; ORgen = 1.07, 95% CI 1.03–1.11). Pathway analysis showed multiple height-associated pathways associating with individual diseases.ConclusionsAdult height is associated with risk of a range of diseases. We confirmed previously reported height associations for coronary artery disease, atrial fibrillation, venous thromboembolism, intervertebral disc disorder, hip fracture and cancer and identified potential novel associations for gastro-oesophageal reflux disease, diaphragmatic hernia and vasculitis. Multiple biological mechanisms affecting height may affect the risks of these diseases.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1175-7) contains supplementary material, which is available to authorized users.

Genetics of height and risk of atrial fibrillation: A Mendelian randomization study

“…We further build on those prior findings using the MR framework, considering both summary-level and individual-level genetic data, examining genetic variants associated with height and atrial fibrillation to provide a causal estimate for the effect of increasing height on risk of atrial fibrillation. Our population-level MR analysis reinforces a prior MR estimate for association between increasing height and atrial fibrillation (OR 1.33; 95% CI 1.26 to 1.40) using updated GWAS summary statistics for height and atrial fibrillation [9]. By including a large multiethnic study of atrial fibrillation, we increase the generalizability of the prior MR findings, which were limited only to white participants of the UK Biobank.…”

“…Even with treatment, affected individuals are at risk of cardioembolic stroke, heart failure, and death [2]. Height has been identified as a risk factor for a number of cardiometabolic diseases, including coronary artery disease, atrial fibrillation, and venous thromboembolism [9,10]. The relationship between height and atrial fibrillation in particular has been identified in large observational studies, with greater height strongly associated with increased risk of atrial fibrillation [4,[11][12][13][14][15][16][17][18].…”

Mendelian randomisation analyses find pulmonary factors mediate the effect of height on coronary artery disease

“…Evidence from observational studies suggests that height is associated with different disease outcomes 1–4 . Other studies have tried to elucidate this inverse association by using a twin design 5 or Mendelian randomisation approaches 4,6,7 . A decrease of one standard deviation in genetically determined height (~6.5 cm) has been associated with a 13% higher risk of coronary artery disease (CAD) 4 .…”

Causal Association Between Birth Weight and Atrial Fibrillation: Evidence from a Two-Sample Mendelian Randomization Analysis

“…[41][42][43][44] Besides, ve possible shared biologic pathways (ERK5 signaling, Wnt/β-catenin signaling, androgen signaling, role of Oct4 in mammalian embryonic stem cell pluripotency, Growth hormone signaling) between adult height and AF have been identi ed in a prior study. [45] In addition, this association appears to be in part mediated via body mass as well. In the Women's Health Study, additional adjustment for body mass further attenuated the association between BW and AF risk.…”