Your height affects your health: genetic determinants and health-related outcomes in Taiwan

Abstract

Background: Height is an important anthropometric measurement and is associated with many health-related outcomes. Genome-wide association studies (GWASs) have identified hundreds of genetic loci associated with height, mainly in individuals of European ancestry.

Methods: We performed genome-wide association analyses and replicated previously reported GWAS-determined single nucleotide polymorphisms (SNPs) in the Taiwanese Han population (Taiwan Biobank; n = 67,452). A genetic instrument composed of 251 SNPs was selected from our GWAS, based on height and replication results as the best-fit polygenic risk score (PRS), in accordance with the clumping and p-value threshold method. We also examined the association between genetically determined height (PRS₂₅₁) and measured height (phenotype). We performed observational (phenotype) and genetic PRS₂₅₁ association analyses of height and health-related outcomes.

Results: GWAS identified 6843 SNPs in 89 genomic regions with genome-wide significance, including 18 novel loci. These were the most strongly associated genetic loci (EFEMP1, DIS3L2, ZBTB38, LCORL, HMGA1, CS, and GDF5) previously reported to play a role in height. There was a positive association between PRS₂₅₁ and measured height (p < 0.001). Of the 14 traits and 49 diseases analyzed, we observed significant associations of measured and genetically determined height with only eight traits (p < 0.05/[14 + 49]). Height was positively associated with body weight, waist circumference, and hip circumference but negatively associated with body mass index, waist-hip ratio, body fat, total cholesterol, and low-density lipoprotein cholesterol (p < 0.05/[14 + 49]).

Conclusions: This study contributes to the understanding of the genetic features of height and health-related outcomes in individuals of Han Chinese ancestry in Taiwan.

Keywords: Genetic single nucleotide polymorphisms; Genome-wide association studies; Health-related outcomes; Height; Polygenic risk score.

Fig. 1

Flowchart of the study design and analysis process

Fig. 2

Manhattan plot for height with Han Chinese ancestry

Fig. 3

Regional plots for the independent signals at seven genetic loci for height in individuals with Han Chinese ancestry. A rs3791675 in EGF containing fibulin extracellular matrix protein 1 (EFEMP1). B rs76803230 in DIS3 like 3′-5′ exoribonuclease 2 (DIS3L2). C rs57345461 in zinc finger and BTB domain containing 38 (ZBTB38). D rs16895971 in ligand dependent nuclear receptor corepressor like (LCORL). E rs2780226 in high mobility group AT-hook 1 (HMGA1). F rs3816804 in citrate synthase (CS). G rs143384 in growth differentiation factor 5 (GDF5). Each plot shows the –log10 p-value on the y-axis for each SNP and the SNP position in the genome region on the x-axis. The top significant SNP is shown by a purple diamond; genes in its proximity are shown below each plot. LD with nearby SNPs is measured using R² values, according to the 1000 Genomes Project Phase 3 East Asia Summit data, and is indicated by the color of each circle

Fig. 4

Association between genetically determined height (PRS₂₅₁) and measured height (phenotype). Measured height (cm) and calculated polygenic risk score (PRS) for height in the testing and validation groups were stratified by sex, mean-centered, and normalized to one standard deviation (SD), respectively (males, N = 10,919; females, N = 17,990). The normalized measured height is shown on the y-axis and normalized genetically determined height (PRS₂₅₁) is shown on the x-axis

Fig. 5

Observational (phenotype) and genetic PRS₂₅₁ associations of height with 63 health-related outcomes. Beta value and 95% confidence interval (CI) per standard deviation (SD) increase in height are shown for A anthropometric trait 1 (hip circumference, waist circumference, and body weight), B anthropometric trait 2 (body fat, waist-hip ratio, and body mass index), and C blood pressure, blood lipid level, and blood glucose level (including systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting glucose, and HbA1c). Odds ratio and 95% CI per SD increase in height are shown for D orthopedic or joint disorders (osteoporosis, arthritis, rheumatoid arthritis, osteoarthritis, and gout), E lung and respiratory diseases (asthma and emphysema or chronic bronchitis), F cardiovascular diseases (valvular heart disease, coronary artery disease, heart arrhythmia, cardiomyopathy, congenital heart defect, other type of heart disease, hyperlipidemia, hypertension, and stroke), G diabetes (type 1 diabetes and type 2 diabetes), H mental or emotional disorders (depression, bipolar disorder, postpartum depression, obsessive-compulsive disorder, alcohol addiction or drug abuse, and schizophrenia), I digestive diseases (peptic ulcer disease, gastroesophageal reflux disease, and irritable bowel syndrome), J nervous system disorders (epilepsy, migraine, multiple sclerosis, Parkinson’s disorder, and dementia), K other types of disease (gallstones, kidney stones, kidney failure, and vertigo), L eye diseases (cataract, glaucoma, dry eye syndrome, retinal detachment, floaters, blindness, color blindness, and others), and M female diseases (severe menstrual cramps, uterine fibroids, ovarian cysts, endometriosis, and Uterine/cervical polyps)