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

Abstract

Background: Adult 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.

Methods: We 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.

Results: Height 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 OR_epi = 0.80, 95% CI 0.78-0.81; OR per SD increase in genetically determined height OR_gen = 0.86, 95% CI 0.82-0.90), hypertension (OR_epi = 0.83, 95% CI 0.82-0.84; OR_gen = 0.88, 95% CI 0.85-0.91), gastro-oesophageal reflux disease (OR_epi = 0.85, 95% CI 0.84-0.86; OR_gen = 0.94, 95% CI 0.92-0.97), diaphragmatic hernia (OR_epi = 0.81, 95% CI 0.79-0.82; OR_gen = 0.91, 95% CI 0.88-0.94), but increased risks of atrial fibrillation (OR_epi = 1.42, 95% CI 1.38-1.45; OR_gen = 1.33, 95% CI 1.26-1.40), venous thromboembolism (OR_epi = 1.18, 95% CI 1.16-1.21; OR_gen = 1.15, 95% CI 1.11-1.19), intervertebral disc disorder (OR_epi = 1.15, 95% CI 1.13-1.18; OR_gen = 1.14, 95% CI 1.09-1.20), hip fracture (OR_epi = 1.19, 95% CI 1.12-1.26; OR_gen = 1.27, 95% CI 1.17-1.39), vasculitis (OR_epi = 1.15, 95% CI 1.11-1.19; OR_gen = 1.20, 95% CI 1.14-1.28), cancer overall (OR_epi = 1.09, 95% CI 1.08-1.11; OR_gen = 1.06, 95% CI 1.04-1.08) and breast cancer (OR_epi = 1.08, 95% CI 1.06-1.10; OR_gen = 1.07, 95% CI 1.03-1.11). Pathway analysis showed multiple height-associated pathways associating with individual diseases.

Conclusions: Adult 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.

Keywords: Adult height; Disease risk; Genetically determined height; Instrumental variables; Mendelian randomisation.

Fig. 1

Epidemiological and genetic associations of height with diseases. Legend: Odds ratio (OR) and 95% confidence intervals per one standard deviation (SD) increase in height based on observed (epidemiology model) and genetically determined height (genetic model) are shown for a cardiovascular diseases (coronary artery disease (CAD), peripheral vascular disease (PVD), stroke, hypertension, aortic valve stenosis (AS), heart failure (HF), venous thromboembolism (VTE) and atrial fibrillation (AF)), b musculoskeletal diseases (osteoporosis, osteoarthritis, gout, sciatica, intervertebral disc disorder (IDD) and hip fracture), c digestive disorders (liver cirrhosis, peptic ulcer, diaphragmatic hernia, inguinal hernia, gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gallstones and appendicitis), d psychiatric and neurological disorders (dementia, epilepsy, anxiety disorder, depression, bipolar disorder, Parkinson’s disease and multiple sclerosis (MS)), e other non-neoplastic diseases (chronic obstructive pulmonary disease (COPD), asthma, diabetes, glaucoma, cataract, hypothyroidism and hyperthyroidism and vasculitis), and f cancers and various sites. One SD is 9.2 cm; for men and women specific diseases, 1-SD corresponds to 6.8 cm and 6.2 cm, respectively. All epidemiological models were adjusted for age, sex, obesity (BMI ≥ 30), socio-economic status (Townsend deprivation index in highest quintile), Smoking status (ever smoker, exposed to environmental tobacco smoke, none), physical activity (vigorous exercise at least once a week or more) and other relevant disease-specific risk factors as described below: models for CAD—waist-hip-ratio, systolic blood pressure, use of insulin and family history of heart diseases; models for AF, VTE, PVD and heart failure—systolic blood pressure, use of insulin and family history of heart diseases; model for hypertension—use of insulin and family history of hypertension; model for stroke—waist-hip-ratio, systolic blood pressure, use of insulin and family history of stroke; model for COPD—family history of COPD; model for asthma—presence of hay fever or eczema; model for dementia—family history of dementia; depression—family history of depression; Parkinson’s disease—family history of Parkinson’s disease; model of glaucoma—systolic blood pressure and use of insulin; model for diabetes—waist-hip-ratio, systolic blood pressure and family history of diabetes; model of cataract—use of insulin; model for cancer overall—family history of lung/breast/prostate/bowel cancer; model for cancer of the breast—nulliparous, ever use of contraceptive pills, ever on hormone replacement therapy and family history of breast cancer; models for lung, prostate and colorectal cancers—family history of respective cancers. *p < 0.05, **p < 0.01, ***p < 0.001 after Bonferroni correction for 50 tests

Fig. 2

Risk of disease by quartiles of weighted genetic score for height. Legend: CAD coronary artery disease, VTE venous thromboembolism, AF atrial fibrillation, IDD intervertebral disc disorder and GORD gastro-oesophageal reflux disease. Associations by quartile of weighted genetic score for height are shown for the 12 diseases which showed an association with genetically determined height (Bonferroni p value < 0.05). Individuals in quartile 1 (Q1) (reference quartile) carry the least number, and Q4 carry the highest number of height-increasing alleles. p values for trends (GORD P_trend = 0.003, colorectal cancer P_trend = 0.003 and breast cancer P_trend = 0.010, all other diseases P_trend < 0.001